LitCovid-sentences  

PMC:7352545 / 3439-82496 JSONTXT 13 Projects

Annnotations TAB TSV DIC JSON TextAE

Id Subject Object Predicate Lexical cue
T27 0-2 Sentence denotes 1.
T28 3-15 Sentence denotes Introduction
T29 16-217 Sentence denotes The recent coronavirus pandemic crisis is due to viral infection of severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2), causing uncontrolled inflammatory conditions in the human lung.
T30 218-456 Sentence denotes Soon after the first transmission emergence of SARS-CoV from animals to humans in China in 2003 [1], a genetically evolved beta-coronavirus genus similar to human viruses was discovered in Chinese horseshoe bats (Rhinolophus sinicus) [2].
T31 457-523 Sentence denotes To date, pneumonia is epidemiologically caused by diverse viruses.
T32 524-741 Sentence denotes For example, adenovirus, influenza virus, Middle East respiratory syndrome virus (MERS-V), parainfluenza virus, respiratory syncytial virus (RSV), SARS-CoV and enteric enveloped CoV can cause pneumonia in human hosts.
T33 742-990 Sentence denotes The World Health Organization (WHO) reported the official terminology of the 2019-Novel Coronavirus (2019-nCoV) on 13 January 2020, and on February 11th, WHO edited the name of the disease caused by 2019-nCoV to Coronavirus Disease-2019 (COVID-19).
T34 991-1189 Sentence denotes In academia, the International Committee on Taxonomy of Viruses (ICTV) provided official nomenclature to the virus as SARS-CoV-2 due to the similarity between the novel coronavirus and SARS-CoV [3].
T35 1190-1268 Sentence denotes SARS-CoV-2 is spreading and causing a global health-threatening emergency [4].
T36 1269-1422 Sentence denotes Researchers have been in a race to develop anti-viral drugs against SARS-CoV-2 even before the WHO declared a worldwide pandemic threatening human lives.
T37 1423-1519 Sentence denotes Preventive and therapeutic drugs for patients infected with SARS-CoV-2 are yet to be discovered.
T38 1520-1664 Sentence denotes The CoVs as enveloped forms can also infect the gastrointestinal track (GIT), although most other enteric viruses are naked in morphology [5,6].
T39 1665-1710 Sentence denotes CoVs can also rarely infect neural cells [7].
T40 1711-1872 Sentence denotes There is, unfortunately, no solid information on how the coronaviruses infect humans and animals with reciprocal infectivity and cause a zoonotic viral outbreak.
T41 1873-1984 Sentence denotes This is in contrast to influenza viruses, which are known to selectively utilize sialic acid (SA) linkages [8].
T42 1985-2134 Sentence denotes Currently, only limited information is available on β-CoVs, such as SARS-CoV and its receptor usage and infectible cell types from different species.
T43 2135-2280 Sentence denotes Host cell surface O-acetylated SAs are recognized by the lectin-like spike proteins of SARS CoV-2 for the first step of attachment to host cells.
T44 2281-2433 Sentence denotes Infectious virus interaction with the host cell surface is mediated by sialoglycans as the most important phenomenon in eukaryote-parasite co-evolution.
T45 2434-2521 Sentence denotes O-GlcNAc, a minor glycan source, is mainly found in the nucleus and cytosol (Figure 1).
T46 2522-2655 Sentence denotes Apart from the general roles of glycans, CoVs recognize host cells and attach to host cell surface molecules to enter the host cells.
T47 2656-2815 Sentence denotes For example, activity of the hemagglutinin-esterase (HE) enzyme relies on the typical carbohydrate-binding lectin and receptor-destroying enzyme (RDE) domains.
T48 2816-2932 Sentence denotes Most β-CoVs target 9-O-acetylated SAs, but certain species have switched to recognizing 4-O-acetyl SA instead [8,9].
T49 2933-3082 Sentence denotes Crystallographic data for the molecular structure of type II HE provides an explanation for the switching mechanism to acquire 4-O acetyl SA binding.
T50 3083-3378 Sentence denotes This event follows the orthodox ligand–receptor interaction (LRI), lectin–carbohydrate interaction (LCI), lectin–glycan interaction (LGI), lectin–sphingolipid interaction (LSI), protein–glycan interaction (PGI), protein–carbohydrate interaction (PCI), and also protein–protein interaction (PPI).
T51 3379-3492 Sentence denotes Recently, 332 protein candidates were suggested to be SARS-CoV-2-human protein interacting proteins through PPIs.
T52 3493-3617 Sentence denotes Among these, 66 human proteins, as druggable host factors, were further characterized as possible FDA-approvable drugs [10].
T53 3618-3717 Sentence denotes If PPI is involved, however, carbohydrates or glycans may serve as co-receptors or co-determinants.
T54 3718-3805 Sentence denotes Previous reports suggest that carbohydrates act as receptor determinants in most cases.
T55 3806-3958 Sentence denotes The general principles of PCI stereochemistry potentiate the SA–ligand switch by way of simple conformational shifts for the lectin and esterase domain.
T56 3959-4168 Sentence denotes This indicates that our examination of natural adaptation should be directed to how carbohydrate-binding proteins measure and observe carbohydrates, leading to virus evolution toward transitional host tropism.
T57 4169-4261 Sentence denotes The 9-carbon SAs are mainly animal-specific with anionic sugars attached to terminal sugars.
T58 4262-4302 Sentence denotes SAs exist in two forms, NeuGc and NeuAc.
T59 4303-4375 Sentence denotes NeuGc is a differentially modified form of the parental SA form, Neu5Ac.
T60 4376-4405 Sentence denotes SAs are structurally diverse.
T61 4406-4749 Sentence denotes For example, several modified SA forms are known for their structures including neuraminic acid (NeuC), N-acetyl neuraminic acid (NeuAc), N-glycolyl neuraminic acid (NeuGc), N,O-diacetyl neuraminic acid (occurs in horses), N,O-diacetyl neuraminic acid (occurs in bovines) and N-acetyl O-diacetyl neuraminic acid (occurs in bovines) (Figure 2).
T62 4750-4811 Sentence denotes Sialyltransferases (STs) biosynthesize different SA linkages.
T63 4812-4909 Sentence denotes SA linkage diversity occurs at the α2-3, α2-6, α2-8 or α2-9 to the SA or Gal residues (Figure 3).
T64 4910-5044 Sentence denotes For example, in formation of α2,3 SA or α2,6 SA structures, α2,3-ST and α2,6-ST utilize substrates such as Galβ-1,4-GlcNAc (Figure 4).
T65 5045-5151 Sentence denotes The most frequent modification of SAs is O-acetylation at positions of C4, C7, C8 and C9 of SA (Figure 5).
T66 5153-5155 Sentence denotes 2.
