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Id Subject Object Predicate Lexical cue
T1 0-44 Sentence denotes The recent outbreaks of human coronaviruses:
T2 45-78 Sentence denotes A medicinal chemistry perspective
T3 79-95 Sentence denotes PILLAIYAR et al.
T4 97-105 Sentence denotes Abstract
T5 106-114 Sentence denotes Abstract
T6 115-167 Sentence denotes Coronaviruses (CoVs) infect both humans and animals.
T7 168-290 Sentence denotes In humans, CoVs can cause respiratory, kidney, heart, brain, and intestinal infections that can range from mild to lethal.
T8 291-521 Sentence denotes Since the start of the 21st century, three β‐coronaviruses have crossed the species barrier to infect humans: severe‐acute respiratory syndrome (SARS)‐CoV‐1, Middle East respiratory syndrome (MERS)‐CoV, and SARS‐CoV‐2 (2019‐nCoV).
T9 522-600 Sentence denotes These viruses are dangerous and can easily be transmitted from human to human.
T10 601-676 Sentence denotes Therefore, the development of anticoronaviral therapies is urgently needed.
T11 677-762 Sentence denotes However, to date, no approved vaccines or drugs against CoV infections are available.
T12 763-988 Sentence denotes In this review, we focus on the medicinal chemistry efforts toward the development of antiviral agents against SARS‐CoV‐1, MERS‐CoV, SARS‐CoV‐2, targeting biochemical events important for viral replication and its life cycle.
T13 989-1220 Sentence denotes These targets include the spike glycoprotein and its host‐receptors for viral entry, proteases that are essential for cleaving polyproteins to produce functional proteins, and RNA‐dependent RNA polymerase for viral RNA replication.
T14 1222-1235 Sentence denotes Abbreviations
T15 1236-1259 Sentence denotes 3CLpro 3C‐like protease
T16 1260-1293 Sentence denotes ACE angiotensin‐converting enzyme
T17 1294-1312 Sentence denotes ACEi ACE‐inhibitor
T18 1313-1336 Sentence denotes ADA adenosine deaminase
T19 1337-1352 Sentence denotes Ang angiotensin
T20 1353-1385 Sentence denotes ARB angiotensin receptor blocker
T21 1386-1426 Sentence denotes ARDS acute respiratory distress syndrome
T22 1427-1444 Sentence denotes CoV coronaviruses
T23 1445-1469 Sentence denotes DPP dipeptidyl peptidase
T24 1470-1518 Sentence denotes ESI‐MS electrospray ionization mass spectrometry
T25 1519-1551 Sentence denotes HKU1 HCoV‐Hong Kong University 1
T26 1552-1569 Sentence denotes HR heptad repeats
T27 1570-1599 Sentence denotes HTS high throughput screening
T28 1600-1651 Sentence denotes ICTV International Committee on Taxonomy of Viruses
T29 1652-1666 Sentence denotes IL interleukin
T30 1667-1681 Sentence denotes kDa kiloDalton
T31 1682-1719 Sentence denotes MERS Middle East respiratory syndrome
T32 1720-1748 Sentence denotes MHV2 mouse hepatitis virus‐2
T33 1749-1767 Sentence denotes Mpro main protease
T34 1768-1801 Sentence denotes NIH National Institutes of Health
T35 1802-1824 Sentence denotes ORF open reading frame
T36 1825-1854 Sentence denotes PCR polymerase chain reaction
T37 1855-1881 Sentence denotes PLpro papain‐like protease
T38 1882-1896 Sentence denotes pp polyprotein
T39 1897-1924 Sentence denotes RBD receptor‐binding domain
T40 1925-1958 Sentence denotes RdRP RNA‐dependent RNA polymerase
T41 1959-1997 Sentence denotes SARS severe‐acute respiratory syndrome
T42 1998-2026 Sentence denotes TACE TNF‐α converting enzyme
T43 2027-2067 Sentence denotes TGEV transmissible gastroenteritis virus
T44 2068-2104 Sentence denotes TMPRSS transmembrane serine protease
T45 2106-2121 Sentence denotes 1 INTRODUCTION
T46 2122-2169 Sentence denotes Coronaviruses (CoVs) infect humans and animals.
T47 2170-2284 Sentence denotes In humans, CoVs cause primarily multiple respiratory and intestinal infections that can range from mild to lethal.
T48 2285-2439 Sentence denotes 1 , 2 , 3 According to the International Committee on Taxonomy of Viruses (ICTV), CoVs constitute the family Coronaviridae under the order Nidovirales.
T49 2440-2610 Sentence denotes Coronaviridae comprise two subfamilies, Torovirinae and Coronavirinae, the latter being further divided into four main genera: α‐, β‐, γ‐, and δ‐coronaviruses (Figure 1).
T50 2611-2843 Sentence denotes 4 The history of human CoVs began in the 1930s, but only in the 1960s, the first human CoVs were identified in patients with mild respiratory infections, which were later named HCoV‐229E and HCoV‐OC43, belonging to α‐coronaviruses.
T51 2844-2994 Sentence denotes 5 , 6 , 7 Since then, virologists have discovered new viruses, studying their infection mechanisms, as well as their replication, and pathogenesis.
T52 2995-3296 Sentence denotes This led to the identification of five novel CoVs belonging to β‐coronaviruses that have crossed the species barrier to infect humans: HCoV‐Hong Kong University 1 (HKU1), HCoV‐NL63, severe‐acute respiratory syndrome (SARS)‐CoV‐1, Middle East respiratory syndrome (MERS)‐CoV, and SARS‐CoV‐2 (COVID‐19).
T53 3297-3431 Sentence denotes Figure 1 Schematic representation of the taxonomy of Coronaviridae (according to the International Committee on Taxonomy of Viruses).
T54 3432-3725 Sentence denotes The seven human‐infecting coronaviruses belong to the α‐ or β‐coronavirus genus (highly infectious pathogens are highlighted red) [Color figure can be viewed at wileyonlinelibrary.com] The three last‐mentioned viruses are extremely dangerous because of their rapid transmission between humans.
T55 3726-3833 Sentence denotes SARS‐CoV‐1, which emerged in 2002, affected 8096 in 32 countries, 774 of whom died (fatality rate 10%–15%).
T56 3834-3968 Sentence denotes 8 MERS‐CoV, which appeared in 2012, affected a total of 1841 individuals, 652 of whom died with the mortality rate of ~35% worldwide.
T57 3969-3970 Sentence denotes 9
T58 3971-4165 Sentence denotes The new coronavirus, known as SARS‐CoV‐2 or 2019‐nCoV has been identified as an etiological agent for the current epidemic with a contagious pneumonia‐like illness, spreading incredibly rapidly.
T59 4166-4309 Sentence denotes As of July 15, 2020, the outbreak of SARS‐CoV‐2 has claimed more than 573 752 lives and infected more than 13 119 239 people around the planet.
T60 4310-4454 Sentence denotes 10 Public life has come to a halt, as many governments impose social distancing strategies and lockdown to prevent further spread of the virus.
T61 4455-4600 Sentence denotes To date, no targeted therapeutics or vaccines are approved, and effective treatment options against any human‐infecting CoVs remain very limited.
T62 4602-4664 Sentence denotes 1.1 Infection cycle of human CoVs and their druggable targets
T63 4665-4743 Sentence denotes Human‐infecting CoVs belonging to the α‐ and β‐CoV genera infect only mammals.
T64 4744-4973 Sentence denotes According to the sequence database, all human CoVs have animal origins; HCoV‐NL63, HCoV‐229E, SARS‐CoV‐1, SARS‐CoV‐2, and MERS‐CoV are suggested to have originated from bats; HCoV‐OC43 and HKU1‐CoV likely originated from rodents.
T65 4974-4982 Sentence denotes 11 , 12
T66 4983-5142 Sentence denotes CoVs are enveloped, single‐stranded, positive‐sense RNA viruses featuring the largest viral RNA genomes known to date, ranging roughly from 26 to 32 kilobases.
T67 5143-5195 Sentence denotes The SARS‐CoV‐2 genome comprises ~30 000 nucleotides.
T68 5196-5338 Sentence denotes 13 For the virus to spread, the information of its structural and functional proteins must be replicated and packed into new virus particles.
T69 5339-5514 Sentence denotes Since the virus lacks the necessary infrastructure for this process, it is entirely dependent on its host organism to translate its RNA into proteins and make more RNA copies.
T70 5515-5625 Sentence denotes To infect its desired host cell, the virus uses its many spike (S) glycoproteins protruding from its membrane.
T71 5626-5757 Sentence denotes 13 In general, the life cycle of CoVs can be classified into four main steps, including entry, replication, assembly, and release.
T72 5758-5820 Sentence denotes The infection cycle of a CoV (Figure 2) begins with its entry.
T73 5821-5905 Sentence denotes Using the S glycoprotein, it attaches itself to a surface receptor of the host cell.
T74 5906-5987 Sentence denotes The host cell receptor and its distribution determine which tissues get infected.
T75 5988-6071 Sentence denotes The specificity of the S protein to a particular receptor influences viral tropism.
T76 6072-6387 Sentence denotes CoVs use different human receptors as points of entry: SARS‐CoV‐1, SARS‐CoV‐2, and HCoV‐NL63 use angiotensin‐converting enzyme 2 (ACE2); 14 , 15 , 16 MERS‐CoV uses dipeptidyl peptidase‐4 (DPP4); 17 CoV‐22E uses aminopeptidase N; 18 and HCoV‐OC43 as well as HCoV‐HKUI use O‐acetylated sialic acid (see Table 1).
T77 6388-6396 Sentence denotes 19 , 20
T78 6397-6465 Sentence denotes Figure 2 Infection cycle of coronaviruses, for example, SARS‐CoV‐2.
T79 6466-6577 Sentence denotes The figure was adapted with permission from Invivogen (https://www.invivogen.com/spotlight-covid-19-infection).
T80 6578-6692 Sentence denotes SARS‐CoV‐2, severe acute respiratory syndrome coronavirus 2 [Color figure can be viewed at wileyonlinelibrary.com]
T81 6693-6798 Sentence denotes Table 1 Classification, discovery, cellular receptor, and natural intermediate host of the coronaviruses
T82 6799-6872 Sentence denotes HCoV genera Coronaviruses Discovery Cellular receptor Natural host(s)
T83 6873-6942 Sentence denotes α‐Coronaviruses HCoV‐229E 1966 Human aminopeptidase N (CD13) Bats
T84 6943-6983 Sentence denotes HCoV‐NL63 2004 ACE2 Palm civets, bats
T85 6984-7052 Sentence denotes β‐Coronaviruses HCoV‐OC43 1967 9‐O‐Acetylated sialic acid Cattle
T86 7053-7102 Sentence denotes HCoV‐HKU1 2005 9‐O‐Acetylated sialic acid Mice
T87 7103-7138 Sentence denotes SARS‐CoV‐1 2003 ACE2 Palm civets
T88 7139-7173 Sentence denotes MERS‐CoV 2012 DPP4 Bats, camels
T89 7174-7207 Sentence denotes SARS‐CoV‐2 2019 ACE2 Bats, (?)
T90 7208-7334 Sentence denotes Note: ? indicate other possible hosts of SARS‐CoV‐2, besides bats ‐ if they exist ‐ have not been conclusively identified yet.
T91 7335-7358 Sentence denotes John Wiley & Sons, Ltd.
T92 7359-7483 Sentence denotes This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response.
T93 7484-7666 Sentence denotes It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.
T94 7667-7798 Sentence denotes When the spike protein attaches to its host cellular receptor, it is cleaved into two parts (S1 and S2) by extracellular proteases.
T95 7799-7927 Sentence denotes While S1 remains attached to its target, S2 is further cleaved by the host cell's own transmembrane serine protease 2 (TMPRSS2).
T96 7928-8012 Sentence denotes This process induces the fusion of the viral membrane with the host cell's membrane.
T97 8013-8015 Sentence denotes 15
T98 8016-8108 Sentence denotes Upon fusion, the contents of the virus particle are released into the host cell's cytoplasm.
T99 8109-8286 Sentence denotes The virus's genomic positive‐sense RNA, which comprises two overlapping open reading frames (ORFs), ORF1a and ORF1b, is quickly translated into two polyproteins, pp1a and pp1ab.
T100 8287-8416 Sentence denotes These proteins are the so‐called replicase‐transcriptase‐complex, because of their role in replication and further transcription.
T101 8417-8640 Sentence denotes The newly formed polyproteins are immediately autocatalytically proteolyzed into smaller proteins by two viral proteases, 3C‐like protease (3CLpro), otherwise known as main protease (Mpro), and papain‐like protease (PLpro).
T102 8641-8649 Sentence denotes 21 , 22
T103 8650-8941 Sentence denotes The cleavage products include 16 nonstructural proteins (nsp) like the RNA‐dependent RNA polymerase (RdRP) that facilitates the production of antisense RNA, as well as 4 structural proteins like the S glycoprotein, envelope (E) proteins, membrane proteins (M), and nucleocapsid (N) proteins.
T104 8942-9199 Sentence denotes 21 , 22 , 23 Newly generated antisense RNA is used as a template for new copies of viral positive‐sense RNA as well as for the production of differently sized subgenomic mRNAs, which can be translated into new viral proteins at the endoplasmic reticulum.
T105 9200-9366 Sentence denotes Finally, proteins and genomic RNA are assembled, packed into vesicles in the Golgi apparatus and exocytosed to the outside to repeat the process in surrounding cells.
T106 9367-9369 Sentence denotes 23
T107 9370-9489 Sentence denotes This process does not pass unnoticed by the host organism, as infected cells present viral structures on their surface.
T108 9490-9668 Sentence denotes As a response, many defensive pathways are initiated, such as the production of different cytokines and chemokines like interleukin 1 (IL‐1), IL‐6, IL‐8, IL‐21, TNF‐β, and MCP‐1.
T109 9669-9782 Sentence denotes The release of these mediators and their effector cells activate inflammatory mechanisms to destroy the intruder.
T110 9783-9785 Sentence denotes 24
T111 9786-9919 Sentence denotes The interruption of any stage of the viral life cycle can become an important therapeutic approach for treating CoV‐related diseases.
T112 9920-10099 Sentence denotes A recent SARS‐CoV‐2‐human protein‐protein interaction analysis showed that SARS‐CoV‐2 contains approximately 66 druggable proteins, each of which has several ligand binding sites.
T113 10100-10215 Sentence denotes 25 The most interesting coronavirus proteins are the S glycoprotein, proteases Mpro and PLpro, RdRP, and helicase.
T114 10216-10368 Sentence denotes In this review, we highlight these targets with potential therapeutic development against the highly dangerous pathogens SARS‐CoV‐1 and 2, and MERS‐CoV.
T115 10369-10483 Sentence denotes Medicinal chemistry efforts toward the evolution of molecules with drug‐like properties is additionally discussed.
T116 10484-10677 Sentence denotes In addition, broad‐spectrum antivirals targeting the major viruses are reviewed in detail, since they represent a highly promising strategy for treating these often fatal respiratory illnesses.
T117 10679-10704 Sentence denotes 2 VIRUS ENTRY INHIBITORS
T118 10705-10882 Sentence denotes Binding of spike protein (S) to its receptor represents the host's first confrontation with the virus and its life cycle, thus providing prophylactic intervention opportunities.
T119 10883-11022 Sentence denotes The genome of SARS‐CoV‐2 has been recently determined to have an 80% identity to that of SARS‐CoV‐1 and 96% identity to the bat‐CoV RaTG13.
T120 11023-11143 Sentence denotes 26 The SARS‐CoV‐2 S protein shows nucleotide sequence identities of 75% or less to all other previously described CoVs.
T121 11144-11240 Sentence denotes However, again, the new SARS‐CoV‐2 S protein shares a 93.1% identity to the S protein of RaTG13.
T122 11241-11520 Sentence denotes SARS‐CoV‐2 spike (S) recognizes, with its receptor‐binding domain (RBD), the cellular ACE2 receptor with high affinity (K d, 14.7 nM) 27 as judged by surface plasmin resonance spectrometry; and intervention at the RBD‐ACE2 interface can potentially disrupt infection efficiency.
T123 11521-11633 Sentence denotes It was observed that the RBDs of the SARS‐CoV‐2‐ACE2 and SARS‐CoV‐1‐ACE2 complexes are quite similar (Figure 3).
T124 11634-11636 Sentence denotes 29
T125 11637-11809 Sentence denotes Figure 3 Comparison of the SARS‐CoV‐2 S and SARS‐CoV‐1 S structures: ribbon diagrams of the (A) SARS‐CoV‐2 S and (D) SARS‐CoV‐1 S [PDB 6NB6] ectodomain cryo‐EM structures.
T126 11810-11863 Sentence denotes S1 subunits of (B) SARS‐CoV‐2 S and (E) SARS‐CoV‐1 S.
T127 11864-11917 Sentence denotes S2 subunits of (C) SARS‐CoV‐2 S and (F) SARS‐CoV‐1 S.
T128 11918-12114 Sentence denotes 28 cryo‐EM, cryogenic electron microscopy; SARS‐CoV‐2, severe acute respiratory syndrome coronavirus 2 [Color figure can be viewed at wileyonlinelibrary.com] As mentioned previously, Zhang et al.
T129 12115-12281 Sentence denotes 30 determined the full‐length genome sequence of SARS‐CoV‐2 and revealed that the virus is remarkably similar (89.1% sequence identity) to a group of SARS‐like CoVs.
T130 12282-12308 Sentence denotes Simultaneously, Shi et al.
T131 12309-12498 Sentence denotes 26 reported that SARS‐CoV‐2 shares 96% sequence identity at a whole‐genome level with a bat coronavirus—and importantly, like SARS‐CoV‐1, SARS‐CoV‐2 utilizes ACE2 receptor for viral entry.
T132 12499-12690 Sentence denotes Recently, Yan et al. solved the cryo‐EM structure of full‐length human ACE2 bound to the RBD of SARS‐CoV‐2, providing important structural information for therapeutic intervention strategies.
T133 12691-12693 Sentence denotes 29
T134 12694-12798 Sentence denotes The sequence identity of the spike protein between SARS‐CoV‐1 (1273 aa) and SARS‐CoV‐2 (1253 aa) is 76%.
T135 12799-12844 Sentence denotes The spike protein has two regions, S1 and S2.
T136 12845-12935 Sentence denotes The S1 region of the SARS‐CoV‐1 has a RBD that forms high‐affinity interactions with ACE2.
T137 12936-13038 Sentence denotes The prevailing understanding is that SARS‐CoV‐2 employs this RBD to enter its human host cell as well.
T138 13039-13109 Sentence denotes Aligning the two different RBDs revealed a sequence identity of 73.5%.
T139 13110-13222 Sentence denotes However, many nonconserved mutations that interact directly with ACE2 are located in the two structural regions.
T140 13223-13414 Sentence denotes 31 And both crystal and cryo‐EM structures of the SARS‐CoV‐1 spike‐ACE2 complex have shown that merely residues of regions 1 and 2 form hydrogen bonds and hydrophobic interactions with ACE2.
T141 13415-13528 Sentence denotes The mutations in these two regions of SARS‐CoV‐2 will, therefore, likely reduce the number of those interactions.
