LitCovid-sentences  

PMC:7074424 / 9635-27257 JSONTXT 15 Projects

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Id Subject Object Predicate Lexical cue
T47 0-22 Sentence denotes Results and Discussion
T48 23-103 Sentence denotes A total of 392 articles were found after preliminary screening of the databases.
T49 104-178 Sentence denotes After title and abstract screening, a total of 230 articles were excluded.
T50 179-238 Sentence denotes Full-text screening of the remaining 154 articles was done.
T51 239-345 Sentence denotes Among these studies, after full-text screening, a total of 122 articles were included in the final review.
T52 346-401 Sentence denotes The PRISMA flowchart of the study is shown in Figure 3.
T53 402-587 Sentence denotes Thirty-two articles were excluded after full-text screen (review articles = 7, articles not specifying drug targets against CoV = 22, articles in other language other than English = 3).
T54 588-690 Sentence denotes Details of studies with important structural and functional target proteins are summarized in Table 1.
T55 691-710 Sentence denotes Figure 3 Flowchart
T56 711-832 Sentence denotes Table 1 Details of studies representing protein database structures of major targets in coronavirus and their structures
T57 833-876 Sentence denotes PDB ID Details Inhibitor IC50 Reference
T58 877-886 Sentence denotes N protein
T59 887-966 Sentence denotes 4KXJ Interaction between PJ34 and NTD of N protein of HCoV-OC43 PJ34 - [26]
T60 967-1003 Sentence denotes 3V3P Structure not released [30]
T61 1004-1074 Sentence denotes 4LM7 Interactions of NTD of N protein of HCoV-OC43 with UMP - [26]
T62 1075-1145 Sentence denotes 4LI4 Interactions of NTD of N protein of HCoV-OC43 with AMP - [26]
T63 1146-1154 Sentence denotes Protease
T64 1155-1209 Sentence denotes 4TWY 3CLPro of SARS-CoV with an inhibitor 3BL [27]
T65 1210-1269 Sentence denotes 4TWW 3CLPro of SARS-CoV with an inhibitor 41 63 µM [27]
T66 1270-1331 Sentence denotes 4WY3 3CLPro of SARS-CoV with an inhibitor 3X5 240 µM [27]
T67 1332-1391 Sentence denotes 4OVZ CoV PLPro complexed with inhibitor P85 490 nM [31]
T68 1392-1456 Sentence denotes 3MJ5 SARS-CoV PLPro complexed with inhibitor GRM 320 nM [32]
T69 1457-1489 Sentence denotes 2FE8 SARS-CoV PLPro - - [33]
T70 1490-1605 Sentence denotes 1UK4 SARS-CoV 3CLPro and its interactions with an inhibitor Substrate analog hexapeptidyl CMK inhibitor IC50 ca.
T71 1606-1616 Sentence denotes 2 mM [34]
T72 1617-1689 Sentence denotes 1UJ1, 1UK3, 1UK2 SARS-CoV M-pro, apo-enzyme at different pH - - [34]
T73 1690-1749 Sentence denotes 3VB6 SARS-CoV 3CLPro in complex with C6Z C6Z 39 µM [35]
T74 1750-1803 Sentence denotes 3VB5 SARS-CoV 3CLPro with C4Z C4Z 1.3-4.6 µM [35]
T75 1804-1840 Sentence denotes 3TLO HCoV-NL63 3CLPro - - [3637]
T76 1841-1921 Sentence denotes 6LU7 Main protease of 2019-nCoV and its complex with N3 (inhibitor) - - [38]
T77 1922-1935 Sentence denotes Spike protein
T78 1936-2038 Sentence denotes 5ZUV HR1 motif of HCoV-229E in complex with EK1 Modified OC43-HR2P peptide (EK1) 0.19-0.62 µM [39]
T79 2039-2087 Sentence denotes 5ZVM EK1 in complex with SARS HR1 motif [39]
T80 2088-2127 Sentence denotes 5X4S NTD of SARS-CoV S protein [40]
T81 2128-2160 Sentence denotes 5WRG SARS-CoV S protein [41]
T82 2161-2224 Sentence denotes 6Q05 MERS-CoV S structure in complex with Sialyl-Lewis [42]
T83 2225-2289 Sentence denotes 6ACG SARS-CoV S protein: ACE-2 (conformation 1) complex [43]
T84 2290-2354 Sentence denotes 6ACK SARS-CoV S protein: ACE-2 (conformation 3) complex [43]
T85 2355-2424 Sentence denotes 3SCI RBD of S protein interaction with ACE-2 [44] to be published
T86 2425-2712 Sentence denotes NTD=N-terminal domain, CoV=Coronovirus, 3CLPro=3C-like protease, PLpro=Papain-like protease, MERS=Middle East respiratory syndrome, SARS=Severe acute respiratory syndrome, ACE-2=Angiotensin converting enzyme-2, RBD=Receptor-binding domain, nCoV=Novel coronavirus, S protein=Spike protein
T87 2714-2727 Sentence denotes Spike protein
T88 2728-3087 Sentence denotes The spike protein is a clove-shaped, type I-TM protein.[2] The spike protein has three segments that are ectodomain (ED) region, TM region, and intracellular domain, which comprises the intracellular short tail part.[2] The receptor-binding S1 domain (three S1 heads) and the membrane fusion subunit S2 (trimeric stalk) on C-terminal together comprise the ED.