T67 5156-5178 Sentence denotes Classification of CoVs
T68 5179-5268 Sentence denotes Mammal- and avian-infectible CoVs consist of the broad-ranged subfamily of Coronavirinae.
T69 5269-5319 Sentence denotes The ICTV recommended classification is as follows:
T70 5320-5445 Sentence denotes Riboviria (Realm)—Nidovirales (Order)— Cornidovirineae (Suborder)—coronavirida (Family)—orthocoronavirinae—Coronavirus genus.
T71 5446-5509 Sentence denotes The four CoV genera [11] are the α-CoV, β-CoV, γ-CoV and δ-CoV.
T72 5510-5658 Sentence denotes The 2019-nCoV or SARS-CoV-2 belong to the β-CoV genus and are zoonotic and cause mammalian infection, causing respiratory disease in the human lung.
T73 5659-5771 Sentence denotes The α-CoV and β-CoV genus target mammal hosts while the δ-CoV and γ-CoV genus target avians and certain mammals.
T74 5772-5815 Sentence denotes The β-CoV genus has A, B, C and D lineages.
T75 5816-5872 Sentence denotes Among these, lineage B includes SARS-CoV and SARS-CoV-2.
T76 5873-5901 Sentence denotes Lineage C includes MERS-CoV.
T77 5902-6041 Sentence denotes The B lineage SARS-CoV and C lineage MERS-CoV, which are classified as β-CoVs, exhibit lethal rates of 10% and 35% in humans, respectively.
T78 6042-6247 Sentence denotes CoVs in humans are associated with respiratory infections such as colds with clinical importance, as experienced for the previous outbreak in 2003 of SARS-human CoV (HCoV), HCoV-HKU1 and HCoV-NL63 [12,13].
T79 6248-6404 Sentence denotes Human infectious HCoV includes seven species, including α-CoV (HCoV-NL63 and HCoV-229E) and β-CoV (SARS-CoV, SARS-CoV-2, HCoV-OC43, HCoV-HKU1 and MERS-CoV).
T80 6405-6450 Sentence denotes CoV RNA sequences mutate at a high frequency.
T81 6451-6541 Sentence denotes Among the known RNA viruses, CoVs bear the longest genome sizes of 26 to 32 kb length RNA.
T82 6542-6773 Sentence denotes Nucleotide sequences of CoV ssRNA genomes isolated from COVID-19 patients in Wuhan show a high homology of 89% with the nucleotide sequence of the previously known bat SARS-like CoV-ZXC-21 strain and 89% with the previous SARS-CoV.
T83 6774-6886 Sentence denotes The initial Wuhan CoV isolates belong to the β-CoV genus and were therefore termed SARS-CoV-2 or 2019-nCoV [14].
T84 6887-6965 Sentence denotes SARS-CoV-2 infects human respiratory tracts and causes outbreaks of pneumonia.
T85 6966-7040 Sentence denotes SARS-CoV-2 is a novel CoV and originates from the Wuhan district in China.
T86 7041-7177 Sentence denotes The genome sequence of SARS-CoV-2 exhibits 79% sequence homology with the SARS-CoV RNA sequence and 50% with the MERS-CoV sequence [15].
T87 7179-7181 Sentence denotes 3.
T88 7182-7226 Sentence denotes Structure, Components and Life Cycle of CoVs
T89 7227-7394 Sentence denotes CoVs are 60–140 nm in size and are enveloped (+) ssRNA viruses, which feature an RNA genome, directly available to function as mRNA and thus result in rapid infection.
T90 7395-7569 Sentence denotes CoVs exhibit RNA genomes of 28–32 kb, comprised of two large overlapping open reading frames (ORFs), which encode the virus replicase (transcriptase) and structural proteins.
T91 7570-7645 Sentence denotes The SARS-CoV-2 genome is 29,891 bp in size, which encodes 9860 amino acids.
T92 7646-7740 Sentence denotes The ssRNA are capped and tailed with a 5′-capping structure and 3′-poly A tail at the termini.
T93 7741-7906 Sentence denotes The genome is the same sense as virus mRNA indicating that the viral RNA is translated through its own (+) RNA to synthesize RNA dependent RNA polymerase (RdRp; PDB:
T94 7907-7913 Sentence denotes 6M71).
T95 7914-8034 Sentence denotes Generally, viral families are determined by the genome structure and virion morphologies of an envelope or naked capsid.
T96 8035-8127 Sentence denotes A virus with a naked capsid has a coat of nucleocapsid protein (N) coating the viral genome.
T97 8128-8220 Sentence denotes Viruses with an envelope have lipid envelopes further surrounding the outmost protein layer.
T98 8221-8356 Sentence denotes The 2019-nCoV (SARS-CoV-2) contains a spike (S) glycoprotein, E, dimeric HE enzyme, a membrane matrix glycoprotein (M), N and RNA [16].
T99 8357-8506 Sentence denotes The structural proteins are the S, N, M and E proteins, while the non-structural proteins are proteases such as Nsp3 and Nsp5 and RdRp such as Nsp12.
T100 8507-8647 Sentence denotes Among the N, M and S glycoproteins, the S glycoprotein is a fusion protein that recognizes the host receptor and enters the host cells [17].
T101 8648-8809 Sentence denotes The S, M and E proteins anchored into the endoplasmic reticulum (ER) membrane are trafficked to the endoplasmic reticulum–Golgi intermediate compartment (ERGIC).
T102 8810-8895 Sentence denotes The RNA genome linked with nucleoprotein buds into the ERGIC to form virus particles.
T103 8896-9007 Sentence denotes Assembled virions transported to the vesicular surface are released to the extracellular milieu via exocytosis.
T104 9008-9076 Sentence denotes The RNA generates the replicase as two polyproteins, pp1a and pp1ab.
T105 9077-9252 Sentence denotes The replicase-encoded viral proteases generate up to 16 nonstructural proteins (Nsps) in the cytosol to produce replicase enzyme and the replicase–transcriptase complex (RTC).
T106 9253-9360 Sentence denotes These enzymes including RTC synthesize RNAs for replication and transcription to generate viral RNA genome.
T107 9361-9451 Sentence denotes CoV genomes bear two or three protease genes and the coding enzymes cleave the replicases.
T108 9452-9549 Sentence denotes Together with the replicases, nonstructural proteins, termed Nsps, assemble into the RTC complex.
T109 9550-9606 Sentence denotes Nsp1 to Nsp16 are known to have multiple enzyme regions.
T110 9607-9736 Sentence denotes For example, Nsp1 degrades cellular mRNAs and, consequently blocks protein translation in host cells and innate immune responses.
T111 9737-9792 Sentence denotes Nsp2 recognizes the specific protein called prohibitin.
T112 9793-9867 Sentence denotes Nsp3 is a multi-domain transmembrane (TM) protein with diverse activities.