T142 13529-13531 Sentence denotes 32
T143 13532-13639 Sentence denotes Studies also have shown that the RdRP, and the Mpro are highly conserved between SARS‐CoV‐2 and SARS‐CoV‐1.
T144 13640-13774 Sentence denotes 33 , 34 Therefore, it is widely accepted that SARS‐CoV‐2 behaves similarly to SARS‐CoV‐1 with regard to viral entry and replication.
T145 13775-13951 Sentence denotes Since the general genomic layout and replication kinetics are so conserved among MERS, SARS‐1, and SARS‐2 CoVs, investigating inhibitors of common structures is a logical step.
T146 13952-14134 Sentence denotes The inhibitory strength against viral enzyme was expressed as IC50, which is the concentration of the inhibitor needed to inhibit half of the enzyme activity in the tested condition.
T147 14135-14204 Sentence denotes The K i value is reflective of ligand‐binding affinity to the enzyme.
T148 14205-14367 Sentence denotes The inhibitory activity for cell‐based bioassays is expressed as EC50, which is a half maximal effective concentration required to induce the biological response.
T149 14368-14536 Sentence denotes The warhead group means a “reactive group” of the inhibitors that can form both covalent and noncovalent interactions with amino acids in the active site of the enzyme.
T150 14538-14560 Sentence denotes 2.1 Targeting the RBD
T151 14561-14673 Sentence denotes Structural investigations of the RBD‐ACE2 complex provided information about essential residues for viral entry.
T152 14674-14687 Sentence denotes Hsiang et al.
T153 14688-14827 Sentence denotes 35 reported a number of peptides that significantly blocked the interaction of the S protein with ACE2 with IC50 values as low as 1.88 nM.
T154 14828-14929 Sentence denotes Michael et al. found charged residues between positions 22 and 57 crucial for SARS‐CoV‐1 viral entry.
T155 14930-15063 Sentence denotes Based on this, they designed peptides P4 (IC50, 50 µM) and P5 (IC50, 6.0 µM) with significant inhibitory activity against SARS‐CoV‐1.
T156 15064-15332 Sentence denotes The antiviral activity was further improved when they introduced the glycine binding linkage of peptide P4 (residues 22–47) with an ACE2‐derived peptide (residues 351–357) against a SARS‐CoV‐1 pseudovirus with an IC50 of 100 nM and devoid of cytotoxicity up to 200 µM.
T157 15333-15420 Sentence denotes 36 It is worth highlighting that a similar strategy could work for the new SARS‐CoV‐2.
T158 15421-15558 Sentence denotes The recently solved cryo‐EM structure of SARS‐CoV‐2 in complex with human ACE2 can provide a structural rationale for the peptide design.
T159 15559-15561 Sentence denotes 29
T160 15562-15735 Sentence denotes For viral entry, MERS‐CoV uses its spike protein (S) to interact with the host‐receptor DPP4, 37 , 38 , 39 also known as adenosine deaminase‐complexing protein‐2 or CD26.
T161 15736-15811 Sentence denotes 37 MERS‐CoV was also the first virus reported to use this particular path.
T162 15812-15960 Sentence denotes 35 , 37 DPP4 is a type II transmembrane glycoprotein, that forms homodimers on the cell surface, and it is involved in the cleavage of dipeptides.
T163 15961-16076 Sentence denotes 37 , 40 In humans, DPP4 is predominantly found on the bronchial epithelial and alveolar cells in the lower lungs.
T164 16077-16085 Sentence denotes 40 , 41
T165 16086-16236 Sentence denotes MERS‐4 and MERS‐27 are monoclonal antibodies targeting the RBD of MERS‐CoV S that were discovered in a nonimmune yeast‐display scFv library screening.
T166 16237-16368 Sentence denotes The more active MERS‐4 potently blocked the infection of DPP4‐expressing Huh‐7 cells with pseudotyped MERS‐CoV (IC50, 0.056 μg/mL).
T167 16369-16476 Sentence denotes It also prevented MERS‐CoV‐induced cytopathogenic effects in MERS‐infected Vero E6 cells (IC50, 0.5 μg/mL).
T168 16477-16479 Sentence denotes 42
T169 16480-16556 Sentence denotes A heptad repeat (HR) is a repeating structural pattern of seven amino acids.
T170 16557-16687 Sentence denotes A crucial membrane fusion framework of SARS‐CoV is the 6‐helix‐bundle (6‐HB) that is formed by HR1 and HR2 of the viral S protein.
T171 16688-16773 Sentence denotes Enfuvirtide (T‐20) is an FDA approved HR2 peptide and the first HIV fusion inhibitor.
T172 16774-16872 Sentence denotes It has opened up new avenues toward identifying and developing peptides as viral entry inhibitors.
T173 16873-17143 Sentence denotes Such molecules represent a promising strategy against enveloped viruses with class 1 fusion proteins such as Nipah virus, Hendra virus, Ebola virus, and other paramyxoviruses, simian immunodeficiency virus, feline immunodeficiency virus, and respiratory syncytial virus.
T174 17144-17343 Sentence denotes 43 , 44 , 45 , 46 The HR regions of SARS‐CoV‐1 and SARS‐CoV‐2 S protein share a high degree of conservation, and such fusion inhibitors have potential applications in preventing SARS‐CoV‐2 entry.
T175 17344-17427 Sentence denotes Small molecule entry inhibitors, on the other hand, are reported to target the RBD.
T176 17428-17604 Sentence denotes Compared to peptides, proteins, and biologics, small molecules have several advantages due to lower production costs, improved pharmacokinetics, stability, and dosage accuracy.
T177 17605-17792 Sentence denotes Sarafianos et al. identified the oxazole‐carboxamide derivative SSAA09E2 (1; Figure 4) as an entry inhibitor against SARS‐CoV‐1 by screening a chemical library composed of 3000 compounds.
T178 17793-18010 Sentence denotes 47 This inhibitor directly blocks ACE2 recognition by interfering with the RBD with an EC50 value of 3.1 µM and a 50% cytotoxic concentration (CC50) value of greater than 100 µM, not affecting ACE2 expression levels.
T179 18011-18013 Sentence denotes 48
T180 18014-18082 Sentence denotes Figure 4 Inhibitors targeting the receptor‐binding domain Xu et al.
T181 18083-18262 Sentence denotes 49 identified two small molecules, TGG (2; Figure 4) and luteolin (3; Figure 4), that can bind avidly to the SARS‐CoV‐1 S2 protein and inhibit its entry into Vero E6 cells (EC50:
T182 18263-18294 Sentence denotes 4.5 µM, 10.6 µM; respectively).
T183 18295-18446 Sentence denotes Compounds 2 and 3 showed cytotoxicity (CC50) of 1.08 and 0.155 mM, and the selectivity index (SI) values of 2 and 3 were 240.0 and 14.62, respectively.
T184 18447-18572 Sentence denotes Further studies regarding acute toxicity revealed that the 50% lethal doses of 2 and 3 were ~456 and 232 mg/kg, respectively.
T185 18573-18679 Sentence denotes These results indicate that these small molecules could be used at relatively high concentrations in mice.
T186 18680-18834 Sentence denotes 49 Quercetin (4; Figure 4), an analog of 3, also showed antiviral activity against SARS‐CoV‐1, with an EC50 value of 83.4 µM and a CC50 value of 3.32 mM.
T187 18835-18837 Sentence denotes 50
T188 18838-18952 Sentence denotes Ngai et al. reported ADS‐J1 (5; Figure 4) as a potential SARS‐CoV‐1 viral entry inhibitor with an EC50 of 3.89 µM.
T189 18953-19092 Sentence denotes Molecular docking studies predicted that 5 can bind into a deep pocket of the SARS‐CoV‐1 S HR region and block viral entry into host cells.
T190 19093-19294 Sentence denotes 51 Imatinib (6; Figure 4), an Abelson kinase inhibitor, could inhibit CoV S protein‐induced fusion with an EC50 value of 10 µM and showed no cytotoxic effects in Vero cells up to 100 µM concentration.
T191 19295-19303 Sentence denotes 52 , 53
T192 19305-19352 Sentence denotes 2.2 Inhibitors targeting the cellular receptor
T193 19353-19471 Sentence denotes The genetic code of SARS‐CoV‐2 shares noticeable similarities with SARS‐CoV‐1, which caused the SARS epidemic in 2002.
T194 19472-19552 Sentence denotes 26 , 54 More importantly, both viruses have identical mechanisms of infection.
T195 19553-19735 Sentence denotes SARS‐CoV‐1 uses the host's ACE2 as a portal to infect cells, which has high expression in the vascular endothelium 55 and the lung, particularly in type 2 alveolar epithelial cells.
T196 19736-19803 Sentence denotes 56 SARS‐CoV‐2 shares 76% of its spike (S) protein with SARS‐CoV‐1.
T197 19804-20038 Sentence denotes Despite a few amino acid differences in its RBD compared to the SARS‐CoV‐1 S protein, the SARS‐CoV‐2 S protein binds to ACE2 with even greater affinity 27 offering an explanation for its greater virulence and preference for the lung.
T198 20039-20207 Sentence denotes ACE, a highly glycosylated type I integral membrane protein, is an essential component of the renin‐angiotensin (Ang) system, which controls blood pressure homeostasis.
T199 20208-20247 Sentence denotes Both ACE1 and ACE2 cleave Ang peptides.
T200 20248-20395 Sentence denotes However, they differ markedly: ACE1 cuts and converts the inactive decapeptide Ang I into the octapeptide Ang II by removing the dipeptide His‐Leu.
T201 20396-20649 Sentence denotes This Ang II induces vaso‐ and bronchoconstriction, increased vascular permeability, inflammation, and fibrosis, thus promoting acute respiratory distress syndrome (ARDS) and lung failure in patients infected with SARS‐CoV‐1 or SARS‐CoV‐2 57 (Figure 5).
T202 20650-20781 Sentence denotes Therefore, ACE‐inhibitors (ACEis) and angiotensin II receptor blockers (ARBs) could block the disease‐propagating effect of Ang II.
T203 20782-20796 Sentence denotes 58 , 59 , 60
T204 20797-20863 Sentence denotes Figure 5 The roles of ACE1 and 2 in the renin‐angiotensin system.
T205 20864-20995 Sentence denotes A, Chemical structures of angiotensin‐related peptides and B, Schematic diagram of roles of ACE1 and 2 in renin‐angiotensin system.
T206 20996-21206 Sentence denotes ACE, angiotensin‐converting enzyme [Color figure can be viewed at wileyonlinelibrary.com] ACE2, on the other hand, is a zinc‐containing metalloenzyme, and shares merely 42% of its amino acid sequence with ACE1.
T207 21207-21362 Sentence denotes 61 It cleaves only one amino acid residue (Leu or Phe) from Ang I and Ang II, respectively, generating Ang (1–9) and Ang (1–7) (a vasodilator) (Figure 5).
T208 21363-21453 Sentence denotes Thus, ACE2 has been considered a potential therapeutic target for cardiovascular diseases.
T209 21454-21720 Sentence denotes Virtual screening combined with a molecular docking approach targeting the ACE2 catalytic site with around 140 000 compounds led to the identification of inhibitor N‐(2‐aminoethyl)‐1 aziridine‐ethanamine (7; Figure 6) with an IC50 value of 57 µM and a K i of 459 µM.
T210 21721-21805 Sentence denotes However, no information about the cytotoxicity of this compound is available so far.
T211 21806-21808 Sentence denotes 62
T212 21809-21866 Sentence denotes Figure 6 Inhibitors for SARS‐CoV‐1 and 2 targeting ACE2.
T213 21867-22082 Sentence denotes ACE, angiotensin‐converting enzyme; SARS‐CoV, severe acute respiratory syndrome coronavirus Chloroquine (8; Figure 6) is a relatively safe, cheap, and effective medication for the treatment of malaria and amebiasis.
T214 22083-22098 Sentence denotes Savarino et al.
T215 22099-22134 Sentence denotes 63 reported its antiviral effects.
T216 22135-22275 Sentence denotes At a molecular level, it increases late endosomal and lysosomal pH, resulting in impaired liberation of virions from endosomes or lysosomes.
T217 22276-22366 Sentence denotes The virus is therefore unable to release its genetic material into the cell and replicate.
T218 22367-22557 Sentence denotes 64 , 65 Furthermore, they hypothesize that chloroquine might block the production of proinflammatory cytokines (such as IL‐6), thereby blocking the pathway that subsequently leads to ARDS.
T219 22558-22560 Sentence denotes 63
T220 22561-22648 Sentence denotes Chloroquine is reasonably active in vitro against SARS‐CoV‐1, MERS‐CoV, and SARS‐CoV‐2.
T221 22649-22723 Sentence denotes It was found to inhibit SARS‐CoV‐2 with an EC50 value of 5.47 µM in vitro.
T222 22724-22913 Sentence denotes 66 Antiviral activity against SARS‐CoV‐1 was reported with an IC50 of 8.8 μM in Vero cells, but it is unclear how this translates into activity in respiratory epithelial cells and in vivo.
T223 22914-23172 Sentence denotes 67 , 68 Mechanistic studies of chloroquine for SARS‐CoV‐1 infection revealed that it could also weaken the interaction between the RBD of SARS‐CoV‐1 and ACE2 by interfering with terminal glycosylation of ACE2, thereby reducing its affinity to SARS‐CoV‐1 S.
T224 23173-23175 Sentence denotes 69
T225 23176-23422 Sentence denotes During the SARS‐CoV‐2 pandemic, chloroquine has been recommended by Chinese, South Korean, and Italian health authorities for the experimental treatment of COVID‐19, 70 , 71 despite contraindications for patients with heart disease or diabetes.
T226 23423-23639 Sentence denotes 72 However, health experts and agencies like the US FDA and European Medicines Agency warned against broad uncontrolled use after reports of misuse of low‐quality versions of chloroquine phosphate intended for fish.
T227 23640-23732 Sentence denotes Hydroxychloroquine (9; Figure 6) is being studied as an experimental treatment for COVID‐19.
T228 23733-23799 Sentence denotes 73 However, the benefits of treatment with this drug are unclear.
T229 23800-23802 Sentence denotes 74
T230 23803-23893 Sentence denotes Hydroxychloroquine was found to inhibit SARS‐CoV‐2 with an EC50 value of 0.74 µM in vitro.
T231 23894-23976 Sentence denotes 66 Some studies imply synergistic effects of hydroxychloroquine and azithromycin.
T232 23977-24186 Sentence denotes Azithromycin is active in vitro against Zika and Ebola virus 75 , 76 and can be used to guard against life‐threatening bacterial superinfections when administered to patients suffering from viral infections.
T233 24187-24343 Sentence denotes 77 A small study that compared hydroxychloroquine monotherapy and combination treatment with azithromycin found a significant advantage of the combination.
T234 24344-24741 Sentence denotes While evaluating the efficacy of therapeutic intervention with hydroxychloroquine as monotherapy and its impact in combination with azithromycin, the number of patients testing negative in polymerase chain reaction (PCR) tests was substantially different in the two groups with 100% of patients cured (6 days post inclusion) in the combination arm of the study versus 57% in the monotherapy group.
T235 24742-24837 Sentence denotes At the same time, 12% of patients in the control group receiving only standard care were cured.
T236 24838-24846 Sentence denotes 78 , 79
T237 24847-25039 Sentence denotes The WHO declared on 18 March that chloroquine and its derivative hydroxychloroquine will be among the four medicines studied in the solidarity clinical trial 80 for the treatment of COVID‐19.
T238 25040-25166 Sentence denotes In April 2020, the US National Institutes of Health (NIH) also commenced a study with the drug for treating COVID‐19 patients.
T239 25167-25169 Sentence denotes 81
T240 25170-25416 Sentence denotes The recent clinical trial involving 96 032 patients with COVID‐19 concluded that it was unable to confirm a benefit of hydroxychloroquine or chloroquine, when used alone or in combination with a macrolide such as azithromycin (or clarithromycin).
T241 25417-25528 Sentence denotes 82 The study actually reported decreased survival rates for patients treated with each of these drug regimens.
T242 25529-25627 Sentence denotes Additionally, patients had an increased risk of developing ventricular arrhythmia under treatment.
T243 25628-25914 Sentence denotes However, still more evidence is needed to adequately assess the drugs' risks or benefits for the treatment or prevention of COVID‐19 (it is important to note that chloroquine and hydroxychloroquine are still considered safe treatment options in certain autoimmune diseases and malaria).
T244 25915-26048 Sentence denotes Besides, the WHO announced the premature pause of its clinical trials using hydroxychloroquine as a safety precaution on 24 May 2020.
T245 26049-26178 Sentence denotes On a different note, it was found that ACE2 undergoes proteolytic shedding; releasing an enzymatic ectodomain during viral entry.
T246 26179-26314 Sentence denotes 83 A disintegrin and metalloproteinase (ADAM), also known as TNF‐α converting enzyme (TACE), assisted the shedding regulation of ACE2.
T247 26315-26373 Sentence denotes Inhibition of this enzyme led to reduced shedding of ACE2.
T248 26374-26477 Sentence denotes GW280264X (10; Figure 6) was found to be a specific inhibitor of ADAM‐induced shedding of ACE2 at 1 nM.
T249 26478-26614 Sentence denotes 84 Two TACE inhibitors, TAPI‐0 (11) and TAPI‐2 (12; Figure 6), reduced ACE2 shedding, with IC50 values of 100 and 200 nM, respectively.
T250 26615-26617 Sentence denotes 83
T251 26618-26713 Sentence denotes MLN‐4760 (13; Figure 6) inhibited the catalytic activity of ACE2 with an IC50 of around 440 pM.
T252 26714-26897 Sentence denotes 85 This is the most potent and selective small‐molecule inhibitor against soluble human ACE2 described to date, thus making it a very promising candidate for SARS‐CoV‐2 interference.
T253 26898-26973 Sentence denotes It binds to the active site zinc and emulates the transition state peptide.
T254 26974-27045 Sentence denotes However, no antiviral data for this compound is available at this time.
T255 27046-27205 Sentence denotes The interference of a virus‐host cell fusion, which is mediated by the viral S protein to its receptor ACE2 on host cells, may be a viable prevention strategy.
T256 27206-27357 Sentence denotes Umifenovir (14; brand name Arbidol), a broad spectrum antiviral drug used against influenza, prevents viral entry by inhibiting virus‐host cell fusion.
T257 27358-27449 Sentence denotes 86 It is currently being investigated in a clinical trial for the treatment of SARS‐CoV‐2.
T258 27450-27458 Sentence denotes 87 , 88
T259 27459-27555 Sentence denotes Do ACEis or ARBs amplify SARS‐CoV‐2 pathogenicity and aggravate the clinical course of COVID‐19?
T260 27556-27725 Sentence denotes After ACE2 was recognized as the SARS‐CoV‐2 receptor, 14 , 29 speculations emerged about potentially negative consequences of ACEi or ARB therapy in COVID‐19 patients.
T261 27726-27813 Sentence denotes This theory caused confusion in the public and alarmed patients taking these medicines.
T262 27814-27935 Sentence denotes One report said that the expression of ACE2 was increased in patients with heart disease compared to healthy individuals.
T263 27936-28097 Sentence denotes It was also insisted that ACE2 expression could be increased by taking ACEis and ARBs, 89 although there is no supporting report of this happening in the lungs.