T89 3088-3737 Sentence denotes Spike proteins gather in the trimeric form on the outer surface of the virion, giving it the appearance of a crown, due to which it is called CoV.[2] The spike protein plays an important role in virus entry into the host.[10] Initial interactions between the S1 domain and its host receptor (ACE2 in case of SARS-CoV and PP 4 In case of MERS-CoV) and subsequent S2 segment mediated fusion of the host and viral membranes allow the CoV- RNA genome to enter inside the host cells and thus, these proteins represent as important targets from drug discovery side.[10] The spike protein also activates the immune response of the host cell toward CoV.[10]
T90 3739-3748 Sentence denotes S1 domain
T91 3749-3850 Sentence denotes The main components of the S1 domain are the N-terminal domain (NTD) and the C-terminal domain (CTD).
T92 3851-4158 Sentence denotes The S1 domain acts as a major antigen on the surface of the virus[40] and has a receptor-binding domain (RBD).[25] The 18 residues of ACE-2 interact with the RBD (contain 14 amino acids) of SARS-CoV spike protein,[45] and for this contact, K341 of ACE-2 and R453 residue of RBD play the most important role.
T93 4159-4323 Sentence denotes If point mutated on the D454 or R441 of RBD, it disturbs the binding activity with ACE-2.[25] The S1 domain interacts with the ACE-2 or DPP-4 receptors of the host.
T94 4324-4792 Sentence denotes Anti-ACE-2 antibody blocked viral entry and replication in Vero E6 cells.[1445] One another mechanism of virus for binding to host cell is using dendritic cell-specific intercellular adhesion molecule-3 grabbing non-integrin (DC-SIGN receptor) or L-SIGN in lymph nodes or in liver.[4647] S protein has seven (109, 118, 119, 158, 227, 589, and 699) glycosylation asparagine-linked sites, which is pivotal for both L-SIGN- or DC-SIGN-based virus entry into the host.[48]
T95 4794-4804 Sentence denotes S2 subunit
T96 4805-4898 Sentence denotes The S2 subunit has two heptad repeat regions (HR 1 and 2) and hydrophobic fusion peptide.[25]
T97 4900-4966 Sentence denotes Drug designing strategies targeting S protein and its interactions
T98 4967-5202 Sentence denotes The RBD is targeted in many drug designing studies.[25] A peptide sequence with sequence similarity to the RBD of S protein hampered S1-RBD: ACE-2 interaction and prevented entry of SARS-CoV into Vero cells (IC50 around 40 μM).[254950]
T99 5203-5292 Sentence denotes A SARS-CoV RBD-specific antibody (FM6) failed to inhibit the occurrence of infection.[39]
T100 5293-5592 Sentence denotes OC43-HR2P, a peptide derived from heptad repeat 2 regions of S2 domain of HCoV-OC43 and its optimized form EK1, showed pan-CoV fusion inhibition property.[39] The structure (protein data bank [PDB] ID 5ZUV and 5ZVM) shows a stable 6-helix bundle structure with α-HCoV and long β-HCoV-HR1 domain.[39]
T101 5593-5788 Sentence denotes Chloroquine, an antimalarial agent, inhibits SERS-CoV by elevation of endosomal pH and alters the terminal glycosylation of ACE-2, which ultimately interferes with the virus receptor binding.[51]
T102 5789-5996 Sentence denotes Other inhibitors SSAA09E2 block the S-ACE2 interaction, SSAA09E1 inhibits the host protease cathepsin L (which is important for viral entry), and SSAA09E3 prevents fusion of host and viral cell membrane.[52]
T103 5997-6488 Sentence denotes Kao et al. identified 18 small molecules that targeted the S-ACE-2-mediated entry of virus into human cell.[53] In 293T cells expressing ACE-2, one of these agents (VE607) showed a significant inhibition of SARS-pseudovirus entry.[53] In Vero E6 cells, two other molecules tetra-O-galloyl beta-D-glucose and luteolin also inhibited SARS-pseudovirus and SARS-CoV infection.[53] In virus-infected Vero E6 cells, a siRNA against the S sequences of SARS-CoV inhibited SARS-CoV replication.[2554]
T104 6489-6740 Sentence denotes The S230 antibody (origin: memory B-cells of SARS-CoV-infected persons) neutralizes wide spectrum of isolates of SARS-CoV.[55] S230 antibody Fab fragment binds to the SARS-CoV complex to neutralize it, and their structures are also available (PDB IDs:
T105 6741-6845 Sentence denotes 6NB6, 6NB7, and 6NB8.[55] The monoclonal antibody, m396, has a competitive role for RBD binding (PDB ID:
T106 6846-6856 Sentence denotes 2DD8).[56]
T107 6857-7187 Sentence denotes Monoclonal antibody can be generated by immunizing the spike protein of SERS-CoV (transgenic mice) or from the B-cells of CoV-infected persons.[25] Spike-specific monoclonal antibodies 80R and CR301 block the S-ACE-2 interactions and thus neutralize infection by human SARS-CoV (HKu39849 and Tor2) and palm civet strain (SZ3).[25]
T108 7188-7384 Sentence denotes Mice vaccinated with SARS-n DNA showed T-cell immune response (both induction and proliferation),[57] and cytotoxic T-cell response was seen against SARS-DNA-transfected alveolar epithelial cells.
T109 7386-7405 Sentence denotes Envelop protein (E)
T110 7406-7591 Sentence denotes The E protein is the smallest (8.4–12 kDa size) TM structural protein of CoV.[5859] Two distinct domains comprise the E protein: the hydrophobic domain and the charged cytoplasmic tail.
T111 7592-7680 Sentence denotes However, the structure is highly variable among different members of the CoV family.[59]
T112 7681-8010 Sentence denotes The E protein has a special role in viral morphogenesis, especially during assembly and egress.[59] CoVs lacking E protein show lower viral titer, immature, and inefficient progenies.[5860] Oligomerization of E proteins leads to the formation of ion channels.[61] However, the importance of these ion channels is still not clear.
T113 8011-8498 Sentence denotes Many other studies infer that the E protein acts in coordination with other intracellular proteins and modulates the activity of those proteins.[59] E protein also acts as a virulence factor.[59] E protein has an important role in CoV assembly and budding formation.[24] Apart from this, E protein found around the ER and Golgi body regions.[60] Hexamethylene amiloride blocks this E protein-associated ion channel activity in the mammalian cells expressing SERS-CoV envelop protein.[62]
T114 8500-8516 Sentence denotes Membrane protein
T115 8517-8796 Sentence denotes Maintenance of the shape of the viral envelope is the most important function of the M protein,[60] and the M protein performs this job by interacting with other CoV proteins,[63] incorporation of Golgi complex into new virions,[60] and stabilization of nucleocapsid protein.[60]
T116 8797-9689 Sentence denotes The M protein is characterized by three TM domains[64] with C-terminal inside (long) and N-terminal (short) outside.[63] The details of the protein structure is available in UniProt.[65] Through multiple protein–protein interactions, the M protein plays a crucial role in viral intracellular homeostasis.[60] Interaction between M–M, M–S, and M–N proteins takes a special part in viral assembly.[60] The M–S interactions are necessary for the interaction of spike protein in the ERGIC complex, also known as the Golgi complex, which is later incorporated into new viral progenies.[60] The M–N interactions are crucial for the stabilization of the RNP complex (nucleocapsid–RNA complex), which forms the viral core.[60] The M protein and the N protein are the major viral envelope proteins, defining viral shape, but it also takes part in the formation and release of virus-like particles.[60]
T117 9690-9907 Sentence denotes M protein also takes part in the sensitization of the host by the virus.[66] The M protein of SARS-CoV activates the nuclear factor kappa pathway and IFN-beta pathway, through a Toll-like receptor-dependent mechanism.
T118 9908-9985 Sentence denotes Again, a mutated M protein (V-68) failed to illicit an IFN-beta response.[66]
T119 9986-10182 Sentence denotes Mice vaccinated with SARS-M DNA showed T-cell immune response (both induction and proliferation),[57] and cytotoxic T-cell response was seen against SARS-DNA-transfected alveolar epithelial cells.