T113 9868-9996 Sentence denotes Ubiquitin-like 1 and acidic domains bind to N protein and ADP-ribose-1′-phosphatase (ADRP) activity induces cytokine expression.
T114 9997-10098 Sentence denotes The papain-like protease (PLpro)(PDB:6WX4)/ deubiquitinase domain cleaves virus-produced polyprotein.
T115 10099-10167 Sentence denotes Nsp4 is a TM scaffold protein for double-membrane vesicle structure.
T116 10168-10285 Sentence denotes Nsp5 has a main protease domain which also cleaves virus-produced polyprotein and Nsp6 acts as a TM scaffold protein.
T117 10286-10428 Sentence denotes The Nsp7 and Nsp8 proteins form the Nsp7-Nsp8 hexadecameric complex, which functions as an RNA polymerase-specific clamp and a primase enzyme.
T118 10429-10530 Sentence denotes Nsp9 is an RNA-binding protein that activates ExoN and 2-O-methyltrnasferase (MTase) enzyme activity.
T119 10531-10594 Sentence denotes Nsp10 binds to Nsp16 and Nsp14 to form a heterodimeric complex.
T120 10595-10666 Sentence denotes Nsp12 is the RdRp and Nsps13 is the RNA helicase and 5′ triphosphatase.
T121 10667-10714 Sentence denotes Nsps14 is a N7 MTase and 3′-5′ exoribonuclease.
T122 10715-10788 Sentence denotes ExoN of Nsap14 acts as an N7 MTase and attaches the 5′ cap to viral RNAs.
T123 10789-10896 Sentence denotes Viral exoribonuclease enzyme proofreads the viral RNA genome, where Nsp15 is a viral endoribonuclease (PDB:
T124 10897-10903 Sentence denotes 6VWW).
T125 10904-11028 Sentence denotes Nsp16 has 2-O-MTase enzyme activity, which shields viral RNA from melanoma differentiation associated protein-5 recognition.
T126 11030-11034 Sentence denotes 3.1.
T127 11035-11071 Sentence denotes Spike (S) Transmembrane Glycoprotein
T128 11072-11112 Sentence denotes In RNA viruses, the S glycoprotein (PDB:
T129 11113-11262 Sentence denotes 6VSB) is the biggest protein, heavily glycosylated and its N-terminal domain (NTD) sequence binds to the host receptor to enter the ER of host cells.
T130 11263-11332 Sentence denotes SARS-CoV-2 S-glycoprotein bears 22 N-glycan sequons in each protomer.
T131 11333-11409 Sentence denotes Therefore, the trimeric S glycoprotein surface is dominated by 66 N-glycans.
T132 11410-11518 Sentence denotes The S glycoprotein mediates direct and indirect interaction of virus with host cells in the infection cycle.
T133 11519-11608 Sentence denotes All CoVs exhibit a surface S glycoprotein, which bears the receptor-binding domain (RBD).
T134 11609-11659 Sentence denotes The S glycoprotein has a distinct spike structure.
T135 11660-11858 Sentence denotes When S glycoprotein binds to its host receptor, a host furin-like protease cleaves the S glycoprotein, which liberates the spike fusion peptides, allowing entry of the virus into the host cell [18].
T136 11859-12036 Sentence denotes The furin-like protease-generated S1 and S2 exist as a S1/S2 complex, where S1 in a homotrimeric form interacts with the host cell membrane and S2 penetrates the cytosolic area.
T137 12037-12155 Sentence denotes For SARS-CoV and MERS-CoV, the S1 C-terminal domains (CTDs) have a dual role in virus entry via attachment and fusion.
T138 12156-12237 Sentence denotes The S1 NTD binds to carbohydrate receptors because the S1 domains act as the RBD.
T139 12238-12290 Sentence denotes The CTD of S1 recognizes protein receptors via RBDs.
T140 12292-12296 Sentence denotes 3.2.
T141 12297-12321 Sentence denotes Nucleocapsid (N) Protein
T142 12322-12384 Sentence denotes In RNA viruses, the N protein recognizes the viral RNA genome.
T143 12385-12404 Sentence denotes The N protein (PDB:
T144 12405-12455 Sentence denotes 6M3M) binds to the RNA genome via the NTD and CTD.
T145 12456-12537 Sentence denotes The N protein tethers to the viral RNA and replicase–transcriptase complex (RTC).
T146 12538-12548 Sentence denotes NSP3 (PDB:
T147 12549-12606 Sentence denotes 6VXS) of CoV blocks the innate immune responses of hosts.
T148 12607-12789 Sentence denotes After entrance into the host cells, for CoV transcription and particle release, RNA chaperones such as nonspecific nucleic acid binding proteins potentiate ssRNA conformation shifts.
T149 12790-12860 Sentence denotes Representatively, the N protein is known as the RNA chaperone protein.
T150 12861-13033 Sentence denotes For example, glycogen synthase kinase 3 (GSK3) phosphorylates the SARS-CoV N-protein and thus, GSK3 inhibition contributes to reduced replication activity of SARS-CoV [19].
T151 13034-13310 Sentence denotes In addition, heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) regulates the preformed mRNA splicing in the nucleus and continuous translation. hnRNPA1 interacts with SARS-CoV N protein to form a replication and transcription complex during ssRNA genome biosynthesis [20].
T152 13312-13316 Sentence denotes 3.3.
T153 13317-13337 Sentence denotes Envelope (E) Protein
T154 13338-13438 Sentence denotes E protein is the most abundant structural protein needed to assemble virus particles in the cytosol.
T155 13439-13521 Sentence denotes As a TM protein, E protein is the smallest structural protein with a MW of 12 kDa.
T156 13522-13609 Sentence denotes The E protein has an NTD in the extracellular region and a CTD in the cytosolic region.
T157 13610-13684 Sentence denotes The E protein bears an ectodomain in the NTD and an endodomain in the CTD.
T158 13685-13719 Sentence denotes It has also an ion channel domain.
T159 13720-13859 Sentence denotes E protein is present in the cytosolic region of infected cells and only a limited amount is incorporated into the envelope of virions [21].
T160 13860-13916 Sentence denotes Most E proteins assemble and bud in new virus particles.
T161 13918-13922 Sentence denotes 3.4.
T162 13923-13948 Sentence denotes Membrane Glycoprotein (M)
T163 13949-14047 Sentence denotes The M protein contains three TM domains and is an abundant structural protein with a MW of 30 kDa.
T164 14048-14150 Sentence denotes It consists of a small glycosylated NTD in the extracellular region and CTD in the cytoplasmic region.
T165 14151-14265 Sentence denotes The M protein forms a scaffold for virus assembly in the cytosol via binding to S glycoprotein and N protein [22].