T264 28098-28307 Sentence denotes In another report, it was suggested that patients suffering from high blood pressure receiving “ACE2‐increasing drugs” have a higher risk for severe COVID‐19, since ACEis and ARBs could elevate levels of ACE2.
T265 28308-28310 Sentence denotes 90
T266 28311-28539 Sentence denotes A joint declaration by the presidents of the HFSA/ACC/AHA on 17 March 2020, 91 followed by a similar statement of the European Medicines Agency, 92 clarified that there was no scientific basis for stopping ACEi or ARB therapy.
T267 28540-28635 Sentence denotes 93 , 94 , 95 This was in accordance with the editors of the New England Journal of Medicine.
T268 28636-28638 Sentence denotes 96
T269 28639-28809 Sentence denotes In case of SARS‐CoV, the experimental data showed that such medications may be beneficial rather than damaging, which led to a new therapeutic approach for lung diseases.
T270 28810-28812 Sentence denotes 97
T271 28814-28852 Sentence denotes 2.3 Proteolytic processing inhibitors
T272 28853-29009 Sentence denotes CoVs enter the host cells via both clathrin (endosomal) and nonclathrin pathways (nonendosomal); however, both pathways are dependent upon receptor binding.
T273 29010-29018 Sentence denotes 98 , 99
T274 29019-29184 Sentence denotes The clathrin‐mediated pathway involves the binding of CoV S protein to the host receptor followed by the internalization of vesicles that maturate to late endosomes.
T275 29185-29392 Sentence denotes Acidification of the endosome promotes the H+‐dependent activation of cellular cathepsin L proteinase in late endosomes and lysosomes, which cleaves and activates the S protein, thus initiating viral fusion.
T276 29393-29524 Sentence denotes Recent research shows that in addition to ACE2 SARS‐CoV‐2 can also use the host cell receptor CD147 to gain access into host cells.
T277 29525-29528 Sentence denotes 100
T278 29529-29819 Sentence denotes Membrane fusion is also the crucial step for the CoV life cycle in the nonclathrin/endosomal route, in which host proteases such as cathepsin L, TMPRSS2, and TMPRSS11D (airway trypsin‐like protease) cut the S protein at the S1/S2 cleavage site to activate the S protein for membrane fusion.
T279 29820-29950 Sentence denotes 101 Interference with this process by targeting these proteases could become an attractive strategy for combating CoV infections.
T280 29951-30056 Sentence denotes A recent study confirms the role of TMPRSS2 for the viral life cycle in SARS‐CoV‐2‐infected VeroE6 cells.
T281 30057-30168 Sentence denotes 5 Furin (a serine endoprotease) activates MERS‐CoV to initiate the nonclathrin mediated membrane fusion event.
T282 30169-30172 Sentence denotes 102
T283 30173-30385 Sentence denotes The neurotransmitter receptor blockers chlorpromazine (15), promethazine (16), and fluphenazine (17; Figure 7), were reported to inhibit MERS‐CoV and SARS‐CoV‐1 most probably by impeding S protein‐induced fusion.
T284 30386-30589 Sentence denotes 103 Chlorpromazine, a clathrin‐mediated viral entry inhibitor, was already described to inhibit human CoV‐229E, hepatitis C virus, infectious bronchitis virus, as well as mouse hepatitis virus‐2 (MHV2).
T285 30590-30621 Sentence denotes 104 , 105 , 106 , 107 , 108
T286 30622-30870 Sentence denotes Figure 7 Neurotransmitter inhibitors targeting clathrin/nonclathrin pathways Matsuyama et al. identified the commercially available serine protease inhibitor camostat (18; Figure 8) to be a SARS‐CoV‐1 inhibitor, blocking TMPRSS2 activity at 10 µM.
T287 30871-31115 Sentence denotes However, at a higher concentration (100 µM), inhibition of viral entry via SARS‐CoV‐1 S protein‐mediated cell fusion never exceeded 65% (inhibition efficiency), indicating that 35% of entry events take place via the endosomal cathepsin pathway.
T288 31116-31278 Sentence denotes Interestingly, treatment with a combination of EST (a cathepsin inhibitor) and 18 resulted in remarkably blocked infection (>95%) activity of pseudotyped viruses.
T289 31279-31282 Sentence denotes 109
T290 31283-31322 Sentence denotes Figure 8 Inhibitors targeting TMPRSS2.
T291 31323-31439 Sentence denotes TMPRSS, transmembrane serine protease A similar approach has been investigated to prevent viral entry of SARS‐CoV‐2.
T292 31440-31574 Sentence denotes Pöhlmann et al. reported the attainment of full inhibition efficiency with a combination of both 18 and E‐64d (a cathepsin inhibitor).
T293 31575-31718 Sentence denotes Both studies indicate that SARS‐CoV‐1 and 2 enter cells in a similar manner showing the potential of 18 as a candidate for further development.
T294 31719-31721 Sentence denotes 15
T295 31722-31888 Sentence denotes Recently, K11777 (19; Figure 8), a cysteine protease inhibitor, was shown in tissue cultures to inhibit SARS‐CoV‐1 and MERS‐CoV replication in the subnanomolar range.
T296 31889-32044 Sentence denotes 110 , 111 Future tissue culture and animal model studies should be conducted to clarify, whether its antiviral activity is mediated by targeting TMPRSS2.
T297 32045-32216 Sentence denotes Teicoplanin is a glycopeptide antibiotic used to prevent infections with Gram‐positive bacteria like methicillin‐resistant Staphylococcus aureus and Enterococcus faecalis.
T298 32217-32345 Sentence denotes It was found that teicoplanin inhibits the entry of SARS‐CoV‐1, MERS‐CoV, and Ebola virus by specifically targeting cathepsin L.
T299 32346-32466 Sentence denotes 112 This knowledge has also been used to block the entry of new SARS‐CoV‐2 pseudoviruses with an IC50 value of 1.66 µM.
T300 32467-32562 Sentence denotes Therefore, teicoplanin could be considered a potential candidate for the treatment of COVID‐19.
T301 32563-32566 Sentence denotes 113
T302 32568-32614 Sentence denotes 2.4 Small‐molecules as cathepsin L inhibitors
T303 32615-32790 Sentence denotes Human cathepsin L is a cysteine endopeptidase and plays a key role for infection efficiency by activation of the S protein into a fusogenic state to escape the late endosomes.
T304 32791-32942 Sentence denotes Targeting this protease with small molecules could interfere with virus‐cell entry and therefore be a possible intervention strategy for CoV infection.
T305 32943-33157 Sentence denotes 114 Bates et al. identified MDL28170 (20; Figure 9) as an antiviral compound that specifically inhibited cathepsin‐L‐mediated substrate cleavage, with an IC50 value of 2.5 nM and EC50 value in the range of 100 nM.
T306 33158-33258 Sentence denotes However, despite its potent inhibitory activity, no cytotoxicity data for 20 is currently available.
T307 33259-33262 Sentence denotes 115
T308 33263-33466 Sentence denotes Figure 9 Cathepsin L inhibitors with antiviral activity Diamond et al. reported CID 16725315 (21) and CID 23631927 (22; Figure 9) as viral entry inhibitors of SARS‐CoV in a cathepsin L inhibition assay.
T309 33467-33587 Sentence denotes Compound 21 could block cathepsin L with an IC50 value of 6.9 nM, while 22 showed slightly weaker potency (IC50, 56 nM).
T310 33588-33700 Sentence denotes Compound 22 was also found to inhibit Ebola virus infection (EC50, 193 nM) of human embryonic kidney 293T cells.
T311 33701-33796 Sentence denotes This compound did not show any sign of toxicity to human aortic endothelial cells up to 100 µM.
T312 33797-33889 Sentence denotes This data offers a new promising point for the treatment of SARS and Ebola virus infections.
T313 33890-33893 Sentence denotes 116
T314 33894-34075 Sentence denotes Screening of ~14 000 compounds in a cell‐based assay resulted in the identification of SSAA09E1 (23; Figure 9) as inhibitor of cathepsin L proteinase, with an IC50 value of 5.33 µM.
T315 34076-34205 Sentence denotes In a pseudotype‐based assay in 293T cells, the EC50 value of 23 was around 6.4 µM, and no cytotoxicity was detected below 100 µM.
T316 34206-34208 Sentence denotes 48
T317 34209-34301 Sentence denotes Phenotypic screening approaches led to the identification of several viral entry inhibitors.
T318 34302-34429 Sentence denotes This approach has the advantage of finding cellular‐active compounds, providing information on drug solubility and cell uptake.
T319 34430-34534 Sentence denotes 117 On the other hand, it is limited in terms of capacity compared to in silico target‐based screening.
T320 34535-34826 Sentence denotes Hsiang et al. identified emodin (24; Figure 9), the active component from Polygonum multiflorum and Rheum officinale, could block the interaction of S protein with ACE2, with an IC50 value of 10 µM and an EC50 value of 200 µM in an S protein‐pseudotyped retrovirus assay using Vero E6 cells.
T321 34827-34906 Sentence denotes However, the mechanism of action of this compound still needs to be determined.
T322 34907-34929 Sentence denotes 118 Sarafianos et al.
T323 34930-35181 Sentence denotes 48 found that SSAA09E3 (25), a benzamide derivative of 24, could prevent virus‐cell membrane fusion in pseudotype‐based and antiviral‐based assays, with an EC50 value of 9.7 µM, but a CC50 value of 20 µM indicates additional unknown cellular targets.
T324 35182-35344 Sentence denotes VE607 (26) was identified among 50 240 structurally diverse small molecules to specifically inhibit SARS‐CoV‐1 entry into cells using a phenotype‐based screening.
T325 35345-35451 Sentence denotes Its EC50 value was reported at 3.0 µM and it inhibited SARS‐CoV‐1 plaque formation with an EC50 of 1.6 µM.
T326 35452-35539 Sentence denotes 119 Cathepsin inhibitor E‐64‐D (27) blocked MERS‐CoV and SARS‐CoV‐1 infection as well.
T327 35540-35550 Sentence denotes 120 , 121
T328 35552-35582 Sentence denotes 3 PROTEASES AS A DRUG TARGETS
T329 35583-35718 Sentence denotes Papain‐like protease (PLpro), and, predominantly, Mpro are required for the proteolytic cleavage of polyproteins produced by the virus.
T330 35719-35805 Sentence denotes Together they produce 16 nsp that are involved in viral replication and transcription.
T331 35806-35994 Sentence denotes 122 PLpro is responsible for cleavage at the first three positions of its polyprotein to produce three nsp, while Mpro cleaves at no less than 11 conserved sites, releasing nsp4 to nsp16.
T332 35995-36130 Sentence denotes Mpro‐mediated cleavage generates functional proteins like RdRP, RNA binding proteins, exoribonuclease, helicase, and methyltransferase.
T333 36131-36270 Sentence denotes 123 The indispensable role of Mpro for the viral life cycle and infection process makes Mpro an ideal target for anti‐coronaviral therapy.
T334 36272-36292 Sentence denotes 3.1 Mpro inhibitors
T335 36294-36335 Sentence denotes 3.1.1 Structure and function of CoV Mpro
T336 36336-36376 Sentence denotes Mpro is a homodimeric cysteine protease.
T337 36377-36423 Sentence denotes The SARS‐CoV‐1 Mpro consists of three domains:
T338 36424-36602 Sentence denotes I (residues 8–101), and II (residues 102–184), which are β‐barrel domains that shape the chymotrypsin‐like structure, while domain III (residues 201–306) is made up by α‐helices.
T339 36603-36777 Sentence denotes 124 The CoV Mpro active site uses a catalytic dyad (Cys145‐His41), in which cysteine acts as the nucleophile in the proteolysis while histidine behaves as general acid‐base.
T340 36778-36855 Sentence denotes The peptide substrate or inhibitor binds in a cleft between domains I and II.
T341 36856-36859 Sentence denotes 125
T342 36860-37008 Sentence denotes As far as the development of new therapeutics against SARS‐ and MERS‐CoV infection is concerned, efforts have mainly focused on protease inhibitors.
T343 37009-37101 Sentence denotes These enzymes are highly attractive drug targets because they are so essential to the virus.
T344 37102-37241 Sentence denotes Peptides, peptidomimetics, and even small molecules can inhibit them, which leads to markedly reduced viral transmission and pathogenicity.
T345 37242-37433 Sentence denotes Although most of the reported molecules display only weak anti‐CoV activity, several of studies elucidated structure–activity relationships that can be used to further improve their activity.
T346 37434-37458 Sentence denotes 100 , 126 , 127 , 128
T347 37460-37500 Sentence denotes 3.1.2 Substrate‐derived Mpro inhibitors
T348 37501-37591 Sentence denotes To date, no approved drugs or vaccines are available for treating a coronavirus infection.
T349 37592-37777 Sentence denotes In a race to identify chemotherapeutic options, various approaches, such as chemical synthesis, testing of natural products, and virtual screening of compound libraries, have been used.
T350 37778-37874 Sentence denotes The systematic design of inhibitors of CoV Mpro was essentially based on the enzyme's substrate.
T351 37875-38068 Sentence denotes In general, a substrate can be transformed into a good inhibitor by modifying part of its sequence such that it binds to the catalytic cysteine in either a reversible or an irreversible manner.
T352 38069-38206 Sentence denotes Peptide inhibitors are designed by attaching a reactive group (also known as warhead group) to peptides that mimic the natural substrate.
T353 38207-38352 Sentence denotes The partial peptide substrate sequence for SARS‐CoV‐1 Mpro is mentioned in Figure 10, indicating the specific subsite of each amino acid residue.
T354 38353-38410 Sentence denotes Figure 10 A, SARS‐CoV‐1 Mpro partial substrate sequence.
T355 38411-38463 Sentence denotes B, (Overlay) structures of SARS‐CoV Mpro inhibitors.
T356 38464-38595 Sentence denotes Mpro, main protease; SARS‐CoV, severe acute respiratory syndrome coronavirus [Color figure can be viewed at wileyonlinelibrary.com]
T357 38597-38655 Sentence denotes 3.1.3 Inhibitors with Michael acceptor as a warhead group
T358 38656-38913 Sentence denotes The disclosure of the first crystal structure of the SARS‐CoV‐1 Mpro in complex with a peptidic inhibitor Cbz‐Val‐Asn‐Ser‐Thr‐Leu‐Gln‐chloromethyl ketone (also known as hexapeptide chloromethyl ketone; 28) 125 provided clues for the substrate‐based design.
T359 38914-39189 Sentence denotes Although it is a substrate analog for the porcine transmissible gastroenteritis CoV (TGEV) Mpro, it offers a structural explanation for the P1‐Gln entering into the specific subsite S1 pocket and decreased P2‐leucine specificity in the hydrophobic S2 site of SARS‐CoV‐1 Mpro.
T360 39190-39360 Sentence denotes Additionally, rupintrivir (29; AG7088), a peptidomimetic inhibitor of human rhinovirus 3C protease is oriented similar to inhibitor 28 in the binding pocket of TGEV Mpro.
T361 39361-39463 Sentence denotes 129 These two molecules became prototype compounds for the development of SARS‐CoV‐1 Mpro inhibitors.
T362 39464-39572 Sentence denotes Compound 29 was only weakly active against SARS‐CoV‐1 Mpro (IC50, 800 µM) also in cellular antiviral assays.
T363 39573-39686 Sentence denotes 130 However, systematic structural modifications led to a series of analogs that show moderate to good activity.
T364 39687-39809 Sentence denotes 131 For example, compound 30 (Figure 11), in which the P1‐lactam was replaced by a phenyl ring, showed moderate activity.
T365 39810-39919 Sentence denotes Compound 31, in which the larger P2 p‐fluorophenyl was replaced with a phenyl group, was even more effective.
T366 39920-40052 Sentence denotes By taking 29 as a lead, Ghosh et al. designed new molecules mainly focusing on the replacement of the large P2 p‐fluorobenzyl group.
T367 40053-40273 Sentence denotes Two of the resulting structures with P2‐benzyl (32) and prenyl (33) moieties showed decent inhibitory potencies at both enzymatic (K inact, 0.014 and 0.045 min−1, respectively) and cell‐based (IC50, 45 and 70 µM) assays.
T368 40274-40364 Sentence denotes 132 Besides, no cytotoxicity was observed for these compounds up to 100 µM concentration.
T369 40365-40415 Sentence denotes However, 32 and 33 were inactive at MERS‐CoV Mpro.
T370 40416-40608 Sentence denotes 133 The same research group further modified the molecule with the introduction of P4 Boc‐serine, to establish additional hydrogen bond interactions as described in compound 34 (IC50, 75 µM).
T371 40609-40680 Sentence denotes Unfortunately, the activity of the resulting compound was not improved.
T372 40681-40829 Sentence denotes Further modification of the isobutyl group in compound 34 to isoprenyl group in compound 35 displayed potent activity with K i = 3.6 µM (Figure 11).
T373 40830-40832 Sentence denotes 14
T374 40833-40916 Sentence denotes Figure 11 SARS‐CoV Mpro inhibitors containing Michael acceptor as a warhead group.
T375 40917-41024 Sentence denotes Mpro, main protease; SARS‐CoV, severe acute respiratory syndrome coronavirus On the other hand, Yang et al.
T376 41025-41104 Sentence denotes 134 reported a series of peptide inhibitors with a greater inhibitory potency.
T377 41105-41174 Sentence denotes In general, they systematically changed the backbone of inhibitor 29.
T378 41175-41284 Sentence denotes As a result, they were able to identify more specific residues for each subsite (compounds 36–38; Figure 12):
T379 41285-41606 Sentence denotes At first, the P1‐lactam ring was identified as a more specific moiety for the S1‐site, forming multiple hydrogen‐bond interactions with the enzyme as can be seen in the crystal structure (36); P2‐leucine showed a fourfold increased inhibitory activity when compared to the P2‐phenylalanine or ‐4‐fluorophenylalanine (37).
T380 41607-41703 Sentence denotes A lipophilic tert‐butyl residue was recognized to be a better P3‐moiety than the P3‐valine (38).
T381 41704-41838 Sentence denotes Finally, the replacement of P4‐methylisoxazole with a benzyloxy group was the best option for activity enhancement (compare 29 vs 36).
T382 41839-41930 Sentence denotes They all showed moderate to high antiviral activity against HCoV‐229E in cell‐based assays.
T383 41931-42018 Sentence denotes Figure 12 Broad‐spectral antiviral compounds containing a Michael acceptor Shie et al.
T384 42019-42147 Sentence denotes 131 reported another series of peptide inhibitors with comparatively reduced molecular weight to increase drug‐like properties.
T385 42148-42239 Sentence denotes These pseudo‐C2‐symmetric inhibitors consist of a Phe‐Phe‐dipeptidic α,β‐unsaturated ester.
T386 42240-42354 Sentence denotes One of these inhibitors (39) had an outstanding inhibitory activity with an EC50 value of 0.52 µM (see Figure 12).
T387 42355-42437 Sentence denotes Besides, it displayed remarkable antiviral activity with an EC50 value of 0.18 µM.
T388 42438-42552 Sentence denotes Structurally, the presence of 4‐dimethylamine on the phenyl ring was found to be crucial for activity enhancement.