T120 10184-10208 Sentence denotes Nucleocapsid protein (N)
T121 10209-10315 Sentence denotes The structure of nucleocapsid protein (N protein) is conserved across different members of the CoV family.
T122 10316-10563 Sentence denotes The three characteristic intrinsically disordered regions (IDRs) of the nucleocapsid (N) protein are the N-arm, central linker (CL), and the C-tail.[4] The NTD and the CTD are the major structural and functional domain of the nucleocapsid protein.
T123 10564-10926 Sentence denotes The most important function of the N protein NTD is RNA binding, while the primary job of the CTD is dimerization.[49] As the CL region is rich in arginine and serine residue content, it also contains a large number of phosphorylation sites.[26] The C-terminal IDRs take an important part in nucleocapsid protein oligomerization and N–M protein interactions.[67]
T124 10927-11395 Sentence denotes Formation and maintenance of the RNP complex are the most important functions of the N protein.[9] It also regulates the replication and transcription of viral RNA, and in the host, it inhibits protein translation through EF1α-mediated action,[9] alteration of host cell metabolism, host cell cycle (N proteins are reported to inhibit CDK4), and apoptosis.[39] In human peripheral blood, N protein inhibits cell proliferation through the inhibition of cytokinesis.[68]
T125 11396-11435 Sentence denotes The NTD contains sites for RNA binding.
T126 11436-11740 Sentence denotes The RNA-binding sites on the NTD of N protein were identified by observing its interactions with ribonucleoside 5'-monophosphates (AMP, UMP, CMP, and GMP).[26] Using the information about interaction between AMP and UMP binding to the NTD of nucleocapsid protein, inhibitors of RNA binding were designed.
T127 11741-12210 Sentence denotes Three-dimensional structure with all complex can see from PDB that is 4LMC, 4LM9, 4LM7, and 4LI4, respectively.[26] One such molecule which was designed with this strategy is N-(6-oxo-5,6-dihydrophenanthridine-2-yl) (N, N dimethyl amino) (PJ34), which was designed using the HCoV-OC43 model.[26] Binding of PJ34 on NTD affects the genome binding and replication process of CoV.[26] The crystal structure of COV-OC43 N-NTD with inhibitor PJ34 complex is given in PDB ID:
T128 12211-12496 Sentence denotes 4KXJ.[26] On the basis of interactions between PJ34 and NTD of nucleocapsid protein, another inhibitor was designed that is H3 (6-chloro-7-(2-morpholin-4-yl-ethylamino) quinoxaline-5,8-dione), which also inhibits RNA binding.[2669] This highlights the importance of NTD in RNA binding.
T129 12497-12666 Sentence denotes Some of the herbal products, such as catechin gallate and gallocatechin gallate (both are polyphenolic compounds), have shown the inhibitory action against SARS-CoV.[70]
T130 12667-12757 Sentence denotes The CTD of N protein has a primary role in oligomerization, especially the C-terminal end.
T131 12758-12923 Sentence denotes A C-terminal tail peptide sequence N377–389 competes with the oligomerization process and significant inhibition of viral titer was seen at 300 μM concentration.[71]
T132 12924-13104 Sentence denotes N220, which is a nucleocapsid protein peptide, showed a high binding affinity to human MHC-1 in T2 cells, and the peptide sequence was successful in activating T-cells (cytotoxic).
T133 13105-13359 Sentence denotes In transgenic animals, the peptide further showed potential to selective killing of nucleocapsid protein expressing cells and is a potential candidate for DNA vaccine.[72] Other N protein-targeted peptides of importance are NP111, NP331, and NP351.[7273]
T134 13361-13370 Sentence denotes Proteases
T135 13371-13420 Sentence denotes The SERS-CoV genome encodes a number of proteins.
T136 13421-13626 Sentence denotes The replicase gene, which is a major component of the CoV genome encoded for 16 NSPs in the form of two large PPs (PP1a and PP1ab).[74] Two types of cysteine proteases act on these PPs to release the NSPs.