T166 14266-14457 Sentence denotes For example, E protein and N protein are co-expressed with M protein to form virus-like particles (VLPs) that are released from the cells, as the M and E protein are involved in CoV assembly.
T167 14458-14583 Sentence denotes Then, CoVs bud into the ERGIC, trafficking by membrane vesicles and transported via the exocytosis-secretory pathway [23,24].
T168 14584-14723 Sentence denotes The dimeric M protein binds to the nucleocapsid.-M protein binds to S glycoprotein for S glycoprotein retention in the ERGIC/Golgi complex.
T169 14724-14923 Sentence denotes The M-N protein complex keeps the N protein–RNA complex stable, for nucleocapsid and the viral assembly.-M and E proteins constitute the virus envelope for successful release of virus-like particles.
T170 14925-14929 Sentence denotes 3.5.
T171 14930-14973 Sentence denotes Hemagglutinin-Esterase (HE) Dimeric Protein
T172 14974-15016 Sentence denotes HE hemagglutinates and destroys receptors.
T173 15017-15145 Sentence denotes As RNA viruses, CoVs bear RDEs, which are used in effective attachment to hosts and also reversely in detachment from the hosts.
T174 15146-15212 Sentence denotes For example, enveloped RNA viruses evade the hosts via their RDEs.
T175 15213-15317 Sentence denotes Currently, RDE-related functional enzymes such as neuraminidase (NA) and SA-O-acetyl-esterase are known.
T176 15318-15484 Sentence denotes SA-O-acetyl-esterase was originally identified in influenza C virus and in nidoviruses (CoV and torovirus) as well as in salmon anemia virus (teleost orthomyxovirus).
T177 15485-15570 Sentence denotes The origin and evolution of CoV SA-O-acetylesterases are correlated to other viruses.
T178 15571-15689 Sentence denotes The fusion event of S glycoprotein and HE is specific for HCoV attachment to SA-associated receptors in the host [25].
T179 15690-15730 Sentence denotes The HE has acetylesterase activity [26].
T180 15731-15840 Sentence denotes In early SA-related biology, influenza A/B viruses were found to recognize chicken erythrocytes in 1942 [27].
T181 15841-15916 Sentence denotes They caused hemagglutination through clumping by virus-borne hemagglutinin.
T182 15917-16030 Sentence denotes These phenomena were widely found in influenza viruses, paramyxoviruses, Newcastle disease (NDV) and mumps virus.
T183 16032-16034 Sentence denotes 4.
T184 16035-16125 Sentence denotes Relationship between C4-O- and C9-O-Acetyl SA Preferences of CoVs in Host Cell Recognition
T185 16127-16131 Sentence denotes 4.1.
T186 16132-16159 Sentence denotes General O-Acetylation of SA
T187 16160-16349 Sentence denotes SAs have various derivatives of more than 50 chemically different structures formed from the basic N-acetylneuraminic acid (Neu5Ac) on the main ring of pyranose and the glycerol side chain.
T188 16350-16458 Sentence denotes SA are modified by acetyl-, lactyl-, methyl- and sulfo-groups individually or in multiple combinations [28].
T189 16459-16515 Sentence denotes Multiple enzymes are involved in the modifications [29].
T190 16516-16654 Sentence denotes Historically, the first discovered SA was crystallized by Gunner Blix via a hot mild acid extraction of bovine submaxillary mucin in 1936.
T191 16655-16689 Sentence denotes It consisted of two acetyl groups.
T192 16690-16755 Sentence denotes Among these, only one acetyl group was attached to nitrogen [30].
T193 16756-16908 Sentence denotes Blix isolated a 9-O-acetyl SA of the common SA N-acetylneuraminic acid (Neu5Ac), chemically described as 9-O-acetyl-N-acetylneuraminic acid (Neu5,9Ac2).
T194 16909-16984 Sentence denotes Neu5,9Ac2, Neu5Ac and Neu5Gc are naturally occurring SA species in mammals.
T195 16985-17024 Sentence denotes A common modification is O-acetylation.
T196 17025-17078 Sentence denotes In fact, O-acetylation of SAs is common in organisms.
T197 17079-17248 Sentence denotes The O-acetyl modification occurs in single positions of C-4, C-7, C-8 and C-9 of SA as well as in combined C-positions to yield Neu4,5Ac2, Neu5,9Ac2 and Neu5,7,9Ac3 SAs.
T198 17249-17324 Sentence denotes Neu5Ac9NAc is a chemical and biologic mimic of Neu5,9Ac2 in the SA-glycans.
T199 17325-17455 Sentence denotes The C-7 and/or C-9 O-acetylations are catalyzed by the SA O-acetyltransferase enzyme, Cas1 domain containing 1 (CasD1) (Figure 6).
T200 17456-17561 Sentence denotes CasD1 catalyzes the addition of acetyl groups to the SA C-7 at the late Golgi apparatus compartment [31].
T201 17562-17706 Sentence denotes Thereafter, an enzyme termed “migrase” transfers the additional acetyl-group from C-7 to C-9, although this enzyme has not been identified [29].
T202 17707-17835 Sentence denotes CasD1 uses acetyl-coenzyme A as a donor substrate and CMP-Neu5Ac as an acceptor substrate, but with weak activity on CMP-Neu5Gc.
T203 17836-17990 Sentence denotes Biologically, the SA O-acetylation event confers merits to hosts such as protection from pathogenic invasion and maintenance of systemic self-homeostasis.
T204 17991-18153 Sentence denotes The O-acetylation event of SAs protects the SA-containing glycans from neuraminidase (NA)/sialidase action, because O-acetyl-groups inhibit microbial NA activity.
T205 18154-18253 Sentence denotes The chemical structure of the O-acetyl group is quite unstable and susceptible to esterase enzymes.
T206 18254-18387 Sentence denotes Sialic acid cleavage of the di-acetylated Neu5,7,9Ac3 by bacterial NAs decreases two-fold, when compared to mono-O-acetylated Neu5Ac.
T207 18388-18497 Sentence denotes The O-acetylated glycan modification invites interaction with viruses, antibodies and mammalian lectins [32].
T208 18498-18583 Sentence denotes Therefore, the SA O-acetylation modification confers specific functions to organisms.
T209 18585-18589 Sentence denotes 4.2.
T210 18590-18674 Sentence denotes Evolutionary Acquisition of C4-O-Acetyl and C9-O-Acetyl SA Recognition by HE Enzymes
T211 18676-18682 Sentence denotes 4.2.1.
T212 18683-18707 Sentence denotes C4-O-Acetyl Modification
T213 18708-18822 Sentence denotes For example, in the horse, C4-O-acetyl modification of Neu5Ac (SA) occupies more than 50% of the total SA content.
T214 18823-18897 Sentence denotes The C4-O-acetylated Neu5Ac, Neu4,5Ac2, inhibits the influenza A2 virus HA.