T389 42553-42688 Sentence denotes Another peptidic drug with a Michael acceptor was N3 (40), which was reported to inhibit SARS‐CoV‐1 3CLpro (K i, 9.0 µM) by Yang et al.
T390 42689-42860 Sentence denotes It was observed to be a broad‐spectrum antiviral compound, also inhibiting other CoVs, such as MERS‐CoV Mpro (IC50, 0.28µM), 135 HCoV‐229E, HCoV‐NL63, and HCoV‐HKU1 Mpro.
T391 42861-42983 Sentence denotes 135 , 136 , 137 , 138 It has also exhibited high antiviral activity in an animal model of infectious bronchitis virus.
T392 42984-43027 Sentence denotes 137 The CC50 of 40 is greater than 133 μM.
T393 43028-43098 Sentence denotes SARS‐CoV‐2 shares only 82% of its genome with its relative SARS‐CoV‐1.
T394 43099-43195 Sentence denotes However, essential viral enzymes of both species show sequence similarities of greater than 90%.
T395 43196-43315 Sentence denotes 137 , 139 , 140 , 141 , 142 SARS‐CoV‐2 3CLpro is highly similar to SARS‐CoV‐1 3CLpro, sharing 96% of its sequence.
T396 43316-43411 Sentence denotes Therefore, one could expect that SARS‐CoV‐1 Mpro inhibitors are active against SARS‐CoV‐2 Mpro.
T397 43412-43567 Sentence denotes Compound 40 was found to be active against SARS‐CoV‐2 Mpro and its value of kobs/[I] for the COVID‐19 virus Mpro was determined to be 11 300 ± 880 M−1·s−1.
T398 43568-43660 Sentence denotes 143 Peptide N3 was co‐crystalized with SARS‐CoV‐1 Mpro at 2.1 Å resolution (see Figure 13).
T399 43661-43751 Sentence denotes Its binding mode to SARS‐CoV‐2 Mpro is highly similar to that of other CoV main proteases.
T400 43752-43880 Sentence denotes Some key features include the Cys‐His catalytic dyad and the substrate‐binding pocket situated in a gap between domain I and II.
T401 43881-44067 Sentence denotes Figure 13 The crystal structure of COVID‐19 virus Mpro in complex with N3. (A) Representation of the dimeric Mpro‐inhibitor complex. (B) Surface representation of the homodimer of Mpro.
T402 44068-44221 Sentence denotes Protomer A (blue), protomer B (salmon), compound N3 is presented as green sticks. (C) Schematic view of compound N3 (40) in the substrate‐binding pocket.
T403 44222-44496 Sentence denotes 143 Mpro, main protease [Color figure can be viewed at wileyonlinelibrary.com] In general, inhibitors possessing a Michael acceptor group as a warhead moiety could form an irreversible (covalent) bond with the catalytic cysteine residue in the following manner (Figure 14):
T404 44497-44600 Sentence denotes First, the cysteine residue undergoes 1,4‐addition at the inhibitor's Michael acceptor group (warhead).
T405 44601-44749 Sentence denotes Rapid protonation of the α‐carbanion from His‐H+ leads to the covalent bond formation between the warhead of the inhibitor and the cysteine residue.
T406 44750-44867 Sentence denotes Figure 14 Mechanism of inhibitors with Michael acceptor group [Color figure can be viewed at wileyonlinelibrary.com]
T407 44869-44919 Sentence denotes 3.1.4 Inhibitors with aldehyde as a warhead group
T408 44920-45229 Sentence denotes Although the above‐described inhibitors with 1,4‐Michael acceptors (e.g., α,β‐vinyl ethyl ester, –CH═CH–C(O)–OEt) showed enzymatic or cell‐based in‐vitro activities, they can be cleaved to their carboxylic acids by plasma esterases; for instance, AG7088 (29) was inactive in the plasma of rodents and rabbits.
T409 45230-45323 Sentence denotes 144 , 145 Therefore, scientists explored different reactive groups that are stable in vivo.
T410 45324-45456 Sentence denotes Based on the highly potent 1,4‐Michael‐acceptor‐based inhibitor 38, which they had previously developed (see Figure 15), Yang et al.
T411 45457-45552 Sentence denotes 134 designed a peptide with a new efficient cysteine‐reactive group, using an aldehyde moiety.
T412 45553-45706 Sentence denotes In addition, the P2‐leucine and the Michael groups of 38 were modified by a cyclohexyl unit and aldehyde group respectively to improve cellular activity.
T413 45707-45826 Sentence denotes Indeed, the resulting peptide‐aldehyde 41 (Figure 15) showed remarkable activity against SARS‐CoV‐1 and HCoV‐229E Mpro.
T414 45827-45972 Sentence denotes 134 It displayed promising antiviral activities decreasing viral load by 4.7 log (at 5 µM) for SARS‐CoV‐1 and 5.2 log (at 1.2 µM) for HCoV‐229E.
T415 45973-46101 Sentence denotes This compound was stable in rat, mouse, and human plasma (even after 120 min, more than 70% of it remained in respective cells).
T416 46102-46189 Sentence denotes Figure 15 SARS‐CoV‐1 and MERS‐CoV Mpro inhibitors with peptide aldehyde functionality.
T417 46190-46279 Sentence denotes Mpro, main protease; SARS‐CoV, severe acute respiratory syndrome coronavirus Kumar et al.
T418 46280-46370 Sentence denotes 146 reported another series of peptide‐aldehyde inhibitors with reduced molecular weight.
T419 46371-46424 Sentence denotes Selected examples (42, 43) are depicted in Figure 15.
T420 46425-46554 Sentence denotes They were potent, cell‐membrane permeable, dual Mpro inhibitors of SARS‐CoV‐1 and MERS‐CoV, without cytotoxicity (CC50 > 100 µM).
T421 46555-46687 Sentence denotes Compound 43, in particular, revealed highly potent activity against SARS‐CoV‐1 Mpro (IC50, 0.2 µM) and MERS‐CoV Mpro (IC50, 1.7 µM).
T422 46688-46824 Sentence denotes It displayed antiviral activity (EC50, 0.06 µM) lowering the viral load and the secretion of virus particles in MERS‐CoV‐infected cells.
T423 46825-46912 Sentence denotes Also, it displayed broad‐spectrum antiviral activity against other human α‐ and β‐CoVs.
T424 46913-47019 Sentence denotes Akaji et al. discovered a series of SARS‐CoV‐1 Mpro inhibitors derived from its natural peptide substrate.
T425 47020-47135 Sentence denotes Initially, they designed a pentapeptide (Ac‐Ser‐Val‐Leu‐N(CH3)2Gln‐CHO, 44) with Mpro inhibitory activity of 37 µM.
T426 47136-47241 Sentence denotes 147 SAR studies of 44 led to inhibitor containing P1‐imidazole with improved potency (45; IC50, 5.7 µM).
T427 47242-47505 Sentence denotes Further systematic structural modifications, primarily concentrating on P1‐, P2‐, and P4‐moieties, driven by X‐ray structure‐based analyses of the Mpro‐inhibitor complex, led to the identification of inhibitor 46 with remarkable inhibitory activity (IC50, 98 nM).
T428 47506-47605 Sentence denotes The crystal structure of Mpro with 46 revealed significant binding interactions in the active site.
T429 47606-47771 Sentence denotes The P1‐imidazole nitrogen atom created a hydrogen bond with the histidine residue's imidazole nitrogen, and the P2‐cyclohexyl moiety fitted well into the S2‐subsite.
T430 47772-47863 Sentence denotes This compound was characterized as a competitive inhibitor without covalent bond formation.
T431 47864-48057 Sentence denotes The same research group disclosed a novel series of peptide inhibitors containing a decahydroisoquinoline moiety in place of P2‐cyclohexyl of 46 to reduce the peptidic nature of the inhibitors.
T432 48058-48104 Sentence denotes A few examples (47–51) are shown in Figure 16.
T433 48105-48189 Sentence denotes Among them, 49 was moderately more active against SARS‐CoV Mpro when compared to 46.
T434 48190-48386 Sentence denotes 148 The X‐ray structure of Mpro in complex with 49 revealed that the P2‐decahydroisoquinoline moiety was fittingly placed in the S2‐subsite, while the P1‐imidazole moiety occupied the S1‐subsite.
T435 48387-48526 Sentence denotes With these key residues located appropriately in their respective pockets, the terminal functional group fits tightly into the active site.
T436 48527-48763 Sentence denotes Figure 16 Peptide inhibitors containing cyclohexyl and decahydroisoquinoline groups [Color figure can be viewed at wileyonlinelibrary.com] This group further extended their study to find inhibitors that interact with S2 to S4 subsites.
T437 48764-48911 Sentence denotes Taking 49 as a lead, they designed a new compound, by combining a nonprime substituent at the decahydroisoquinoline moiety, as shown in example 52.
T438 48912-49009 Sentence denotes 149 The resulting 52 showed more than twofold increased Mpro inhibitory activity compared to 49.
T439 49010-49101 Sentence denotes This indicates that the additional interactions at S2–S4 sites enhance inhibitory activity.
T440 49102-49258 Sentence denotes Rather recently, the same research group explored the ability of octahydroisochromene to interact with the hydrophobic S2 pocket as an innovative P2‐moiety.
T441 49259-49351 Sentence denotes 150 To identify the best specific configuration, all possible diastereomers were evaluated.
T442 49352-49537 Sentence denotes It was found that the molecule with (1S,3S)‐octahydroisochromene 53–56 could secure the optimal position of the P1‐imidazole as well as the aldehyde functional group at the active site.
T443 49538-49700 Sentence denotes Additionally, the N‐butyl side chain attached to the 1‐position of the fused ring system was recognized to be important for establishing hydrophobic interactions.
T444 49701-49724 Sentence denotes In 2018, Groutas et al.
T445 49725-49857 Sentence denotes 151 disclosed a novel class of dual MERS‐CoV and SARS‐CoV‐1 Mpro inhibitors that contain a P3‐piperidine moiety (58–59; Figure 17).
T446 49858-50084 Sentence denotes These inhibitors were derived from the dipeptidic‐aldehyde bisulfite adduct 57 (GC376), which was clinically studied as a protease inhibitor for its efficacy against CoVs such as the feline infectious peritonitis virus (FIPV).
T447 50085-50218 Sentence denotes Compounds 58 and 59 showed potent antiviral activity toward MERS‐CoV in cell‐based bioassays (EC50, 0.5 µM for 58 and 0.8 µM for 59).
T448 50219-50354 Sentence denotes SAR studies revealed that the piperidine moiety engaged in favorable hydrophobic interactions at the S3 and S4 pockets of the protease.
T449 50355-50597 Sentence denotes Figure 17 Inhibitors with aldehyde, aldehyde bisulfite adduct, and epoxide warhead group The X‐ray crystal structures of MERS‐CoV 3CLpro in complex with inhibitor 59 showed that the piperidine ring is likely projecting toward the S4 subsite.
T450 50598-50679 Sentence denotes Additionally, 59 was engaged in backbone H‐bonds with Gln192, Gln167, and Glu169.
T451 50680-50828 Sentence denotes Azapeptide epoxides (APEs) are another class of SARS‐CoV‐1 Mpro inhibitors, although they were originally developed for clan CD cysteine peptidases.
T452 50829-50980 Sentence denotes 152 , 153 The epoxide S,S‐diastereomer 60 (K inact/K i, 1900 (±400) M−1·s−1; Figure 17) exhibited the best inhibitory activity against SARS‐CoV Mpro.
T453 50981-51124 Sentence denotes 154 The X‐ray structure of Mpro in complex with 60 confirmed the formation of a covalent bond between the cysteine‐S atom and the epoxide C‐3.
T454 51125-51205 Sentence denotes It is worth noting that the S,S‐configured epoxide is required for the activity.
T455 51206-51446 Sentence denotes Very recently, Dai et al. designed and synthesized two novel peptidomimetic SARS‐CoV‐2 Mpro inhibitors 61 and 62 (Figure 18) which exhibited extremely high inhibitory activity on purified Mpro with IC50 values of 50 and 40 nM, respectively.
T456 51447-51581 Sentence denotes Furthermore, the group observed high antiviral activity of both compounds in cell‐based assays (61: EC50, 0.42 µM; 62: EC50, 0.33 µM).
T457 51582-51735 Sentence denotes X‐ray structures were determined for both derivatives in complex with SARS‐CoV‐2 Mpro at 1.5 Å, providing detailed information about the binding pockets.
T458 51736-51892 Sentence denotes Similar to related molecules that employ the aldehyde moiety as a warhead, a covalent bond with the active‐site Cys145 was demonstrated for both structures.
T459 51893-51954 Sentence denotes Cytotoxicity assays revealed CC50 values greater than 100 µM.
T460 51955-51958 Sentence denotes 155
T461 51959-52034 Sentence denotes Figure 18 Peptidomimetic SARS‐CoV‐2 Mpro inhibitors with P3‐indole moiety.
T462 52035-52111 Sentence denotes Mpro, main protease; SARS‐CoV, severe acute respiratory syndrome coronavirus
T463 52113-52140 Sentence denotes 3.1.5 Ketoamide inhibitors
T464 52141-52311 Sentence denotes Liu et al. reported dipeptidic α‐ketoamides as broad‐spectrum antiviral agents against the main proteases of human α and β‐CoVs as well as the 3C protease of enterovirus.
T465 52312-52565 Sentence denotes The α‐ketoamide warhead group was promising, as it provides two hydrogen bond acceptors—one from the keto and one from the amide oxygen—whereas other warhead groups, such as Michael acceptor esters and aldehydes, provide only one hydrogen bond acceptor.
T466 52566-52662 Sentence denotes Compound 63 was identified as SARS‐CoV Mpro inhibitor with an IC50 value of 1.95 µM (Figure 19).
T467 52663-52666 Sentence denotes 156
T468 52667-52725 Sentence denotes Figure 19 Ketoamide inhibitors targeting SARS‐CoV‐2 Mpro.
T469 52726-52999 Sentence denotes Mpro, main protease; SARS‐CoV, severe acute respiratory syndrome coronavirus Taking 63 as a lead, aided by its X‐ray structure in complex with SARS‐CoV‐1, HCoV‐NL63, and coxsackievirus Mpros, systematic structural modifications were investigated, focusing on the P2‐moiety.
T470 53000-53189 Sentence denotes As a result, the replacement of P2‐phenyl with P2‐cyclohexyl (64) was found to be the best substitution, while P2‐cyclopentyl (65) showed similar potency against the enzyme SARS‐CoV‐1 Mpro.
T471 53190-53349 Sentence denotes In Huh7 cells, 64 also showed strong antiviral activity with an EC50 of 400 pM, but in Vero cells the antiviral activity of 64 was drastically reduced to 5 µM.
T472 53350-53453 Sentence denotes This compound also exhibited antiviral activity against a range of enteroviruses in various cell lines.
T473 53454-53596 Sentence denotes Due to the high similarity between SARS‐CoV‐1 Mpro and SARS‐CoV‐2 Mpro authors speculated that 64 was likely to inhibit the new virus as well.
T474 53597-53703 Sentence denotes Zhang et al. recently reported this molecule as a SARS‐CoV‐2 Mpro inhibitor with an IC50 value of 0.18 µM.
T475 53704-53877 Sentence denotes They first resolved the unliganded crystal structure of SARS‐CoV‐2 Mpro (Figure 20), 157 which is largely identical to that of SARS‐CoV‐1 Mpro with a 96% sequence identity.
T476 53878-54019 Sentence denotes Compound 64 was docked to SARS‐CoV‐2 Mpro, and a series of structural modifications were performed to improve its pharmacokinetic properties.
T477 54020-54276 Sentence denotes Specifically, masking the P2‐P3 amide bond with the pyridone ring could improve plasma half‐life; and exchanging the lipophilic cinnamoyl residue for the less lipophilic Boc group, could increase plasma solubility and reduce its binding to plasma proteins.
T478 54277-54325 Sentence denotes Figure 20 Crystal structure of SARS‐CoV‐2 Mpro.
T479 54326-54586 Sentence denotes 157 Mpro, main protease; SARS‐CoV, severe acute respiratory syndrome coronavirus [Color figure can be viewed at wileyonlinelibrary.com] Indeed, the resulting 66 had a ~3‐fold improved plasma half‐life in mice when compared to the lead 65 (from 18 min to 1 h).
T480 54587-54792 Sentence denotes The in vitro kinetic plasma solubility has been increased by a factor of ~19 (from 6 µM for the lead to 112 µM for best derivative), and the thermodynamic solubility by a factor of ~13 (from 41 to 530 µM).
T481 54793-54857 Sentence denotes Compound 66 also showed reduced binding to mouse plasma protein.
T482 54858-55035 Sentence denotes However, compared to the lead (IC50, 0.18 µM), the structural modifications caused a reduction of activity against SARS‐CoV‐2 Mpro (IC50, 2.39 µM) and enteroviral 3 C proteases.
T483 55036-55180 Sentence denotes Nevertheless, the introduction of a cyclopropyl group as in 67 instead of P2‐cyclohexyl enhanced the antiviral activity against β‐coronaviruses.
T484 55181-55264 Sentence denotes Compound 67 (Figure 19) inhibited purified SARS‐CoV‐2 Mpro with an IC50 of 0.67 µM.
T485 55265-55370 Sentence denotes It also inhibited SARS‐CoV‐1 Mpro (IC50, 0.90 µM) and MERS‐CoV Mpro (IC50, 0.58 µM) with similar potency.
T486 55371-55449 Sentence denotes It was effective against SARS‐CoV‐1 replication with an EC50 value of 1.75 µM.
T487 55450-55685 Sentence denotes In SARS‐CoV‐2 infected human Calu3 cells, it inhibited the viral replication with an EC50 of 4–5 µM, when in fact the Boc‐unprotected 68 was inactive, suggesting a bulky hydrophobic group is necessary for cellular membrane penetration.
T488 55686-55843 Sentence denotes On the other hand, increasing hydrophobicity of molecules should be pondered carefully, as it can increase plasma protein binding as it was described for 64.
T489 55844-55990 Sentence denotes The pharmacokinetic properties of 67 revealed striking lung tropism and was suitable for inhalation in mice without any perceived adverse effects.
T490 55991-56092 Sentence denotes Compound 67 was cocrystallized with the enzyme in two different forms at 1.95 and 2.20 Å (Figure 21).
T491 56093-56271 Sentence denotes The key feature observed from this crystal structure was that the inhibitor binds to the shallow substrate‐binding site at the surface of each protomer, between domains I and II.
T492 56272-56567 Sentence denotes The thioketal that resulted from the nucleophilic Cys145 attacking the inhibitor, is stabilized by a H‐bond from His41, whereas the amide oxygen of 67 accepts a H‐bond from the main‐chain amides of Gly143, Cys145, and in part, Ser144 that make up the cysteine protease's canonical oxyanion hole.
T493 56568-56755 Sentence denotes 157 The P1 lactam moiety is deeply embedded in the S1 pocket where the lactam nitrogen donates a three‐center H‐bond to the main chain oxygen of the Phe140 and the carboxylate of Glu166.
T494 56756-56801 Sentence denotes The carbonyl oxygen forms a H‐bond to His163.
T495 56802-56853 Sentence denotes The P2‐cyclopropyl moiety fits into the S2 subsite.