T137 13627-14015 Sentence denotes The C-terminal end of these PPs is cleaved by chymotrypsin-like cysteine protease (main protease [Mpro] or 3C-like protease [3CLpro]) and the N-terminal end is processed by the Mpro (also known as papain-like protease [PLpro]).[74] The first three cleavage sites of the PPs is cut by PLpro while the rest 11 sites are cleaved by CLpro, and this cleavage results in release of 16 NSPs.[75]
T138 14017-14033 Sentence denotes 3C-like protease
T139 14034-14240 Sentence denotes The 3CLpro is present in homodimer form and has cys-his dyad on active site which shows protease activity.[27] If mutated on the Ser139 and phe140 positions, it abolishes the dimerization of 3CLPro (PDB ID:
T140 14241-14450 Sentence denotes 3F9G).[76] This protease can cleave 11 sites in the p1 position of PP1a and PP1ab and can produce a mature protein that anchors the replication/transcription complex[377] and also releases the mature NSPs.[78]
T141 14451-14574 Sentence denotes N-(benzo[1,2,3]triazol-1-yl)-N-(benzyl) acetamido) phenyl) carboxamides are also found to be important inhibitors of CLPro.
T142 14575-14653 Sentence denotes The structure of CLPro inhibitor is with ML188 (IC50 1.5 μM) is reported (CID:
T143 14654-14671 Sentence denotes 46897844, PDB ID:
T144 14672-14738 Sentence denotes 3V3M).[7980] Another structure with CLPro inhibitor ML300 (PDB ID:
T145 14739-14750 Sentence denotes 4MDS, IC50:
T146 14751-15258 Sentence denotes 6.2 μM) is reported.[79] Some metal-conjugated and peptidomimetic compounds showed inhibitory activity against 3CLpro.[77] Some of the small molecules also act as an inhibitor that is arylboronic acids, quinolinecarboxylate derivatives, thiophenecarboxylate, and phthalhydrazide-substituted ketoglutamine analogs.[77] Some flavonoids are also reported to inhibit Mpro.[75] GC376 also has protease inhibitor activity.[81] A crystal structure of Mpro with small molecule inhibitor N3 is also reported (PDB ID:
T147 15259-15615 Sentence denotes 2AMQ).[82] Lopinavir and ritonavir, which are the inhibitors of HIV protease, also inhibit Mpro.[83] In silico studies directed that among commercially available drugs, colistin, valrubicin, icatibant, bepotastine, epirubicin, epoprostenol, vapreotide, aprepitant, caspofungin, and perphenazine also bind to the lopinavir/ritonavir-binding site on CoV.[83]
T148 15617-15637 Sentence denotes Papain-like protease
T149 15638-16072 Sentence denotes The PLpro cleaves the N-terminal region of the PP to generate three NSPs (NSP 1, 2, and 3).[374] PLpro has a catalytic core domain that contains 316 amino acid, which is responsible for cleaving replicase substrates, and a consensus sequence LXGG was required for cleavage.[78] Higher doses of zinc and zinc conjugates were found to inhibit both types of SARS protease (CLpro and PLpro).[84] Benzodioxole can inhibit the PLpro enzyme.
T150 16073-16129 Sentence denotes The crystal structure of interaction is shown in PDB ID:
T151 16130-16554 Sentence denotes 4OVZ, 4OWZ.[31] Through in silico approach, another new lead was identified (6577871) which was further optimized, and compound 15h (S configuration, enzyme IC50 =0.56 μM, antiviral EC50 =9.1 μM) and 15g (R configuration, enzyme IC50 =0.32 μM; antiviral EC50 =9.1 μM) were found to be the most important inhibitors.[32] The crystallized structural details of these interactions can be visualized in the PDB database (PDB ID:
T152 16555-16574 Sentence denotes 2FE8 and 3E9S).[32]
T153 16575-16695 Sentence denotes Many of the protease inhibitors are being used in the treatment of COVID-19, e.g., lopinavir–ritonavir combinations.[85]
T154 16697-16719 Sentence denotes Hemagglutinin esterase
T155 16720-17089 Sentence denotes This HE enzyme is present in the envelope of CoV, more specifically among beta-coronaviridiae.[86] The HE is a marker of CoV and influenza virus evolution.[86] HE mediates reversible attachment to O-acetylated-sialic-acids by acting both as lectins and as receptor-destroying enzymes.[86] Interactions between HE in complex with sialic acid can be visualized in PDB ID:
T156 17090-17099 Sentence denotes 3CL5.[86]
T157 17101-17116 Sentence denotes NTPase/helicase
T158 17117-17244 Sentence denotes NTPase/helicase plays an important role in the central dogma of the virus.[87] SARS-CoV helicase enzyme is a member of the SF1.
T159 17245-17622 Sentence denotes This enzyme prefers ATP, dATP, and dCTP as substrates; it also hydrolyzed all NTPs.[88] Toxicity issues are main obstacles in the development of inhibitors of helicase, and nonspecificity of inhibitors may cause serious toxicity.[87] However, despite theoretical limitations, helicase is being increasingly recognized as a druggable target for different disease conditions.[89]