T215 18898-19035 Sentence denotes De-acetylation reagents such as NaOH or NaIO4 treatment completely hemagglutinate Neu4,5Ac2 by elimination of the C4-O-acetyl group [33].
T216 19036-19173 Sentence denotes The C4-O-acetyl Neu5Ac species are found in various sources such as equine erythrocyte GM3, starfish A. rubens and fish [34,35,36,37,38].
T217 19174-19259 Sentence denotes C4-O-acetylated Neu5Ac facilitates the initial attachment of viruses to target cells.
T218 19260-19429 Sentence denotes Like the influenza C virus, infectious salmon anemia virus (ISAV), a member of the Orthomyxoviridae family, contains HE and HEF proteins to mediate virus entry and exit.
T219 19430-19583 Sentence denotes C4-O-Ac Neu5Ac is the major receptor determinant of ISAV in receptor binding and destruction [38], while the influenza C virus recognizes C9-O-Ac Neu5Ac.
T220 19584-19775 Sentence denotes The acetylesterase RDE of ISAV cleaves C4-O-Ac via 4-SA-O-acetylesterase with a short turnover time, whereas C9-O-Ac Neu5Ac is cleaved by 9-SA-O-acetylesterase with a long turnover time [34].
T221 19776-19915 Sentence denotes The position of SA O-acetylation is linked to functions including substrate differentiation of enzymes such as NAs and esterase by C4 O-Ac.
T222 19916-20045 Sentence denotes Previous development of O-Ac site-selective NA inhibitors were based on the conceptual consideration of different O-Ac positions.
T223 20046-20154 Sentence denotes The O-Ac of SAs is site-specific, as C4 of Neu5Ac is considered to be a potential position for modification.
T224 20155-20263 Sentence denotes Historically, inhibitors of influenza A and B viruses-sialidases were designed by Von-Itzstein in 1993 [39].
T225 20264-20373 Sentence denotes The Ac group-based C4 substitution interacts with amino acid Glu-119 present in the active site of sialidase.
T226 20374-20543 Sentence denotes Guanidine-attached C4 of C2–C3 unsaturated SA (Neu5Ac2en) inhibits activity of sialidases isolated from influenza A virus (Singapore/1/57) and B virus (Victoria/102/85).
T227 20544-20678 Sentence denotes The same scenario was applied for sialidase inhibition of the human parainfluenza virus type 3, which has HN and fusion proteins [40].
T228 20679-20757 Sentence denotes The C4 of Neu5Ac2en was substituted by alkyl groups such as the O-ethyl group.
T229 20758-20847 Sentence denotes For example, Zanamivir has a substitution with a 4-guanidino group with an IC50 of 25 μM.
T230 20848-20921 Sentence denotes Thus, sialidase inhibition is important for C4 modification of Neu5Ac2en.
T231 20922-21065 Sentence denotes Later, oseltamivir with the tradename Tamiflu (Basel, Switzerland) and zanamivir with the tradename Relenza (London, UK) were established [41].
T232 21066-21139 Sentence denotes These drugs exhibit some adverse side effects that restrict clinical use.
T233 21141-21147 Sentence denotes 4.2.2.
T234 21148-21175 Sentence denotes SA C9-O-Acetyl Modification
T235 21176-21354 Sentence denotes The SA 9-O-acetylation in hosts allows hosts to evade influenza A virus hemagglutinin (HA) recognition and some lectins of factor H (FH), CD22/Siglec-2 and sialoadhesin/Siglec-1.
T236 21355-21484 Sentence denotes Instead, the influenza C virus HA recognizes the hosts. β-elimination and permethylation eliminate the 9-O-acetyl group from SAs.
T237 21485-21727 Sentence denotes Chemical modification of the C-9 position of Neu5,9Ac2 generates a 9-N-acetyl analog, 9-acetamido-9-deoxy-N-acetylneuraminic acid (Neu5Ac9NAc), a mimic of Neu5,9Ac2 with influenza C virus-binding capacity, which is not cleaved by the HE [42].
T238 21728-21794 Sentence denotes SA O-acetylesterase regulates the presence of 7,9-O-Ac and 9-O-Ac.
T239 21795-21881 Sentence denotes SA O-acetylation and deacetylation are involved in development, cancer and immunology.
T240 21882-21948 Sentence denotes SA O-acetylation alters host lectin bindings such as siglecs [29].
T241 21949-22013 Sentence denotes The presence of 9-O-Ac can also reduce the activity of NAs [43].
T242 22014-22073 Sentence denotes SA modifications regulate pathogen binding or pathogen NAs.
T243 22074-22132 Sentence denotes Influenza A/B/C/D viruses use SA as their entry receptors.
T244 22133-22268 Sentence denotes Influenza A and B subtypes bind to SAs via HA and NA to allow endocytosis of the virus and fusion of the viral envelope with endosomes.
T245 22269-22379 Sentence denotes In contrast, influenza C and D subtypes bear only one coated glycoprotein, termed the HE fusion protein (HEF).
T246 22380-22410 Sentence denotes The HEF acts as the HA and NA.
T247 22411-22598 Sentence denotes HEF recognizes 9-O-acetyl SA for entry into cells, while the esterase domain removes 9-O-acetyl-groups and liberates the virus from mucus and mis-assembled virus aggregates after budding.
T248 22599-22694 Sentence denotes The 9-O-Ac on cells prevents the NA activity and HA binding of the influenza A type virus [44].
T249 22696-22698 Sentence denotes 5.
T250 22699-22709 Sentence denotes HE of CoVs
T251 22711-22715 Sentence denotes 5.1.
T252 22716-22768 Sentence denotes Evolutionary Origin and Classification of the CoV HE
T253 22769-22870 Sentence denotes Certain viruses use glycoproteins such as HA, HE, S and HEF for host receptor binding or destruction.
T254 22871-22995 Sentence denotes Coronaviridae, Orthomyxoviridae, Paramyxoviridae and Adenoviridae utilize SAs as binding molecules for attachment and entry.
T255 22996-23052 Sentence denotes However, only limited human pathogens recognize O-Ac SA.
T256 23054-23060 Sentence denotes 5.1.1.
T257 23061-23112 Sentence denotes Influenza Virus A and B Spike Proteins of HA and NA
T258 23113-23190 Sentence denotes Influenza A and B viruses bear two spikes of receptor-binding HA and NA [45].
T259 23192-23198 Sentence denotes 5.1.2.
T260 23199-23223 Sentence denotes Influenza C virus HA-HEF
T261 23224-23277 Sentence denotes HEF is indeed an ancient type of SA-O-acetylesterase.
T262 23278-23386 Sentence denotes In contrast to A/B, the influenza C virus bears one spike with triple functions of HEF as a homotrimer [46].