T496 56854-56945 Sentence denotes The P3‐P2 pyridone moiety occupies the space normally filled by the substrate's main chain.
T497 56946-57126 Sentence denotes The Boc group is not situated in the canonical S4 site, rather it is located near Pro168, which explains why the removal of the Boc group as in 68 weakened the inhibitory activity.
T498 57127-57183 Sentence denotes Figure 21 Crystal structure of 67 with SARS‐CoV‐2 Mpro.
T499 57184-57315 Sentence denotes Mpro, main protease; SARS‐CoV, severe acute respiratory syndrome coronavirus [Color figure can be viewed at wileyonlinelibrary.com]
T500 57317-57360 Sentence denotes 3.1.6 Inhibitors with electrophilic ketone
T501 57361-57695 Sentence denotes It was envisioned that a fluorinated ketone moiety could be utilized as a warhead for targeting proteases, because it forms a thermodynamically stable hemiketal or hemithioketal after nucleophilic attack by Ser‐OH or Cys‐SH residues, which are present in the active sites of serine or cysteine proteases, respectively (see Figure 22).
T502 57696-57984 Sentence denotes Figure 22 Peptide inhibitors containing electrophilic ketone warheads [Color figure can be viewed at wileyonlinelibrary.com] Initially, Hayashi et al. reported a series of natural‐substrate‐derived peptide inhibitors containing a trifluoromethyl ketone warhead targeting SARS‐CoV‐1 Mpro.
T503 57985-58087 Sentence denotes Compound 69 (Figure 22) was the best of the series with a K i value of 116 µM against SARS‐CoV‐1 Mpro.
T504 58088-58267 Sentence denotes 158 It was sequentially modified mainly focusing on the warhead moiety since the formation of a cyclic structure prevented the nucleophilic attack by cysteine at the active site.
T505 58268-58416 Sentence denotes This study led to the discovery of 70 containing a P1‐lactam and P1'‐thiazole moiety with a >50‐fold increase in inhibitory activity compared to 69.
T506 58417-58549 Sentence denotes 159 Docking studies of 70 to Mpro highlighted key H‐bond interactions with backbone amino acid residues Cys143, Ser144, and Cys145.
T507 58550-58687 Sentence denotes The nitrogen atom of the thiazole warhead moiety also engaged in H‐bond interactions, and the P1‐lactam nicely fitted into the S1‐pocket.
T508 58688-58855 Sentence denotes Continued computer‐assisted structural design led to a tripeptide containing benzothiazole as a warhead group and an m‐N,N‐dimethylaminophenyl group as P4‐moiety (71).
T509 58856-58956 Sentence denotes 160 This compound was extremely potent in inhibiting Mpro of SARS‐CoV‐1 with a K i value of 3.1 nM.
T510 58957-59055 Sentence denotes Docking studies of 71 confirmed that the benzothiazole group was tightly bound to the active site.
T511 59056-59203 Sentence denotes Consequently, the same research group disclosed a series of dipeptides with reduced molecular weight in an attempt to improve drug‐like properties.
T512 59204-59288 Sentence denotes The P3‐valine in the tripeptide 71 was exchanged for a variety of functional groups.
T513 59289-59356 Sentence denotes 161 The study determined N‐arylglycyl to be the optimal P3‐moiety.
T514 59357-59408 Sentence denotes Compound 72 displayed the best inhibitory activity.
T515 59409-59633 Sentence denotes Docking studies of 72 to the protease highlighted the amino hydrogen of the P3‐N‐phenyl glycyl forming a H‐bond with backbone Glu166 of Mpro, in addition to the best P2‐leucine and P1'‐benzthiazole moieties (see Figure 23A).
T516 59634-59873 Sentence denotes Further structural optimization at the P3‐N‐arylglycyl moiety found the indole‐2 carbonyl group to be one of the best P3‐moeities, thus reaching inhibitors with low nanomolar potency, for example 73 (K i, 0.006 µM) against SARS‐CoV‐1 Mpro.
T517 59874-60085 Sentence denotes 162 Docking studies of compound 73 to the protease revealed that the indole amino hydrogen and the carbonyl group attached to the 2‐position formed H‐bond interactions with the backbone Glu166 (see Figure 23B).
T518 60086-60285 Sentence denotes These interactions are of great importance, seeing as shifting the position of the carbonyl group from position 2 to 3, or replacing the indole with benzofuran drastically reduced inhibitory potency.
T519 60286-60353 Sentence denotes Figure 23 (A) Docking poses of 72 and (B) 73 with SARS‐CoV‐1 Mpro.
T520 60354-60543 Sentence denotes Mpro, main protease; SARS‐CoV, severe acute respiratory syndrome coronavirus [Color figure can be viewed at wileyonlinelibrary.com] Zhao et al. reported a series of trifluoromethyl ketones.
T521 60544-60700 Sentence denotes Among them, 74, which has the same sequence as the peptide substrate from sites P1 to P4, exhibited moderate inhibitory activity with an IC50value of 10 µM.
T522 60701-60769 Sentence denotes Inhibitor 74 also displayed time‐dependent inhibition (K i, 0.3 µM).
T523 60770-60773 Sentence denotes 163
T524 60774-60883 Sentence denotes Zhang et al. described a series of dipeptides containing difluoromethyl ketone as SARS‐CoV‐1 Mpro inhibitors.
T525 60884-61006 Sentence denotes Compound 75 displayed the best inhibitory activity in infected Vero and Caco‐2 cell cultures with an IC50 value of 2.5 µM.
T526 61007-61041 Sentence denotes It also exhibited little toxicity.
T527 61042-61045 Sentence denotes 164
T528 61046-61146 Sentence denotes A library of small peptide‐anilides was developed as anti‐SARS‐CoV‐1 Mpro agents (77–80; Figure 23).
T529 61147-61251 Sentence denotes These inhibitors were basically designed from niclosamide (76) which was inactive at Mpro of SARS‐CoV‐1.
T530 61252-61327 Sentence denotes Proper structural modifications led to the discovery of 77 (IC50, 0.06 µM).
T531 61328-61394 Sentence denotes It behaved as a competitive, noncovalent inhibitor (K i, 0.03 µM).
T532 61395-61542 Sentence denotes SAR investigations pointed out that the N,N‐dimethyl group on the phenyl ring, and electron‐withdrawing groups at the warhead phenyl are important.
T533 61543-61630 Sentence denotes Structural modification of 77 resulted in compounds 78 – 80 displaying reduced potency.
T534 61631-61634 Sentence denotes 165
T535 61635-61795 Sentence denotes A novel series of ketoglutamide tripeptides bearing a phthalhydrazido warhead group were identified as reversible SARS‐CoV‐1 Mpro inhibitors (81–84; Figure 24).
T536 61796-61867 Sentence denotes 166 Among them, compound 83 showed the best inhibition (IC50, 0.6 µM).
T537 61868-62124 Sentence denotes SAR studies revealed the presence of β and β'‐amino functionality adjacent to the keto and the intramolecular hydrogen bond to the carbonyl group made the keto center more electrophilic and inclined to build a hemithioacetal with Cys‐SH at the active site.
T538 62125-62263 Sentence denotes Additionally, the hydrophobic P3‐benzyloxy moiety, the P1‐lactam, and the nitro group significantly contributed to the activity increment.
T539 62264-62353 Sentence denotes Figure 24 Small peptide anilides and ketoglutamide tripeptides as SARS‐CoV‐1 inhibitors.
T540 62354-62421 Sentence denotes SARS‐CoV, severe acute respiratory syndrome coronavirus Wang et al.
T541 62422-62558 Sentence denotes 167 described the development of selective and reversible SARS‐CoV‐1 Mpro inhibitors derived from HIV proteases inhibitors (Figure 25).
T542 62559-62657 Sentence denotes The compound 85 as a SARS‐CoV‐1 Mpro lead inhibitor was continuously modified to obtain 86 and 87.
T543 62658-62741 Sentence denotes These derivatives were highly selective toward SARS‐CoV‐1 Mpro versus HIV protease.
T544 62742-62877 Sentence denotes Docking studies of 87 to Mpro demonstrated that both indole amino hydrogens establish H‐bond networks with side chain His142 and His41.
T545 62878-62954 Sentence denotes Figure 25 SARS‐CoV‐1 Mpro inhibitors derived from HIV proteases inhibitors.
T546 62955-63066 Sentence denotes HIV, human immunodeficiency virus; Mpro, main protease; SARS‐CoV, severe acute respiratory syndrome coronavirus
T547 63068-63108 Sentence denotes 3.1.7 Small molecule inhibitors of Mpro
T548 63109-63229 Sentence denotes Benzotriazole esters (88–91; Figure 26) were discovered as novel nonpeptidic irreversible inhibitors of SARS‐CoV‐1 Mpro.
T549 63230-63347 Sentence denotes 168 Among them, 91 exhibited the best enzymatic inhibitory activity, but no antiviral activity in cell‐based assays.
T550 63348-63457 Sentence denotes The covalent binding mode of 91 was confirmed by electrospray ionization mass spectrometry (ESI‐MS) analyses.
T551 63458-63513 Sentence denotes Figure 26 Active esters as SARS‐CoV‐1 Mpro inhibitors.
T552 63514-63783 Sentence denotes Mpro, main protease; SARS‐CoV, severe acute respiratory syndrome coronavirus With a slight structural modification from benzotriazole ester, Zhang et al. reported a series of active halopyridyl esters containing thiophene, furan, and indole moieties (92–95; Figure 26).
T553 63784-63870 Sentence denotes Among them, 93 displayed the highest enzymatic inhibitory activity at SARS‐CoV‐1 Mpro.
T554 63871-63942 Sentence denotes 169 However, no antiviral activity for this compound was communicated.
T555 63943-64012 Sentence denotes The irreversible binding mode of 93 was confirmed by ESI‐MS analysis.
T556 64013-64023 Sentence denotes 170 , 171
T557 64024-64036 Sentence denotes Ghosh et al.
T558 64037-64212 Sentence denotes 172 studied the SARs of halopyridinyl indole carboxylates and identified a series of analogs (96–101; Figure 27) as SARS‐CoV‐1 Mpro inhibitors in the nanomolar potency range.
T559 64213-64332 Sentence denotes The best derivative (100) had high enzymatic inhibitory potency (IC50, 0.030 µM) and antiviral activity (EC50, 6.9 µM).
T560 64333-64451 Sentence denotes Compound 97 was also observed to inhibit the MERS‐CoV Mpro both in enzymatic and cell‐based (EC50, 12.5 µM) bioassays.
T561 64452-64538 Sentence denotes 173 This molecule covalently modified Mpro, which was confirmed by MALDI‐TOF studies.
T562 64539-64621 Sentence denotes Figure 27 SAR of halopyridinyl indole carboxylates as SARS‐CoV‐1 Mpro inhibitors.
T563 64622-64860 Sentence denotes Mpro, main protease; SARS‐CoV, severe acute respiratory syndrome coronavirus 5‐Halopyridinyl esters are troublesome drug candidates because of their potential for rapid hydrolysis by various esterases and other enzymes in mammalian cells.
T564 64861-64971 Sentence denotes They can potentially also react nonspecifically with other thiols and nucleophiles, a recipe for cytotoxicity.
T565 64972-65052 Sentence denotes To bypass this problem by developing stable noncovalent inhibitors, Zhang et al.
T566 65053-65234 Sentence denotes 174 reported a group of methylene ketones and analogous mono‐ and di‐fluorinated methylene ketones based on pyridinyl esters (102 and 103; Figure 28) as SARS‐CoV‐1 Mpro inhibitors.
T567 65235-65373 Sentence denotes Enzymatic investigations and ESI‐MS experiments illustrate that those inhibitors bind to their target in a noncovalent, reversible manner.
T568 65374-65453 Sentence denotes Figure 28 Etacrynic acid and isatin derivatives as SARS‐CoV‐1 Mpro inhibitors.
T569 65454-65696 Sentence denotes Mpro, main protease; SARS‐CoV, severe acute respiratory syndrome coronavirus An HPLC‐based screening of electrophilic compounds identified the etacrynic acid‐derived amide 106 and ester 107 as SARS‐CoV‐1 Mpro inhibitors with moderate potency.
T570 65697-65938 Sentence denotes 175 Etacrynic carboxamide (105; K i, 35.3 µM) bound more strongly to SARS‐CoV‐1 Mpro than to papain protease, while etacrynic acid ester 104 was more active at papain protease (K i, 3.2 µM) than at SARS‐CoV‐1 Mpro (K i, 45.8 µM; Figure 28).
T571 65939-66025 Sentence denotes SAR studies suggested that chloro substituents were necessary for protease inhibition.
T572 66026-66165 Sentence denotes Docking studies of 105 to Mpro revealed that it forms hydrogen bonds with Gln189, Glu166, Thr190, and Gln192 with its terminal amino group.
T573 66166-66287 Sentence denotes The Michael system carbonyl group interacts with Gly143, and the reactive double bond remained next to the Cys145 sulfur.
T574 66288-66385 Sentence denotes Previously, isatin (2,3‐dioxoindole) derivatives were observed to inhibit rhinovirus 3C protease.
T575 66386-66534 Sentence denotes 176 Due to the structural similarity between the rhinovirus 3C protease and SARS‐CoV‐1 Mpro, these derivatives were tested against SARS‐CoV‐1 Mpro.
T576 66535-66674 Sentence denotes Among them, 106 (IC50, 0.95 µM) and 107 (IC50, 0.98 µM) exhibited the best SARS‐CoV‐1 Mpro inhibitory activity in the low micromolar range.
T577 66675-66833 Sentence denotes 176 SAR studies suggested that the inhibition efficiency was mainly reliant on hydrophobic and electronic properties of the isatin core substitution pattern.
T578 66834-66922 Sentence denotes Docking studies revealed that the molecules fit well in the active site of the protease.
T579 66923-67027 Sentence denotes Both carbonyl groups of the isatin core engaged in H‐bonds with NH of Gly143, Ser144, Cys145, and His41.
T580 67028-67250 Sentence denotes Compounds 106 and 107 176 were more selective for SARS‐CoV‐1 Mpro than other proteases like papain (106, 103 µM; 107, 87.24 µM), chymotrypsin (106, ~1 mM; 107, 10.4 µM), and trypsin (106, 362 µM; 107, 243 µM; Figure 28).
T581 67251-67321 Sentence denotes Zhou et al. extended the SAR studies for further activity improvement.
T582 67322-67407 Sentence denotes Compound 108 bearing carboxamide showed the best SARS‐CoV‐1 Mpro inhibitory activity.
T583 67408-67498 Sentence denotes However, this derivative did not bind covalently to the Cys145 residue of the active site.
T584 67499-67636 Sentence denotes 177 Further structural investigations at the carboxamide of 108 with a variety of substituted sulfonamides did not improve the activity.
T585 67637-67694 Sentence denotes Compound 109 was the best one of that series (Figure 28).
T586 67695-67698 Sentence denotes 178
T587 67699-67867 Sentence denotes The modification of 110, identified by high‐throughput screening (HTS; Figure 29), led to pyrazolone and pyrazole derivatives 111 and 112 as SARS‐CoV‐1 Mpro inhibitors.
T588 67868-67919 Sentence denotes 179 , 180 Taking these as leads, Ramajeyam et al.
T589 67920-68040 Sentence denotes 181 reported compounds 112–114 to be the best‐performing inhibitors of the series(IC50 5.5, 6.8, 8.4 µM, respectively).
T590 68041-68108 Sentence denotes They also observed moderate inhibitory activity against CVB3 3Cpro.
T591 68109-68273 Sentence denotes Structure‐functionality analyses illustrated that the benzylidene ring next to pyrazolone C4 in addition to electron‐withdrawing groups, favors inhibitory activity.
T592 68274-68468 Sentence denotes Molecular modeling studies of 112 predicted that for its inhibitory function, the N1‐phenyl residue in the Mpro S1 site as well as the carboxyl benzylidene moiety in the S3 pocket are important.
T593 68469-68536 Sentence denotes Figure 29 Pyrazoles and pyrimidines as SARS‐CoV‐1 Mpro inhibitors.
T594 68537-68749 Sentence denotes Mpro, main protease; SARS‐CoV, severe acute respiratory syndrome coronavirus Kumar et al. described furan‐inserted pyrazolone derivatives as dual SARS‐CoV‐1 Mpro and MERS‐CoV Mpro inhibitors (115–118; Figure 29).
T595 68750-68829 Sentence denotes 182 Compounds 115, 117, and 118 exhibited the best dual inhibitory activities.
T596 68830-68947 Sentence denotes Compounds 115 and 116 also displayed inhibitory activity against H5N1 neuraminidase (IC50 2.8, 2.9 µM, respectively).
T597 68948-69059 Sentence denotes 183 Ramajeyam et al. also disclosed a range of pyrimidine derivatives as SARS‐CoV‐1 Mpro inhibitors (119–121).
T598 69060-69130 Sentence denotes Compound 121 showed high inhibitory potency with an IC50 value 6.1 µM.
T599 69131-69134 Sentence denotes 181
T600 69135-69316 Sentence denotes HTS of NIH molecular libraries (~293 000 substances) yielded the dipeptide 122 containing 3‐pyridyl as hit compound against SARS‐CoV‐1 Mpro with an IC50 value of 2.2 µM (Figure 30).
T601 69317-69411 Sentence denotes Preliminary SAR studies identified 123 and 124 as the most promising inhibitors of the series.
T602 69412-69422 Sentence denotes 184 , 185
T603 69423-69493 Sentence denotes Figure 30 Simple dipeptide derivatives as SARS‐CoV‐1 Mpro inhibitors.
T604 69494-69767 Sentence denotes Mpro, main protease; SARS‐CoV, severe acute respiratory syndrome coronavirus The X‐ray crystal structure of 123 attached to SARS‐CoV‐1 Mpro highlighted the compound's identical orientation in the pocket to that of established covalent peptidomimetic inhibitors (Figure 31).
T605 69768-69853 Sentence denotes The compound with an R‐configuration occupied the S3‐S1' subsites of SARS‐CoV‐1 Mpro.
T606 69854-70195 Sentence denotes Indeed, only (R)‐123 was able to inhibit the Mpro enzyme with an IC50 value of 1.5 µM, while the (S)‐enantiomer was inactive. (R)‐123 inhibited SARS‐CoV‐1 Mpro in a competitive manner (K i, 1.6 µM) with a noncovalent mode of inhibition. (R)‐123 also showed antiviral activity (12.9 µM) in mock infected and SARS‐CoV‐1 infected Vero E6 cells.
T607 70196-70297 Sentence denotes Figure 31 The X‐ray crystal structure of 123 bound to the binding pocket of SARS‐CoV‐1 Mpro (PDB ID:
T608 70298-70304 Sentence denotes 3V3M).
T609 70305-70336 Sentence denotes Pockets S1'–S3 are highlighted.
T610 70337-70660 Sentence denotes Mpro, main protease; SARS‐CoV, severe acute respiratory syndrome coronavirus [Color figure can be viewed at wileyonlinelibrary.com] To enhance the inhibitory activity, SAR study efforts around P1' of 123 provided compounds containing imidazole (125) and 5‐chlorofuran (126) with equipotent activity to lead 123 (Figure 30).
T611 70661-70814 Sentence denotes Next, the exploration of P1 3‐pyridyl unit of 123 revealed pyridazine (127) and pyrazine (128) which were only tolerated, albeit without any improvement.