T263 23387-23472 Sentence denotes Each HEF subunit bears two Neu5,9Ac2-binding sites and binds to the 9-O-acetyl group.
T264 23473-23533 Sentence denotes In parallel, another modification of O-acetylation is found.
T265 23534-23652 Sentence denotes Indeed, influenza C virus bears SA-O-acetylesterase [47], which converts 5-N-acetyl-9-O-NeuAc (Neu5,9Ac2) to 5-Neu5Ac.
T266 23653-23808 Sentence denotes The 9-O-acetyl SA is a unique determinant for the influenza C virus receptor and Neu5,9Ac2 is crucial for receptor activity, but not Neu5Gc or Neu5Ac [48].
T267 23809-23901 Sentence denotes Neu5,9Ac2 is an essential determinant for influenza virus C type-specific host cell tropism.
T268 23902-23961 Sentence denotes NAs cleave the α-ketosidic linkages to the D-Gal or GalNAc.
T269 23962-24029 Sentence denotes SA-O-acetylesterases cleave different O-acetyl linkages (Figure 5).
T270 24030-24132 Sentence denotes The OH-group of Tyr224 and the guanidino group of Arg236 interact with the CH3CO-carbonyl oxygen [49].
T271 24133-24272 Sentence denotes HEF SA-O-acetylesterase is found in several enveloped (+) ssRNA viruses of influenza C virus and also in certain CoVs and toroviruses [47].
T272 24273-24451 Sentence denotes The CoVs are different from the orthomyxoviruses, which hold a segmented (−) ssRNA genome and are instead evolutionary linked to the family Coronaviridae, order Nidovirales [45].
T273 24453-24459 Sentence denotes 5.1.3.
T274 24460-24486 Sentence denotes CoV SA-O-Acetylesterase HE
T275 24487-24575 Sentence denotes CoVs and toroviruses of the Coronaviridae family are specific for the O-Ac SA receptors.
T276 24576-24642 Sentence denotes Their S and HE glycoproteins are similar to influenza C virus HEF.
T277 24643-24800 Sentence denotes CoVs and all toroviruses bear HE gene form class I envelope membrane proteins of about 400 amino acid residues which bear 7 to 12 N-glycosylation sites [50].
T278 24801-24833 Sentence denotes HE multimer forms enter virions.
T279 24834-24952 Sentence denotes Bovine CoV (BCoV) and HCoV-OC43, similar to influenza C virus, recognize Neu5,9Ac2 and bear SA-9-O-acetylesterase [8].
T280 24953-24987 Sentence denotes CoV HEs are all O-acetylesterases.
T281 24988-25181 Sentence denotes The HE enzymes found in torovirus, CoV and influenza C virus are evolutionarily interspecies-mutated with about 30% homology by heterologous RNA recombination [51] and horizontal gene transfer.
T282 25182-25245 Sentence denotes Therefore, viral HEs are diverse and widespread over evolution.
T283 25247-25251 Sentence denotes 5.2.
T284 25252-25286 Sentence denotes Substrate Diversity of the CoV HEs
T285 25287-25364 Sentence denotes HEs as envelope proteins are found in CoVs, orthomyxoviruses and toroviruses.
T286 25365-25428 Sentence denotes Coronaviral HEs are involved in virus attachment to SA species.
T287 25429-25537 Sentence denotes HE protein in β-CoVs binds to Neu5,9Ac2 form SA and agglutinates the red blood cells (RBCs) of rodents [52].
T288 25538-25651 Sentence denotes As with SA-O-acetylesterase, HE potentiates viral entry with the S protein and spreading via the mucosal glycans.
T289 25652-25720 Sentence denotes It contains a carbohydrate-recognizing domain (CRD) known in lectin.
T290 25721-25803 Sentence denotes The HE glycan-binding domain (GBD) mediates virus attachment to SAs on host cells.
T291 25804-25822 Sentence denotes HE is the only HA.
T292 25823-25956 Sentence denotes This indicates that compared to the S glycoprotein, HE is only minor a HA and the S glycoprotein mainly attaches to the cell surface.
T293 25957-26179 Sentence denotes The HE protein of murine hepatitis virus (MHV), an enveloped CoV, binds to SA-4-acetylester or SA-9-O-acetylester of the carcinoembryonic antigen cell adhesion molecule 1a (CEACAM; known as CD66a) as the key receptor [53].
T294 26180-26257 Sentence denotes Murine CoVs HEs acquired by horizontal gene transfer, bind to C9-O-Ac Neu5Ac.
T295 26258-26317 Sentence denotes However, some murine CoV HEs cannot bind to C4-O-Ac Neu5Ac.
T296 26318-26468 Sentence denotes The original mouse MHV HE binds to C9-O-Ac Neu5Ac, while the MHV S-strain HE evolutionarily acquired the ability to bind to C4-O-Ac Neu5Ac [12,53,54].
T297 26469-26620 Sentence denotes In terms of structure, the C5 N- and C9 O-Ac Neu5Ac-accomodating hydrophobic pocket was shifted to a C5 N- and C4-O-Ac Neu5Ac-accomodating pocket [55].
T298 26621-26683 Sentence denotes Type I HE is specific for the 9-O-acetylated SAs (9-O-Ac-SAs).
T299 26684-26722 Sentence denotes Type II HE is specific for 4-O-Ac-SAs.
T300 26723-26847 Sentence denotes The SA-binding shift indicates quasi-synchronous adaptations of the SA-recognition sites of the lectin and esterase domains.
T301 26848-26983 Sentence denotes Type I HE monomers of β-CoV lineage A have a bimodular enzyme–lectin domain similar to cellular glycan/carbohydrate-modifying proteins.
T302 26984-27188 Sentence denotes Originally, HE homologs are found in various viruses including toroviruses and orthomyxoviruses such as the influenza virus C/D and isavirus, as well as the exceptional case of β-CoV lineage A among CoVs.
T303 27189-27345 Sentence denotes The HE gene was transmitted to a β-CoV lineage A progenitor via horizontal gene transfer from a 9-O-Ac-Sia–recognizing HEF, as shown in influenza virus C/D.
T304 27346-27521 Sentence denotes HE acquisition and expansion occurred by cross-species transmission over HE evolution and this phenomenon reflects viral evolutionary adaptation to host SA-containing glycans.
T305 27522-27634 Sentence denotes Therefore, CoV HE receptor switching precedes virus evolution driven by SA-containing glycan diversity of hosts.
T306 27635-27736 Sentence denotes For instance, the BcoV HE prefers 7,9-di-O-Ac-SAs, which is also a target of the bovine torovirus HE.
T307 27737-27880 Sentence denotes For a more outstanding case, such a switching event occurred in the murine CoVs for the β-CoV lineage A type switch toward O-Ac-SA recognition.
T308 27881-28125 Sentence denotes In the HE specificity of murine CoVs, two different murine CoV subtypes of virus group exist with one subtype possessing the typical 9-O-Ac-SA (type I) attachment factor and the other exclusively 4-O-Ac-SA (type II) attachment virus group [56].
T309 28126-28315 Sentence denotes The first coronaviral HE proteins identified were from the porcine hemagglutinating encephalomyelitis virus (PHEV), BCoV and HCoV-OC43, which bear SA-9-O-acetylesterases similar to HEF [8].
T310 28316-28401 Sentence denotes Rat CoV (RCoV) has SA-4-O-acetylesterases, converting Neu4,5Ac2 to Neu5Ac [53,57,58].
T311 28402-28459 Sentence denotes Some murine CoVs prefer 4-O-Ac-SAs and others 9-O-Ac-SAs.
T312 28460-28541 Sentence denotes HCoV-OC43 and BCoV prefer α2-6-SA 9-O-acetylation by their SA-O-acetyleseterases.
T313 28542-28714 Sentence denotes The S glycoproteins of BCoV and HCoV-OC43 are Neu5,9Ac2-recognizing lectins and agglutinate murine, rat and chicken erythrocytes due to the enriched 9-O-Ac-SA species [52].
T314 28715-28798 Sentence denotes BCoV and HCoV-OC43 adapted to SA receptor determinants of 9-O-Ac-SA receptors [59].
T315 28799-28908 Sentence denotes For a second receptor, the binding of S glycoprotein to Neu5,9Ac2 receptor is essential for entry into cells.
T316 28909-29096 Sentence denotes BCoV-infection is prevented by prior treatment of cells with NA enzyme or with viral SA-O-acetylesterases, blocking the roles of HE and S glycoprotein in SA-dependent entry to host cells.
T317 29098-29100 Sentence denotes 6.
T318 29101-29130 Sentence denotes CoVs Infection of Human Hosts
T319 29132-29136 Sentence denotes 6.1.
T320 29137-29219 Sentence denotes CoVs Utilize SAs and SA Linkages as Attachment and Entry Sites to Human Host Cells
T321 29220-29339 Sentence denotes Several β-CoV genera such as BCoV bind to O-acetylated SAs and bear an acetylesterase enzyme to act as a host cell RDE.
T322 29340-29475 Sentence denotes Certain α-CoV and γ-CoV are deficient for the comparable acetylesterase enzyme but have a preference to NeuAc or NeuGc type SA species.
T323 29476-29568 Sentence denotes Infectious bronchitis virus (IBV) and transmissible gastroenteritis virus are such examples.
T324 29569-29670 Sentence denotes Additionally, both α-CoV and γ-CoV also include sub-members deficient of any SA-recognizing activity.
T325 29671-29758 Sentence denotes During evolution, some subtypes of SARS-CoV and HCoV-229E acquired SA-binding capacity.
T326 29759-29871 Sentence denotes The SA-binding activities of BCoV, transmissible gastroenteritis coronavirus (TGEV) and IBV are well known [60].
T327 29873-29893 Sentence denotes 6.1.1. α-Coronavirus
T328 29894-29997 Sentence denotes In α-CoVs such as TGEV, HA-activity is attributed to the SA-recognizing activity to α2,3-NeuGc [61,62].
T329 29998-30084 Sentence denotes The SA-binding site is present on the N-terminal region of the S-glycoprotein of TGEV.
T330 30085-30141 Sentence denotes TGEV has two types with enteric and respiratory tropism.
T331 30142-30240 Sentence denotes The respiratory TGEV has the porcine aminopeptidase N (pAPN)-binding domain and SA-binding domain.
T332 30241-30397 Sentence denotes Nucleotide 655 of the S gene is essential for enteric tropism and the S219A mutation of the S glycoprotein confers the enteric to respiratory tropism shift.
T333 30398-30566 Sentence denotes In addition, a 6-nucleotide insertional mutation at nucleotide 1124, which yields the Y374-T375insND shift of the S glycoprotein, causes enhanced enteric tract tropism.
T334 30567-30726 Sentence denotes TGEV interacts with SA species on mucin-like glycoprotein (MGP), a highly glycosylated protein, in an SA-dependent manner, on mucin-secreting goblet cells [6].
T335 30727-30811 Sentence denotes MGP SA-binding allows virus entry via the mucus layer to the intestinal enterocytes.
T336 30812-30966 Sentence denotes Different from TGEV, the S glycoprotein of porcine CoV has no hemagglutination activity due to deletion of the SA-binding site of the S glycoprotein [61].
T337 30967-31044 Sentence denotes The loss of SA-binding activity is correlated to the non-enteropathogenicity.
T338 31045-31234 Sentence denotes SAs function as HA-mediated entry determinants for TGEV, causing the enteropathogenic outcome of the virus, and SA-recognition activity is also responsible for virus amplification in cells.
T339 31235-31344 Sentence denotes SA-binding activity-deficient TGEV can propagate in cells through pAPN, known as CD13, as a receptor [62,63].
T340 31345-31431 Sentence denotes The SA-binding activity potentiates infection and is crucial for intestinal infection.
T341 31433-31453 Sentence denotes 6.1.2. β-Coronavirus
T342 31454-31565 Sentence denotes In β-CoV, HE mediates viral attachment to O-Ac-SAs and its function relies on the combined CBD and RDE domains.
T343 31566-31683 Sentence denotes Most β-CoVs target 9-O-Ac-SAs (type I), but certain strains switched to alternatively targeting 4-O-Ac-SAs (type II).
T344 31684-31833 Sentence denotes For example, the SA-acetylesterase enzyme in BCoVs and HCoV-OC43 is known to have hemagglutinizing activities as a type of SA-9-O-acetylesterase [8].
T345 31834-31895 Sentence denotes The SA-acetylesterase is the HE surface glycoprotein in BCoV.
T346 31896-31979 Sentence denotes The three-dimensional structure of BCoV HE is similar to other viral esterases [9].
T347 31980-32025 Sentence denotes The HE gene is found only in the β-CoV genus.
T348 32026-32197 Sentence denotes The acetylesterase of murine CoVs differs in its substrate binding specificity from that of BCoV and HCoV-OC43, which is specific for O-acetyl residue release from SA C-9.
T349 32198-32251 Sentence denotes Murine CoVs prefer to esterize 4-O-acetyl-NeuAc [64].
T350 32252-32361 Sentence denotes The β-CoV acetylesterase destroys the receptors and this specificity is similar to that of influenza viruses.
T351 32362-32487 Sentence denotes Acetylesterase activity can be inhibited by diisopropyl fluorophosphate and this agent decreases viral infection levels [65].
T352 32488-32643 Sentence denotes As deduced from the SA acetylesterase of HCoV-OC43 [8], the 9-O-Ac-SA species is a receptor binding determinant for erythrocytes and entry into cells [59].