T612 70815-71049 Sentence denotes The same group of researchers discovered potent, noncovalent SARS‐CoV‐1 Mpro blockers based on a benzotriazole scaffold in an MLPCN screening, 186 resulting in hit compound 129 (Figure 32) with a SARS‐CoV‐1 Mpro IC50 value of 6.2 µM.
T613 71050-71126 Sentence denotes Figure 32 SARS‐CoV‐1 Mpro inhibitors containing the benzotriazole scaffold.
T614 71127-71295 Sentence denotes Mpro, main protease; SARS‐CoV, severe acute respiratory syndrome coronavirus SAR studies focusing on the benzotriazole moiety of 129 were performed to improve activity.
T615 71296-71417 Sentence denotes The replacement of this group with 4‐phenyl‐1,2,3‐triazole (as in 130) was somewhat tolerated (IC50 of 11 µM; Figure 32).
T616 71418-71638 Sentence denotes Further modifications to the acetamide (P2‐P1' region) resulted in molecules bearing a thiophene ring on one side and a branched i‐propyl amide (131) or cyclobutylamide (132) on the other—reaching IC50 values below 5 µM.
T617 71639-71772 Sentence denotes To cut overall molecular weight of the inhibitors, P3‐truncation was performed, which led to potent derivatives (133–137; Figure 32).
T618 71773-71836 Sentence denotes Compound 137 displayed extremely high inhibition (IC50, 51 nM).
T619 71837-71907 Sentence denotes SARS‐CoV‐1 Mpro inhibitors were also discovered from medicinal plants.
T620 71908-71927 Sentence denotes In 2011, Ryu et al.
T621 71928-72003 Sentence denotes 187 disclosed a range of inhibitors obtained from Torreya nucifera leaves.
T622 72004-72157 Sentence denotes Of all the isolated chemicals, the biflavone, amentoflavone (138; Figure 33), was identified as a potent noncompetitive inhibitor with an IC50 of 8.3 µM.
T623 72158-72259 Sentence denotes Docking studies of 138 identified the interactions of Val186 and Gln192 as major sites at the target.
T624 72260-72356 Sentence denotes Figure 33 Flavone and terpenoid derivatives with inhibitory activity against SARS‐CoV‐1 3CLpro.
T625 72357-72539 Sentence denotes 3CLpro, 3C‐like protease; SARS‐CoV, severe acute respiratory syndrome coronavirus They also isolated a series of terpenoids from T. nucifera as anti‐SARS‐CoV Mpro agents (Figure 33).
T626 72540-72617 Sentence denotes 187 Among them, ferruginol (139; IC50 49.6 µM) was the most active compound.
T627 72618-72859 Sentence denotes Additionally, they isolated quinone‐methide triterpenoids celastrol (140), pritimererin (141), and tingenone (142) from methanol extracts of Tripterygium regelii which exhibited fair inhibition activity (IC50 2.6, 9.9, 5.5 µM, respectively).
T628 72860-72994 Sentence denotes SAR studies indicated that for effective inhibition, the quinone‐methide group in ring A and the more lipophilic ring E were critical.
T629 72995-73077 Sentence denotes All compounds were characterized as competitive inhibitors using kinetic analyses.
T630 73078-73088 Sentence denotes Wen et al.
T631 73089-73187 Sentence denotes 188 reported abietane‐type diterpenoids and lignoids with a powerful anti‐SARS‐CoV‐1 Mpro effect.
T632 73188-73323 Sentence denotes Especially betulinic acid (143) and savinin (144) effectively inhibited SARS‐CoV‐1 Mpro (K i 8.2 µM, 9.1 µM, respectively) (Figure 33).
T633 73324-73371 Sentence denotes These inhibitors acted in a competitive manner.
T634 73372-73560 Sentence denotes Lu et al. discovered two hit SARS‐CoV‐1 3CLpro inhibitors, sulfone 145 and dihydroimidazole 146, by structure‐based virtual screening of a compound library of 58 855 chemicals (Figure 34).
T635 73561-73692 Sentence denotes 189 The central structural elements of the hits, determined in docking experiments, were then used for additional analog searches.
T636 73693-73752 Sentence denotes Figure 34 Structure of SARS‐CoV‐1 Mpro inhibitors 145–149.
T637 73753-73903 Sentence denotes Mpro, main protease; SARS‐CoV, severe acute respiratory syndrome coronavirus Computational similarity screening discovered 21 analogs from these hits.
T638 73904-74001 Sentence denotes Among them, the two best compounds 147 and 148 display IC50 values of 0.3 and 3 µM, respectively.
T639 74002-74119 Sentence denotes A variety of SARS‐CoV‐1 Mpro inhibitors have been identified through virtual screening (VS) as an alternative to HTS.
T640 74120-74234 Sentence denotes VS of 50 240 structurally diverse small molecules allowed to identify 104 molecules with anti‐SARS‐CoV‐1 activity.
T641 74235-74386 Sentence denotes Compound 149 (Figure 34) demonstrated potent enzyme inhibition (IC50, 2.5 μM) and an EC50 of 7 μM in Vero cell‐based SARS‐CoV‐1 plaque reduction assays
T642 74387-74502 Sentence denotes Virtual screening identified the serotonin antagonist cinanserin (150, Figure 35) as a potential inhibitor of Mpro.
T643 74503-74587 Sentence denotes It had previously shown activity against SARS‐CoV‐1 Mpro with an IC50 value of 5 µM.
T644 74588-74710 Sentence denotes 190 Subsequent tests revealed its anti‐SARS‐CoV‐2 activity (EC50, 20.6 µM) and an IC50 value of 125 µM (SARS‐CoV‐2 Mpro).
T645 74711-74755 Sentence denotes Figure 35 Covalent bond inhibitors of Mpro.
T646 74756-74967 Sentence denotes Mpro, main protease Their HTS yielded seven primary hits including the approved drugs disulfiram (151) and carmofur (152), as well as ebselen (153), shikonin (154), tideglusib (155), and PX‐12 (156) (Figure 35).
T647 74968-75122 Sentence denotes Using MS/MS analysis, they deduced that ebselen (153) and 156 are irreversible inhibitors of Mpro by covalently attaching to Cys145 of the catalytic dyad.
T648 75123-75199 Sentence denotes Molecular docking was used to illustrate how 151, 154, and 155 bind to Mpro.
T649 75200-75364 Sentence denotes Antiviral activity assays, using real‐time reverse transcription‐PCR, indicated that ebselen and inhibitor “N3” (40; Figure 12) had the strongest antiviral effects.
T650 75365-75479 Sentence denotes Ebselen displayed an EC50 value of 4.67 µM, and “N3” showed an EC50 value of 16.77 µM in a plaque‐reduction assay.
T651 75480-75545 Sentence denotes Ebselen's IC50 value for SARS‐CoV‐2 Mpro was reported at 0.67 µM.
T652 75546-75614 Sentence denotes The activity data of remaining compounds is summarized in Figure 35.
T653 75615-75693 Sentence denotes Ebselen has been studied for an array of diseases and has a very low toxicity.
T654 75694-75765 Sentence denotes 191 , 192 , 193 Its safety has been demonstrated in clinical trials.
T655 75766-75887 Sentence denotes 191 , 192 , 194 It can therefore be considered a promising molecule for the treatment or prevention of CoV infections.
T656 75889-75922 Sentence denotes 3.2 Coronavirus PLpro inhibitors
T657 75923-76051 Sentence denotes Along with the Mpro, papain‐like protease (PLpro) also cleaves polyproteins which is an important process for viral replication.
T658 76052-76156 Sentence denotes PLpro cleaves at the first three positions creating three nonstructural functional proteins (nsp1‐nsp3).
T659 76157-76240 Sentence denotes In particular, nsp3 is central for the generation of the viral replication complex.
T660 76241-76451 Sentence denotes The multifunctionality of PLpro in deubiquitinating, de‐ISGylation (ISG: interferon‐stimulated gene), 195 , 196 and in the evasion of the innate immune response make PLpro an attractive antiviral drug target.
T661 76452-76562 Sentence denotes PLpro is a cysteine protease and its active site contains a catalytic triad composing of Cys112‐His273‐Asp287.
T662 76563-76630 Sentence denotes Cys112 behaves as a nucleophile, and His273 is a general acid‐base.
T663 76631-76712 Sentence denotes Asp287 helps His273 to align perfectly, thus promoting His to deprotonate Cys‐SH.
T664 76713-76725 Sentence denotes Ghosh et al.
T665 76726-76841 Sentence denotes 197 contributed significantly to the development of SARS‐CoV‐1 PLpro inhibitors based on the naphthalene scaffold.
T666 76842-76974 Sentence denotes Two lead compounds 157 and 158 (Figure 36) were identified by an HTS of a chemical library containing greater than 50 000 compounds.
T667 76975-77071 Sentence denotes They both inhibit PLpro of SARS‐CoV‐1 at a moderate potency (IC50 20.1 and 59 µM, respectively).
T668 77072-77222 Sentence denotes The (R)‐enantiomer of compound 157 was found to be a greater than twofold more potent inhibitor of PLpro when compared with its racemic mixture (157).
T669 77223-77461 Sentence denotes Subsequent SAR studies highlighted the 2‐naphthyl substitution as an important structural requirement rather than at the position 1 of the naphthyl ring in addition to the presence of o‐methyl and m‐amino groups, in the other phenyl ring.
T670 77462-77610 Sentence denotes Compound 159 displayed the best inhibitory activity of PLpro (IC50, 0.6 µM) and acts in a noncovalent reversible manner with a K i value of 0.49 µM.
T671 77611-77713 Sentence denotes 198 Compound 159 also showed moderate antiviral activity in Vero cells with an EC50 value of 14.5 µM.
T672 77714-77783 Sentence denotes Figure 36 SARS‐CoV‐1 PLpro inhibitors based on naphthalene scaffold.
T673 77784-78021 Sentence denotes PLpro, papain‐like protease; SARS‐CoV, severe acute respiratory syndrome coronavirus Compound 159 was further scrutinized by investigating the importance of the amide NH, and the effect of the substituent on the benzamide ring (160–164).
T674 78022-78208 Sentence denotes Among them, compounds 163 and 164 exhibited the most potent enzymatic (163: IC50, 0.46 µM; 164: IC50, 1.23 µM) and cell‐based antiviral (163: EC50, 6.0 µM; 164: EC50, 5.2 µM) activities.
T675 78209-78272 Sentence denotes Next, the same group studied the SARs for compound 158 further.
T676 78273-78433 Sentence denotes This led to the discovery of compound 165 with high PLpro inhibitory activity of SARS‐CoV‐1 (IC50, 0.32 µM) and antiviral activity (EC50, 9.1 µM) in Vero cells.
T677 78434-78528 Sentence denotes 199 The mode of action of 165 was found to be a noncovalent, competitive inhibition of PLpro.
T678 78529-78660 Sentence denotes Unlike the previous series, the stereochemistry at the α‐methyl group did not make a significant difference in inhibition of PLpro.
T679 78661-78870 Sentence denotes For example, both (S)‐ and (R)‐methyl inhibitors, 165 (IC50, 0.32 µM; EC50, 9.1 µM and 166 (IC50, 0.56 µM; EC50, 9.1 µM), respectively, shared equipotent inhibitory activity in enzymatic and cell‐based assays.
T680 78871-78941 Sentence denotes Further SARs of 159 and 165 were investigated to improve the activity.
T681 78942-79081 Sentence denotes However, no significant improvement in the activity was observed for the prepared compounds either in the enzymatic or cell‐based bioassay.
T682 79082-79153 Sentence denotes Compounds 167–169 (Figure 36) displayed the best inhibitory activities.
T683 79154-79296 Sentence denotes Especially, the m‐fluoro‐substituted benzamide derivative 168 (IC50, 0.15 µM; EC50, 5.4 µM) showed the best inhibition activity against PLpro.
T684 79297-79353 Sentence denotes It also inhibited SARS‐CoV‐1 in the cell‐based bioassay.
T685 79354-79433 Sentence denotes Both compounds 168 and 169 were metabolically more stable when compared to 167.
T686 79434-79593 Sentence denotes HTS of a chemical library of 25000 molecules identified 170 (Figure 37) as a dual SARS‐CoV‐1 PLpro (IC50, 10.9 µM) and MERS‐CoV PLpro (IC50, 6.2 µM) inhibitor.
T687 79594-79724 Sentence denotes 200 This compound acts via competitive inhibition against MERS‐CoV PLpro, yet via allosteric inhibition against SARS‐CoV‐1 PLpro.
T688 79725-79903 Sentence denotes This compound also exhibited a preference for SARS‐CoV‐1 PLpro and MERS‐CoV PLpro versus two human homologs of the PLpro, ubiquitin C‐terminal hydrolase, (hUCH‐L1) and (hUCH‐L3).
T689 79904-79970 Sentence denotes Figure 37 Broad spectral PLpro inhibitors from different sources.
T690 79971-80067 Sentence denotes PLpro, papain‐like protease; SARS‐CoV, severe acute respiratory syndrome coronavirus Chou et al.
T691 80068-80211 Sentence denotes 201 identified thiopurine (171) and 6‐thioguanine (172) as SARS‐CoV‐1 PLpro inhibitors by the screening of a library containing 160 compounds.
T692 80212-80270 Sentence denotes The thiocarbonyl group was important for PLpro inhibition.
T693 80271-80373 Sentence denotes However, the toxicity of these anticancer agents limits their therapeutic utility as anti‐SARS agents.
T694 80374-80394 Sentence denotes In 2012, Park et al.
T695 80395-80498 Sentence denotes 202 reported a tanshinone derivative 173 as a SARS‐CoV‐1 PLpro inhibitor with an IC50 value of 0.8 µM.
T696 80499-80581 Sentence denotes The same research group also described diarylheptanoids blocking SARS‐CoV‐1 PLpro.
T697 80582-80688 Sentence denotes In particular compound 174 performed as the best inhibitor of SARS‐CoV PLpro with an IC50 value of 4.1 µM.
T698 80689-80768 Sentence denotes An α,β‐unsaturated carbonyl functionality was crucial for effective inhibition.
T699 80769-80915 Sentence denotes The geranylated flavonoid 175 was another plant‐derived natural product, which displayed SARS‐CoV‐1 PLpro inhibition with an IC50 value of 5.0 µM.
T700 80916-80919 Sentence denotes 203
T701 80920-80940 Sentence denotes In 2017, Park et al.
T702 80941-81010 Sentence denotes 204 assessed the inhibitory activity of polyphenols isolated from B.
T703 81011-81064 Sentence denotes Papyrifera against SARS‐CoV PLpro and MERS‐CoV PLpro.
T704 81065-81217 Sentence denotes Two of them (176 and 177 Figure 37) displayed moderate inhibition at both SARS‐CoV‐1 PLpro and MERS‐CoV PLpro with a noncompetitive mechanism of action.
T705 81218-81452 Sentence denotes Disulfiram (151; Figure 35) was also reported as a SARS‐CoV‐1 PLpro inhibitor (IC50, 24.1 µM), 205 probably by reacting with the active site cysteine, thereby covalently modifying the enzyme target, as was reported for other targets.
T706 81454-81480 Sentence denotes 4 RdRP AND ITS INHIBITORS
T707 81481-81584 Sentence denotes The ability to produce new RNA copies from available template molecules is necessary for life on earth.
T708 81585-81665 Sentence denotes RNA polymerases are therefore found in all living cells as well as many viruses.
T709 81666-81781 Sentence denotes RdRP are essential enzymes to all RNA viruses, as they catalyze the synthesis of new RNA from a given RNA template.
T710 81782-81968 Sentence denotes 206 Due to their importance for viral life cycles, and their high conservation among different RNA viruses, they have been attractive drug targets for antiviral therapy for a long time.
T711 81969-82043 Sentence denotes SARS‐CoV‐2 also uses an RdRP to replicate its genome within the host cell.
T712 82044-82170 Sentence denotes Three nonstructural viral proteins (nsp) form its replication/transcription complex, with nsp12 forming the catalytic subunit.
T713 82171-82252 Sentence denotes Bound to it are nsp7 and nsp8—accessory factors that facilitate template binding.
T714 82253-82341 Sentence denotes 207 , 208 , 209 Their individual structures and that of the complex have been solved.
T715 82342-82515 Sentence denotes 210 , 211 , 212 , 213 , 214 Interestingly, the only nsp that interacts directly with RNA seems to be nsp12, whereas nsp7 and nsp8 are needed to increase its efficiency.
T716 82516-82526 Sentence denotes 210 , 215
T717 82527-82658 Sentence denotes RdRP is the target of inhibitors like remdesivir (178), galidesivir (179), ribavirin (180), favipiravir (181), and EIDD‐2801 (182).
T718 82659-82733 Sentence denotes These molecules have shown promise for the treatment of COVID‐19 patients.
T719 82734-82809 Sentence denotes 87 , 216 , 217 , 218 (For structures and biological data see Figure 38)
T720 82810-82956 Sentence denotes Figure 38 Nucleoside analogs with inhibition activity against SARS‐CoV‐2 RdRP (adenosine, guanosine, and sofosbuvir are included for comparison).
T721 82957-83121 Sentence denotes RdRP, RNA‐dependent RNA polymerase; SARS‐CoV, severe acute respiratory syndrome coronavirus Remdesivir is a 1'‐cyano‐substitued adenine C‐nucleoside analog prodrug.
T722 83122-83241 Sentence denotes The prodrug strategy used is similar to that of the FDA‐approved anti‐hepatitis C drug sofosbuvir (183; see Figure 38).
T723 83242-83413 Sentence denotes Upon its diffusion into cells, the phosphoramidate undergoes an intracellular conversion process that results in the formation of the triphosphate active metabolite (RTP).
T724 83414-83519 Sentence denotes The triphosphate is recognized as adenine by viral RdRP, which causes heavy disruptions in RNA synthesis.
T725 83520-83634 Sentence denotes The exact molecular mechanism of remdesivir's action against SARS‐CoV‐2 has recently been elucidated by Yin et al.
T726 83635-83765 Sentence denotes 219 who reported cryo‐EM structures of SARS‐CoV‐2 RdRP with remdesivir monophosphate (RMP) covalently bound to the primer strand.
T727 83766-83910 Sentence denotes As only a single RMP was incorporated in each observed primer strand the inhibition mechanism was shown to be nonobligate RNA chain termination.
T728 83911-84080 Sentence denotes The addition of RTP led to a complete inhibition of RNA polymerization activity at a concentration of 1 mM, even in the presence of ATP in high concentrations of 100 mM.
T729 84081-84282 Sentence denotes The authors further highlight the high conservation level of catalytic sites of RdRPs in different RNA viruses, which makes the discovery of future broad‐spectrum antiviral RdRP inhibitors seem likely.
T730 84283-84426 Sentence denotes Remdesivir was previously reported to inhibit SARS‐CoV‐1 and MERS‐CoV replication in multiple in vitro systems, with submicromolar IC50 values.
T731 84427-84691 Sentence denotes 220 In primary human airway epithelial (HAE) cell cultures, the antiviral activity assessment of remdesivir against SARS‐CoV‐1 and MERS‐CoV showed a dose‐dependent reduction in replication with average IC50 values of 0.069 µM (SARS‐CoV‐1) and 0.074 µM (MERS‐CoV).
T732 84692-84881 Sentence denotes In a mouse model of SARS‐CoV‐1 pathogenesis, remdesivir greatly decreased the virus concentration in the lung and mitigated clinical symptoms of infection and restored respiratory function.
T733 84882-84950 Sentence denotes Galidesivir is another C‐nucleoside analog that resembles adenosine.
T734 84951-85016 Sentence denotes However, the base is not linked to a ribose, but to an aza‐sugar.
T735 85017-85143 Sentence denotes Although it is recognized as adenosine by RdRP, its properties are different enough to cause a disruption in chain elongation.
T736 85144-85312 Sentence denotes Galidesivir has been used in the treatment of Ebola and Marburg virus infections, and in vitro studies against SARS‐ and MERS‐CoVs have suggested efficacy against CoVs.
T737 85313-85421 Sentence denotes 221 Therefore, it is a likely future anti SARS‐CoV‐2 agent, and currently being studied in clinical trials.
T738 85422-85432 Sentence denotes 222 , 223
T739 85433-85514 Sentence denotes Ribavirin is a nucleoside analog, which shows structural similarity to guanosine.
T740 85515-85584 Sentence denotes But guanosine's 6‐membered ring is only hinted at by the amide group.
T741 85585-85663 Sentence denotes As such, it is incorporated by viral RdRPs, but interrupts RNA polymerization.
T742 85664-85757 Sentence denotes 224 It is an approved drug in most countries and used against a variety of viral infections.
T743 85758-85920 Sentence denotes Although its efficacy against SARS‐CoV‐2 has not been determined in large clinical trials, ribavirin has shown some promise in the treatment of COVID‐19 patients.
T744 85921-85924 Sentence denotes 225
T745 85925-86027 Sentence denotes Favipiravir (Avigan®) is an approved antiviral drug for the treatment of influenza in Japan and China.
T746 86028-86122 Sentence denotes It is a pyrazinamide derivative that has shown some activity against a variety of RNA viruses.
T747 86123-86190 Sentence denotes 226 Favipiravir inhibits viral RdRP via its similarity to guanine.
T748 86191-86424 Sentence denotes After biotransformation into its active metabolite, favipiravir‐ribofuranosyl‐5'‐triphosphate, it is incorporated into newly synthesized RNA by RdRP, leading to premature chain termination 227 similar to remdesivir's mode of action.
T749 86425-86520 Sentence denotes Favipiravir is currently being studied around the world as a treatment option against COVID‐19.
T750 86521-86550 Sentence denotes Very recently, Sheahan et al.
T751 86551-86638 Sentence denotes 228 reported the discovery of EIDD‐1931 and its orally bioavailable prodrug EIDD‐2801.
T752 86639-86838 Sentence denotes These nucleoside analogs have shown remarkable potency against SARS‐CoV‐2 and other related CoVs in vitro and in vivo, with IC50 values in the low nanomolar range, outperforming remdesivir 3–10‐fold.
T753 86839-86979 Sentence denotes The reason for this increased potency could be additional interactions with viral RdRP involving the N4‐hydroxyl group of the cytidine ring.
T754 86980-87071 Sentence denotes 219 The efficacy of EIDD‐2801 in COVID‐19 patients is being evaluated in a clinical trial.
T755 87072-87075 Sentence denotes 229
T756 87076-87311 Sentence denotes Remdesivir and other potential RdRP inhibitors 230 are currently being studied in clinical trials around the world, but even though preliminary results appear promising, it is too early to assess their clinical value against COVID‐19.
T757 87313-87344 Sentence denotes 5 DRUGS REPOSITIONING APPROACH
T758 87345-87495 Sentence denotes Drug repurposing is an attractive strategy for finding new indications for already well‐established, marketed drugs or highly characterized compounds.
T759 87496-87660 Sentence denotes It is a fast way to identify of new therapeutic options directly available for clinical use or eligible for accelerated approval for various diseases and disorders.
T760 87661-87758 Sentence denotes An extensive effort has been made in repurposing approved drugs since the outbreak of SARS‐CoV‐1.
T761 87759-87864 Sentence denotes Below, we summarize selected drug repositioning strategies for anticoronaviral therapy and their results.
T762 87865-87954 Sentence denotes The host's innate interferon (IFN) response is one key for controlling viral replication.
T763 87955-88039 Sentence denotes The IFN response can be increased by administering artificial IFNs and IFN inducers.
T764 88040-88135 Sentence denotes The recombinant IFN‐α and ‐β inhibited the replication of SARS‐ and MERS‐CoVs in animal models.
T765 88136-88279 Sentence denotes 231 Several studies also described the combination of IFNs with antiviral drugs like ribavirin (180) or lopinavir‐ritonavir for treating SARS.
T766 88280-88290 Sentence denotes 232 , 233
T767 88291-88513 Sentence denotes In 2004, SARS patients in an open‐label study had better clinical outcomes when treated with ribavirin in combination with lopinavir‐ritonavir (400 and 100 mg, respectively) than the control group receiving only ribavirin.
T768 88514-88648 Sentence denotes 227 A study in SARS patients found that viral replication could not be blocked at ribavirin concentrations achievable in human serum.
T769 88649-88777 Sentence denotes 234 Nevertheless, the combination of ribavirin with IFN‐β had a synergistic effect on the inhibition of SARS‐CoV‐1 replication.
T770 88778-88887 Sentence denotes The effects of PEGylated IFN together with ribavirin against SARS‐CoV‐2 are being studied in clinical trials.
T771 88888-88890 Sentence denotes 87
T772 88891-89027 Sentence denotes Nitazoxanide (178; Figure 39), a broad‐spectrum antiparasitic drug, was reported to inhibit SARS‐CoV‐2 (EC50, 2.12 μM in Vero E6 cells).
T773 89028-89131 Sentence denotes 215 It is also an IFN‐inducing agent, and it is being studied for treating a wide range of infections.
T774 89132-89224 Sentence denotes Figure 39 Selected structures of drugs suitable for repositioning against SARS‐CoV‐1 and 2.
T775 89225-89394 Sentence denotes SARS‐CoV, severe acute respiratory syndrome coronavirus The antiarrhythmic drug amiodarone (179, Figure 39) also inhibited SARS‐CoV‐1 replication in infected Vero cells.
T776 89395-89489 Sentence denotes 235 The drug appears to alter the endocytotic pathway, thus inhibiting endosomal viral entry.
T777 89490-89618 Sentence denotes Glycyrrhizin inhibited viral replication in Vero cells with an EC50 value of 300 mg/L, possibly by blocking viral entry as well.
T778 89619-89622 Sentence denotes 232
T779 89623-89826 Sentence denotes As nitric oxide (NO) has been associated with antiviral activity, the NO donor, S‐nitroso‐N‐acetylpenicillamine (180; Figure 39) was reported to inhibit SARS‐CoV‐1 replication in a dose‐dependent manner.
T780 89827-89830 Sentence denotes 236
T781 89831-90089 Sentence denotes In a search for potential antiviral agents against SARS‐CoV‐1, the screening of a library of 8000 approved drugs identified cinanserin (150; Figure 39), a serotonin antagonist, as a potential inhibitor of SARS‐CoV‐1 targeting its Mpro with IC50 value 4.0 µM.
T782 90090-90093 Sentence denotes 189
T783 90094-90227 Sentence denotes A virtual screening and docking study identified the calmodulin antagonist calmidazolium as a SARS‐CoV‐1 Mpro inhibitor (K i, 61 µM).
T784 90228-90231 Sentence denotes 237
T785 90232-90424 Sentence denotes In 2014, Dyall et al. reported an array of pharmaceutical drugs with antiviral activity against MERS‐CoV, and SARS‐CoV‐1 (Table 2, chemical structure of all drugs were indicated in Figure S1).
T786 90425-90489 Sentence denotes 121 The agents were grouped according to their modes of action.
T787 90490-90528 Sentence denotes Hits inhibited both investigated CoVs.
T788 90529-90599 Sentence denotes Table 2 Compounds with inhibitory activity at MERS‐CoV and SARS‐CoV‐1
T789 90600-90652 Sentence denotes Drugs Class MERS‐CoVEC50 (µM) SARS‐CoV‐1EC50 (µM)
T790 90653-90695 Sentence denotes Emetine Antibacterial agent 0.014 0.051
T791 90696-90740 Sentence denotes Chloroquine Antiparasitic agent 6.27 6.53
T792 90741-90792 Sentence denotes Hydroxychloroquine Antiparasitic agent 8.27 7.96
T793 90793-90837 Sentence denotes Mefloquine Antiparasitic agent 7.41 15.55
T794 90838-90882 Sentence denotes Amodiaquine Antiparasitic agent 6.21 1.27
T795 90883-90925 Sentence denotes Loperamide Antidiarrheal agent 4.8 5.90
T796 90926-90963 Sentence denotes Lopinavir HIV‐1 inhibitor 8.0 24.4
T797 90964-91003 Sentence denotes E‐64‐D Cathepsin inhibitor 1.27 0.76
T798 91004-91053 Sentence denotes Gemcitabine DNA metabolism inhibitor 1.21 4.95
T799 91054-91106 Sentence denotes Tamoxifen Estrogen receptor inhibitor 10.11 92.88
T800 91107-91160 Sentence denotes Toremifene Estrogen receptor inhibitor 12.91 11.96
T801 91161-91215 Sentence denotes Terconazole Sterol metabolism inhibitor 12.20 15.32
T802 91216-91264 Sentence denotes Triparanol Sterol metabolism inhibitor 5.28 ‐
T803 91265-91318 Sentence denotes Anisomycin Protein‐processing inhibitor 0.003 0.19
T804 91319-91375 Sentence denotes Cycloheximide Protein‐processing inhibitor 0.189 0.04
T805 91376-91433 Sentence denotes Homoharringtonine Protein‐processing inhibitor 0.071 ‐
T806 91434-91487 Sentence denotes Benztropine Neurotransmitter inhibitor 16.62 21.61
T807 91488-91540 Sentence denotes Fluspirilene Neurotransmitter inhibitor 7.47 5.96
T808 91541-91592 Sentence denotes Thiothixene Neurotransmitter inhibitor 9.29 5.31
T809 91593-91648 Sentence denotes Chlorpromazine Neurotransmitter inhibitor 9.51 12.97
T810 91649-91702 Sentence denotes Fluphenazine Neurotransmitter inhibitor 5.86 21.43
T811 91703-91756 Sentence denotes Promethazine Neurotransmitter inhibitor 11.80 7.54
T812 91757-91807 Sentence denotes Astemizole Neurotransmitter inhibitor 4.88 5.59
T813 91808-91866 Sentence denotes Chlorphenoxamine Neurotransmitter inhibitor 12.64 20.03
T814 91867-91920 Sentence denotes Thiethylperazine Neurotransmitter inhibitor 7.86 ‐
T815 91921-91976 Sentence denotes Triflupromazine Neurotransmitter inhibitor 5.75 6.39
T816 91977-92030 Sentence denotes Clomipramine Neurotransmitter inhibitor 9.33 13.23
T817 92031-92080 Sentence denotes Imatinib Kinase signaling inhibitor 17.68 9.82
T818 92081-92130 Sentence denotes Dasatinib Kinase signaling inhibitor 5.46 2.10
T819 92131-92154 Sentence denotes John Wiley & Sons, Ltd.
T820 92155-92279 Sentence denotes This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response.
T821 92280-92462 Sentence denotes It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.
T822 92463-92595 Sentence denotes In particular, the protein‐processing inhibitors cycloheximide and anisomycin showed strong inhibitory activities against both CoVs.
T823 92596-92693 Sentence denotes The HIV protease inhibitor lopinavir was more effective against SARS‐CoV‐1 than against MERS‐CoV.
T824 92694-92784 Sentence denotes The antidiarrheal agent loperamide showed moderate inhibitory activitiy against both CoVs.
T825 92785-92914 Sentence denotes The anti‐protozoal and emetic alkaloid with antibacterial properties, emetine, showed strong antiviral activity against MERS‐CoV.
T826 92915-93042 Sentence denotes The antiparasitic drugs chloroquine, hydroxychloroquine, and mefloquine showed moderate antiviral activities against both CoVs.
T827 93043-93095 Sentence denotes Cathepsin inhibitor, E‐64‐D, inhibited both as well.
T828 93096-93348 Sentence denotes Two of the neurotransmitter inhibitors, chlorpromazine and triflupromazine also blocked both viruses (see Section 2) The DNA synthesis inhibitor gemcitabine was able to inhibit SARS‐CoV‐1 and MERS‐CoV with an EC50 value of 1.2 and 4.9 µM, respectively.
T829 93349-93481 Sentence denotes Toremifene is an estrogen receptor 1 antagonist that inhibited both MERS‐CoV and SARS‐CoV‐1 (EC50, 12.9 and 11.97 µM, respectively).
T830 93482-93590 Sentence denotes Kinase signaling pathway inhibitors imatinib and dasatinib were active against both MERS‐CoV and SARS‐CoV‐1.
T831 93591-93718 Sentence denotes Imatinib was reported to act at an early stage of viral infection by hampering the fusion of viral particles with the endosome.
T832 93719-93721 Sentence denotes 53
T833 93722-93908 Sentence denotes Niclosamide (181; Figure 39), an anthelmintic drug, exhibited very potent antiviral activity against SARS‐CoV‐1 replication and stopped viral antigen synthesis at 1.56 μM concentrations.
T834 93909-94074 Sentence denotes 238 It prevented the cytopathic effect of SARS‐CoV‐1 at low concentrations of 1 μM and halted SARS‐CoV‐1 replication with an EC50 less than 0.1 μM in Vero E6 cells.
T835 94075-94285 Sentence denotes 188 Gassen et al. demonstrated that niclosamide inhibits SKP2 activity, increases the lysine‐48‐linked polyubiquitination of the Benclin 1 level, boosts autophagy, and effectively impedes MERS‐CoV replication.
T836 94286-94375 Sentence denotes 239 Niclosamide inhibited MERS‐CoV replication by up to 1000‐fold at 48 h p.i. at 10 μM.
T837 94376-94379 Sentence denotes 239
T838 94380-94527 Sentence denotes Jeon et al. conducted a screening of FDA approved drugs in Vero cells to discover promising antiviral drug candidates against SARS‐CoV‐2 infection.
T839 94528-94629 Sentence denotes 240 They reported 24 drugs that exhibited antiviral efficacy with IC50 values between 0.1 and 10 µM.
T840 94630-94793 Sentence denotes Among them two approved drugs, niclosamide (181) and ciclesonide (182; Figure 39), exhibited notable inhibitory activities against virus replication in Vero cells.
T841 94794-94882 Sentence denotes Niclosamide exhibited very potent antiviral activity against SARS‐CoV‐2 (IC50, 0.28 µM).
T842 94883-94974 Sentence denotes The action of niclosamide might be attributed to autophagy as it was reported for MERS‐CoV.
T843 94975-95120 Sentence denotes 239 Ciclesonide (182; Figure 39) is another interesting drug candidate with far lower antiviral potency (IC50, 4.33 µM) compared to niclosamide.
T844 95121-95192 Sentence denotes It is a cortisol derivative used to treat asthma and allergic rhinitis.
T845 95193-95304 Sentence denotes 241 A recent report by Matsuyama et al. confirmed ciclesonide as a possible antiviral drug against SARS‐CoV‐2.
T846 95305-95462 Sentence denotes 242 A treatment report of three COVID‐19 patients (https://www3.nhk.or.jp/nhkworld/en/news/20200303_20/) merits further clinical investigation of this drug.
T847 95463-95571 Sentence denotes The molecular target of ciclesonide's antiviral activity was revealed to be NSP15, a viral riboendonuclease.
T848 95572-95717 Sentence denotes Together with its well‐established anti‐inflammatory effects, ciclesonide could offer an interesting option for the control of COVID‐19 symptoms.
T849 95718-95882 Sentence denotes Azithromycin showed a synergistic effect in combination with hydroxychloroquine in vitro against SARS‐CoV‐2 at realistic concentrations reachable in the human lung.
T850 95883-95964 Sentence denotes Clinical trials with this antibiotic were initiated in New York on 24 March 2020.
T851 95965-96073 Sentence denotes 243 Very recently, however, the clinical benefit of the drug in COVID‐19 patients was called into question.
T852 96074-96076 Sentence denotes 82
T853 96077-96236 Sentence denotes Studies for colchicine as an anti‐SARS‐CoV‐2 agent are currently ongoing with the aim of curtailing inflammation and lung complications in mild COVID‐19 cases.
T854 96237-96240 Sentence denotes 244
T855 96241-96338 Sentence denotes Famotidine has been proposed as a therapeutic against COVID‐19, and a clinical trial is underway.
T856 96339-96428 Sentence denotes 245 It is used to treat peptic ulcers and gastroesophageal reflux disease, among others.
T857 96429-96514 Sentence denotes Cimetidine is a similar drug and has also been suggested as a treatment for COVID‐19.
T858 96515-96618 Sentence denotes Dipyridamole was proposed as a treatment for COVID‐19 as well, and a clinical study is being conducted.
T859 96619-96707 Sentence denotes 246 It is a nucleoside transport and PDE3 inhibitor that prevents blood clot formation.
T860 96708-96815 Sentence denotes Sildenafil was proposed as treatment for COVID‐19, and it is currently being investigated in a small trial.
T861 96816-96911 Sentence denotes 247 It is a medication used to treat erectile dysfunction and pulmonary arterial hypertension.
T862 96912-96990 Sentence denotes Fenofibrate and bezafibrate have been suggested for the treatment of COVID‐19.
T863 96991-97119 Sentence denotes Fenofibrate is a blood lipid‐lowering medicine of the fibrate class.  248 , 249 Bezafibrate is a related lipid‐lowering agent.
T864 97120-97265 Sentence denotes The HIV‐protease inhibitor nelfinavir (183; Figure 39) strongly inhibited replication of SARS‐CoV‐1 in Vero cells with an EC50 value of 0.048 µM.
T865 97266-97350 Sentence denotes It was suggested to exert its effect at the post‐entry step of SARS‐CoV‐1 infection.
T866 97351-97539 Sentence denotes 250 Recently, Yamamoto et al reported that nelfinavir also potently inhibited replication of SARS‐CoV‐2 among nine other Anti‐HIV drugs tested (IC50, 1.13 µM; CC50, 24.32 µM; SI = 21.52).
T867 97540-97651 Sentence denotes 251 The measured serum concentrations of nelfinavir were 3–6 times higher than the reported EC50 of this drug.
T868 97652-97736 Sentence denotes This indicates that it is a promising drug candidate for the management of COVID‐19.
T869 97737-97955 Sentence denotes Other drugs tested against SARS‐CoV‐2 replication were amprenavir (EC50, 31.32 µM; CC50 > 81 µM; SI > 2.59), darunavir (EC50, 46.41 µM; CC50 > 81 µM; SI > 1.75), and indinavir (EC50, 59.14 µM; CC50 > 81 µM; SI > 1.37).
T870 97956-98051 Sentence denotes Tipranavir inhibited SARS‐CoV‐2 replication as well (EC50, 3.34 µM; CC50, 76.80 µM; SI = 5.76).
T871 98052-98258 Sentence denotes Ritonavir (EC50, 8.63 µM; CC50, 74.11 µM, SI = 8.59), saquinavir (EC50, 8.83 µM; CC50, 44.43 µM; SI = 5.03), and atazanavir (EC50, 9.36 µM; CC50 > 81 µM; SI > 8.65) suppressed SARS‐CoV‐2 at less than 10 µM.
T872 98259-98445 Sentence denotes Lopinavir, which was studied in SARS and COVID‐19 patients, also potently inhibited SARS‐CoV‐2 replication with the highest selectivity index (EC50, 5.73 µM; CC50, 74.44 µM; SI = 12.99).
T873 98446-98638 Sentence denotes De Wilde et al. identified four drugs—chloroquine (8), chlorpromazine (15), loperamide (184), and lopinavir (185)—by screening of an FDA approved drugs library (for structures, see Figure 40).
T874 98639-98794 Sentence denotes 252 All of them blocked SARS‐CoV‐1, MERS‐CoV, and HCoV‐229E replication at small concentrations, suggesting potential as broad‐spectrum virostatic agents.
T875 98795-98857 Sentence denotes Figure 40 Drugs repurposed for MERS‐ and SARS‐CoV infections.
T876 98858-99198 Sentence denotes MERS, Middle East respiratory syndrome; SARS‐CoV, severe acute respiratory syndrome coronavirus Chloroquine (8) was able to inhibit SARS‐CoV‐2 viral replication in vitro, but a recent study found no clinical benefit for COVID‐19 patients who had received the drug 82 (the drug is discussed in detail in the section viral entry inhibitors).
T877 99199-99282 Sentence denotes Chlorpromazine (15) stopped the replication of SARS‐CoV‐1, MERS‐CoV, and HCoV‐229E.
T878 99283-99396 Sentence denotes It is a neuroleptic drug used against schizophrenia; 253 here, it interferes with clathrin‐mediated endocytosis.
T879 99397-99650 Sentence denotes Since, clathrin‐mediated endocytosis is a crucial port for viral entry into the host cell, used by MHV, 254 , 255 , 256 SARS‐CoV‐1, 99 and MERS‐CoV, 102 future clinical trials could help elucidate this drug's therapeutic potential against COVID‐19.
T880 99651-99784 Sentence denotes Loperamide (184), an opioid receptor agonist against diarrhea, 257 inhibited the replication of SARS‐CoV‐1, MERS‐CoV, and HCoV‐229E.
T881 99785-99880 Sentence denotes Lopinavir (185) is an HIV protease inhibitor and was previously shown to block SARS‐CoV‐1 Mpro.
T882 99881-99884 Sentence denotes 258
T883 99885-100023 Sentence denotes Shin et al. analyzed a library of 2334 approved medications and bioactive molecules to find possible antiviral compounds against MERS‐CoV.
T884 100024-100222 Sentence denotes 259 A series of hit compounds was identified, categorized as anticancer (189, 190), antipsychotics (191, 192), and antidepressant (193) with inhibition activity between 2.1 and 14.4 µM (Figure 38).
T885 100223-100344 Sentence denotes Saracatinib (189) was especially interesting, as it had remarkable anti‐MERS‐CoV activity (EC50 of 2.9 µM, CC50 > 50 µM).
T886 100345-100495 Sentence denotes It is a small molecule drug with oral bioavailability used in the management of malignant neoplasms via Src‐family tyrosine kinases (SFKs) inhibition.
T887 100496-100638 Sentence denotes It also suppressed other CoVs such as SARS‐CoV‐1 (EC50, 2.4 µM), HCoV‐229E (EC50, 5.1 µM), and FIPV (EC50, 7.0 µM) at nontoxic concentrations.
T888 100639-100693 Sentence denotes Drugs 190 to 193 showed moderate antiviral activities.
T889 100695-100731 Sentence denotes 6 Conclusions and future directions
T890 100732-100920 Sentence denotes The SARS‐CoV‐2 outbreak has caused worldwide disruption and was recently declared a global pandemic by the World Health Organization (WHO) owing to its rapid spread and high fatality rate.
T891 100921-101017 Sentence denotes As there is no effective treatment to date, the number of infections continues to rise globally.
T892 101018-101159 Sentence denotes This has led numerous research groups around the world to prioritize the identification and development of new therapeutics against COVID‐19.
T893 101160-101328 Sentence denotes Although it is often considered the most promising method to prevent or contain future coronavirus outbreaks, an all‐round anti‐CoV vaccine is possibly a long way away.
T894 101329-101425 Sentence denotes Small molecule drugs have the potential to be effective, rapidly produced, and widely available.
T895 101426-101645 Sentence denotes Indeed, several small molecules have been investigated and advanced to clinical trials for the treatment of COVID‐19, selected drug candidates are indicated in Table 3 (https://covid-19.heigit.org/clinical_trials.html).
T896 101646-101731 Sentence denotes Table 3 Selection of molecules investigated in ongoing clinical studies (July, 2020)
T897 101732-101775 Sentence denotes Name Structure Description Recent trials
T898 101776-101833 Sentence denotes Azithromycin Macrolide antibiotic IRCT20200428047228N2
T899 101834-101845 Sentence denotes NCT04405921
T900 101846-101868 Sentence denotes EUCTR2020‐001605‐23‐ES
T901 101869-101925 Sentence denotes Favipiravir Broad spectrum antiviral drug NCT04434248
T902 101926-101942 Sentence denotes ChiCTR2000033491
T903 101943-101954 Sentence denotes NCT04425460
T904 101955-102016 Sentence denotes Triazavirin Broad‐spectrum antiviral drug ChiCTR2000030001
T905 102017-102066 Sentence denotes Umifenovir Antiviral drug IRCT20200523047550N1
T906 102067-102088 Sentence denotes IRCT20151227025726N15
T907 102089-102109 Sentence denotes IRCT20200325046859N2
T908 102110-102163 Sentence denotes Baloxavir marboxil Antiviral drug ChiCTR2000029548
T909 102164-102180 Sentence denotes ChiCTR2000029544
T910 102181-102221 Sentence denotes Remdesivir Antiviral drug NCT04431453
T911 102222-102233 Sentence denotes NCT04409262
T912 102234-102245 Sentence denotes NCT04410354
T913 102246-102294 Sentence denotes Ribavirin Antiviral drug IRCT20200324046850N2
T914 102295-102311 Sentence denotes ChiCTR2000030922
T915 102312-102378 Sentence denotes Lopinavir/ritonavir Anti‐HIV combination medication NCT04403100
T916 102379-102390 Sentence denotes NCT04376814
T917 102391-102442 Sentence denotes Celecoxib COX‐2 selective NSAID ChiCTR2000031630
T918 102443-102498 Sentence denotes Chloroquine Antimalarial drug EUCTR2020‐001441‐39‐IT
T919 102499-102510 Sentence denotes NCT04447534
T920 102511-102522 Sentence denotes NCT04443270
T921 102523-102585 Sentence denotes Hydroxychloroquine Antimalarial drug EUCTR2020‐001558‐23‐IT
T922 102586-102608 Sentence denotes EUCTR2020‐001441‐39‐IT
T923 102609-102631 Sentence denotes EUCTR2020‐001501‐24‐IT
T924 102632-102686 Sentence denotes Mefloquine Antimalarial drug EUCTR2020‐001194‐69‐ES
T925 102687-102746 Sentence denotes Ivermectin Broad‐spectrum antiparasitic drug NCT04445311
T926 102747-102758 Sentence denotes NCT04435587
T927 102759-102770 Sentence denotes NCT04431466
T928 102771-102834 Sentence denotes Colchicine Broad‐spectrum anti‐inflammatory drug NCT04416334
T929 102835-102857 Sentence denotes EUCTR2020‐001841‐38‐ES
T930 102858-102878 Sentence denotes IRCT20190810044500N5
T931 102879-102965 Sentence denotes Corticosteroids (misc.) Broad‐spectrum anti‐inflammatory drug IRCT20151227025726N17
T932 102966-102977 Sentence denotes NCT04395105
T933 102978-103000 Sentence denotes IRCT20120215009014N354
T934 103001-103073 Sentence denotes Pirfenidone Antifibrotic, anti‐inflammatory drug IRCT20200314046764N1
T935 103074-103090 Sentence denotes ChiCTR2000031138
T936 103091-103143 Sentence denotes Tranilast Anti‐inflammatory drug ChiCTR2000030002
T937 103144-103184 Sentence denotes Selinexor Anticancer drug NCT04355676
T938 103185-103196 Sentence denotes NCT04349098
T939 103197-103219 Sentence denotes EUCTR2020‐001411‐25‐GB
T940 103220-103280 Sentence denotes Valsartan Angiotensin II receptor antagonist DRKS00021732
T941 103281-103292 Sentence denotes NCT04335786
T942 103293-103347 Sentence denotes Dipyridamole PDE3 inhibitor NCT04424901 NCT04391179
T943 103348-103417 Sentence denotes Vidoflumidus (IMU‐838) Investigational drug EUCTR2020‐001264‐28‐HU
T944 103418-103472 Sentence denotes Azvudine Investigational antiviral ChiCTR2000032769
T945 103473-103484 Sentence denotes NCT04425772
T946 103485-103501 Sentence denotes ChiCTR2000030487
T947 103502-103552 Sentence denotes EIDD‐2801 Investigational antiviral NCT04405570
T948 103553-103564 Sentence denotes NCT04405739
T949 103565-103576 Sentence denotes NCT04392219
T950 103577-103600 Sentence denotes John Wiley & Sons, Ltd.
T951 103601-103725 Sentence denotes This article is being made freely available through PubMed Central as part of the COVID-19 public health emergency response.
T952 103726-103908 Sentence denotes It can be used for unrestricted research re-use and analysis in any form or by any means with acknowledgement of the original source, for the duration of the public health emergency.
T953 103909-104092 Sentence denotes As outlined in this review, inhibitors of important viral enzymes or structures, such as Mpro, PLpro, or RdRP have displayed encouraging activity against various human‐infecting CoVs.
T954 104093-104361 Sentence denotes Since, both contagious viruses, SARS‐CoV‐1 and SARS‐CoV‐2, have a similar mechanism of infection; and both share the same human receptor, ACE2, for viral entry, for example—already developed inhibitors against the former could potentially be used to combat the latter.
T955 104362-104506 Sentence denotes But despite the efficacy demonstrated by many inhibitors of SARS‐CoV‐1, no specific prophylactic or postexposure therapy is currently available.
T956 104507-104565 Sentence denotes The first step in the viral life cycle is the viral entry.
T957 104566-104690 Sentence denotes It represents an attractive intervention point by blocking the RBD‐ACE2 interaction or the virus‐cell membrane fusion event.
T958 104691-104843 Sentence denotes A large number of inhibitors, including peptides, antibodies, small‐molecule compounds, and natural products have been identified to hamper viral entry.
T959 104844-105025 Sentence denotes Some of the peptides and antibodies displayed substantial anti‐SARS activity and are therefore considered promising entry inhibitors with high potencies in the low micromolar range.
T960 105026-105146 Sentence denotes Despite the apparent match of SARS‐CoV‐2 S and ACE2, other possible viral entry receptors should not be left unexplored.
T961 105147-105388 Sentence denotes The glucose‐regulated protein 78 (GRP‐78, aka HSPA5), for instance, is employed as a coreceptor for entry by several viruses, including bat‐CoVs and MERS‐CoV, 260 and a study predicted that SARS‐CoV‐2 S might utilize this mechanism as well.
T962 105389-105470 Sentence denotes 261 Elevated levels of GRP‐78 in COVID‐19 patients suggest a supplementary link.
T963 105471-105608 Sentence denotes 262 Although as of yet unconfirmed, the development of therapeutics against additional targets like GRP‐78 should receive due attention.
T964 105609-105768 Sentence denotes Viral proteases are another very important target for the development of antiviral therapies, as they are directly involved in the viral replication processes.
T965 105769-105947 Sentence denotes Especially the Mpro is one of the best‐characterized viral targets, and numerous medicinal chemistry efforts have been already reported for the past outbreaks of SARS‐1 and MERS.
T966 105948-106066 Sentence denotes Main proteases are highly conserved among other CoVs, which allows the development of broad spectral antiviral agents.
T967 106067-106123 Sentence denotes Moreover, no human protease analog to the Mpro is known.
T968 106124-106192 Sentence denotes Thus, drugs targeting Mpro could be highly virus‐selective and safe.
T969 106193-106365 Sentence denotes In light of the urgency of the current outbreak, repositioning of already approved drugs is becoming a popular approach due to the availability of toxicity and safety data.
T970 106366-106458 Sentence denotes Drug repurposing has become fashionable, promising quick solutions to complicated questions.
T971 106459-106520 Sentence denotes Old and, presumably, safe drugs are proclaimed miracle cures.
T972 106521-106552 Sentence denotes The reality is a different one:
T973 106553-106765 Sentence denotes Widely employed broad‐spectrum antiviral drugs, such as (hydroxy)chloroquine, favipiravir, ribavirin, or umifenovir were reported to be effective against SARS‐CoV‐2, but could not convince in clinical trials yet.
T974 106766-106880 Sentence denotes Clinicians are faced with an avalanche of contraindications and a myriad of case reports to choose the right drug.
T975 106881-106966 Sentence denotes The drug repositioning strategy is, therefore, not a sound scientific path to a cure.
T976 106967-107100 Sentence denotes At best, it can provide a basis for extensive future research in all related fields, including synthetic organic medicinal chemistry.
T977 107101-107201 Sentence denotes A new problem with the current COVID‐19 outbreak is related to the spread of scientific information.
T978 107202-107395 Sentence denotes When initial unfounded speculations about the alleged dangers of antihypertensive therapies with ACEis and ARBs were widely publicized in the media they caused great uncertainty among patients.
T979 107396-107505 Sentence denotes Impetuous communications such as these can have serious consequences and should not be proclaimed carelessly.
T980 107506-107641 Sentence denotes As it turns out, the benefits of continued antihypertensive therapy with these medicines in COVID‐19 patients far outweigh their risks.
T981 107642-107799 Sentence denotes There is even evidence of additional protective effects of ACEis and ARBs in this cohort, although the clinical relevance of this has yet to be investigated.
T982 107800-107989 Sentence denotes It is clear that governments and societies all over the world have been surprised by the recent coronavirus outbreak—as they were by the SARS outbreak in 2003 and the MERS epidemic in 2013.
T983 107990-108078 Sentence denotes Human‐infecting CoVs are on the rise, but quickly forgotten once life returns to normal.
T984 108079-108164 Sentence denotes However, this problem will not disappear by itself, but likely increase in intensity.
T985 108165-108271 Sentence denotes Viral spillover events are expected to increase in frequency as humans continue to invade new territories.
T986 108272-108416 Sentence denotes We hope that, this time, the world will heed nature's warning to finance and conduct groundbreaking research on CoVs and their disease patterns.
T987 108417-108554 Sentence denotes Only with a profound understanding of the viral life cycle and the affected human physiology we can prevent and control future outbreaks.
T988 108556-108577 Sentence denotes CONFLICT OF INTERESTS
T989 108578-108631 Sentence denotes The authors declare there is no conflict of interest.
T990 108633-108654 Sentence denotes AUTHORS CONTRIBUTIONS
T991 108655-108694 Sentence denotes TP, LLW, MM, and ME collected the data.
T992 108695-108745 Sentence denotes TP wrote the manuscript, which was revised by all.
T993 108747-108769 Sentence denotes Supporting information
T994 108770-108793 Sentence denotes Supporting information.
T995 108794-108830 Sentence denotes Click here for additional data file.
T996 108832-108847 Sentence denotes ACKNOWLEDGMENTS
T997 108848-108908 Sentence denotes Manoj Manickam thanks PSG managementfor their moral support.
T998 108909-108967 Sentence denotes Open access funding enabled and organized by Projekt DEAL.
T999 108969-109147 Sentence denotes Thanigaimalai Pillaiyar received his doctoral degree in Medicinal Chemistry in 2011 under the supervision of Prof. Dr. Sang‐Hun Jung at Chungnam National University, South Korea.
T1000 109148-109344 Sentence denotes In 2011, he won a “Japanese Society for the Promotion of Science Postdoctoral Fellowship (JSPS)” for 2 years with Prof. Dr. Yoshio Hayashi at Tokyo University of Pharmacy and Life Sciences, Japan.
T1001 109345-109461 Sentence denotes He was awarded an Alexander von Humboldt postdoctoral fellowship (AvH) in 2013 for 2 years with Prof. Dr. Christa E.
T1002 109462-109500 Sentence denotes Müller at University of Bonn, Germany.
T1003 109501-109557 Sentence denotes He worked as a visiting scientist at the Prof. Steven V.
T1004 109558-109629 Sentence denotes Ley's Laboratory, Department of Chemistry, and University of Cambridge.
T1005 109630-109750 Sentence denotes Currently he is working on developing modulators/inhibitors for SARS‐CoV‐2 Mpro and various G‐protein‐coupled receptors.
T1006 109751-109759 Sentence denotes Lukas L.
T1007 109760-109824 Sentence denotes Wendt is a PhD student in the research group of Prof. Christa E.
T1008 109825-109867 Sentence denotes Müller at the University of Bonn, Germany.
T1009 109868-109936 Sentence denotes He studied Pharmacy at the University of Frankfurt am Main, Germany.
T1010 109937-110170 Sentence denotes In 2016, he started his PhD in a Medicinal Chemistry PhD program at the University of Bonn, where he is working on the design and preparation of small molecule ligands for G protein‐coupled receptors with immunomodulatory properties.
T1011 110171-110258 Sentence denotes He is actively involved in teaching students of medicinal and pharmaceutical chemistry.
T1012 110259-110345 Sentence denotes Manoj Manickam received his PhD in 2010 from Bharathiar University, Coimbatore, India.
T1013 110346-110435 Sentence denotes He continued to work as a Research Associate at Orchid Chemicals and Pharmaceuticals Ltd.
T1014 110436-110607 Sentence denotes Then he moved to Chungam National University, South Korea, to continue his research as Postdoctoral Researcher and Research Professor working with Professor Sang‐Hun Jung.
T1015 110608-110758 Sentence denotes Currently, he is working in PSG Institute of Technology and Applied Research, Coimbatore, India as Assistant Professor in the Department of Chemistry.
T1016 110759-110900 Sentence denotes He is actively involved in the preparation of small molecules for various therapeutic targets such as heart failure, hypertension and cancer.
T1017 110901-111075 Sentence denotes Maheswaran Easwaran received his doctoral degree in veterinary medicine in 2016 under the supervision of Prof. Dr. Hyun‐Jin Shin at Chungnam National University, South Korea.
T1018 111076-111158 Sentence denotes He continued his research as a postdoctoral researcher in the same lab for 1 year.
T1019 111159-111292 Sentence denotes Then, he moved to Kangwon National University, South Korea, to continue his research as a senior researcher with Prof. Dr. Juhee Ahn.
T1020 111293-111444 Sentence denotes Presently, he is working at the Sethu Institute of Technology, Virudhunagar, India, as Assistant Professor in the Department of Biomedical Engineering.
T1021 111445-111539 Sentence denotes He is actively involved to combat multidrug resistant bacterial pathogens using phage therapy.