T353 32644-32711 Sentence denotes The BCoV HE protein has dual activity of acetylesterase and HA [9].
T354 32712-32833 Sentence denotes BCoV widely agglutinates erythrocytes and purified HE only agglutinates Neu5,9Ac2-enriched erythrocytes of rats and mice.
T355 32834-32916 Sentence denotes BCoV and HCoV-OC43 can agglutinate chicken erythrocytes, while purified HE cannot.
T356 32917-33104 Sentence denotes In contrast to the HE protein, purified S glycoprotein can agglutinate chicken erythrocytes [52], indicating that the major HA is the S protein which acts as the major SA-binding protein.
T357 33105-33280 Sentence denotes However, the role of O-Ac-SAs is not certain to be essential in receptors, and SA-binding activity may be essential only to the HE protein, but not to the S glycoprotein [54].
T358 33282-33302 Sentence denotes 6.1.3. γ-Coronavirus
T359 33303-33407 Sentence denotes In γ-CoVs, IBV strains, known as poultry respiratory infectious pathogens, can agglutinate erythrocytes.
T360 33408-33509 Sentence denotes IBV prefers to recognize α2,3-NeuAc and the SA functions as a host entry receptor for infection [66].
T361 33510-33688 Sentence denotes Glycosylation of IBV M41 S1 protein RBD is crucial for interaction with chicken trachea tissue and RBD N-glycosylation confers receptor specificity and enables virus replication.
T362 33689-33747 Sentence denotes The heavy glycosylated M41 RBD has 10 glycosylation sites.
T363 33748-33803 Sentence denotes N-glycosylation of IBV determines receptor specificity.
T364 33804-33854 Sentence denotes However, the host receptor has not yet been found.
T365 33855-33941 Sentence denotes NA treatment reduces the binding of soluble S to kidney and tracheal epithelial cells.
T366 33942-34013 Sentence denotes The IBV S protein recognizes epithelial cells in a SA-dependent manner.
T367 34014-34143 Sentence denotes The SA-binding ability of IBV is necessary for infection of tracheal epithelial cells and lung respiratory epithelial cells [67].
T368 34144-34259 Sentence denotes The SA-binding site is located on S1 of the IBV S protein, although the IBV-specific protein receptor is not known.
T369 34260-34311 Sentence denotes In contrast to BCoV or HCoV-OC43, IBV lacks an RDE.
T370 34312-34390 Sentence denotes SA binding of IBV is likely more essential than in other viruses such as TGEV.
T371 34392-34398 Sentence denotes 6.1.4.
T372 34399-34408 Sentence denotes Torovirus
T373 34409-34549 Sentence denotes In torovirus, which belongs to the family Coronaviridae, the toroviruses are grouped into the Torovirinae subfamily and the Torovirus genus.
T374 34550-34665 Sentence denotes The known toroviruses can infect four species of hosts, constituting bovine, equine, porcine and human toroviruses.
T375 34666-34772 Sentence denotes They mildly infect swine and cattle through the HE protein, which is similar to the β-CoV HE protein [68].
T376 34773-34866 Sentence denotes The HE protein is a class I membrane glycoprotein which forms homodimers with a MW of 65 kDa.
T377 34867-34942 Sentence denotes The RDE protein HE reversibly binds to glycans [15] through binding to SAs.
T378 34943-34992 Sentence denotes The acetyl-esterase activity disrupts SA binding.
T379 34993-35148 Sentence denotes HE hemagglutinates mouse erythrocytes and cleaves the acetyl-ester linkage of glycans and acetylated synthetic substrate p-nitrophenyl acetate (pNPA) [69].
T380 35149-35312 Sentence denotes Similar to CoV, torovirus HE is an acetylesterase type, which cleaves the O-acetyl group from the SA C-9 position using Neu5,9Ac2 and N-acetyl-7(8),9-O-NeuAc [64].
T381 35313-35565 Sentence denotes However, torovirus HE exhibits a restricted specificity for the Neu5,9Ac2 substrate, but not for the Neu5,7(8),9Ac3 substrate, with a unique SA-binding site generated by a single amino acid difference in porcine Thr73 and bovine Ser64 for each HE [70].
T382 35567-35571 Sentence denotes 6.2.
T383 35572-35665 Sentence denotes SARS-CoV-2 Recognizes 9-O-Acetyl-SAs and MERS-CoV Recognizes α2,3-SAs as Attachment Receptors
T384 35666-35734 Sentence denotes The S glycoprotein SARS-CoV-2 initiates infection of the host cells.
T385 35735-35957 Sentence denotes The molecular basis of CoV attachment to sugar/glycan receptors is an important issue, as demonstrated by recent cryo-EM defining the structure of the CoV-OC43 S glycoprotein trimer complexed with a 9-O-acetylated SA [56].
T386 35958-36180 Sentence denotes Cryo-EM structures of the trimeric ectodomain of S glycoprotein were observed using forms complexed with Neu5Ac, Neu5Gc, sialyl–LewisX (SLeX), α2,3-sialyl-N-acetyl-lactosamine (α2,3-SLacNAc) and α2,6-SLacNAc, respectively.
T387 36181-36434 Sentence denotes The receptor-binding site is commonly conserved in all CoV S glycoproteins, which attach to 9-O-Ac-SA species with similar ligand-binding pockets to the CoV HEs and influenza virus C/D HEF glycoproteins, indicating conserved recognizing structures [25].
T388 36435-36576 Sentence denotes The S glycoprotein-9-O-acetyl-SA interaction resembles the ligand-binding pockets of CoV HEs and influenza virus C/D HE fusion glycoproteins.
T389 36577-36616 Sentence denotes HCoV-OC43 and BCoV recognize 9-O-Ac-SA.
T390 36617-36655 Sentence denotes S glycoproteins engage 9-O-acetyl-SAs.
T391 36656-36897 Sentence denotes The 9-O-acetyl SAs are the binding site for HCoV-OC43 S glycoprotein and related β-1 CoV S glycoproteins, however SA-binding sites on the 9-O-acetyl sialyl receptors of MERS-CoV S glycoprotein and HCoV-OC43 S glycoprotein are different [71].
T392 36898-36958 Sentence denotes Thus, CoVs use two different entry and attachment receptors.
T393 36959-37095 Sentence denotes Therefore, S glycoproteins of CoVs are distinct from influenza virus A HAs, which bind to the Neu5Ac species by conserved binding sites.
T394 37096-37349 Sentence denotes The ligand-binding sites of BCoV HE enzyme, influenza HEF enzyme and CoV S glycoprotein have evolved 9-O-Ac-SA binding through hydrogen bonding with the 9-O-acetyl carbonyl group and hydrophobic pocket formation with the 9-O-acetyl methyl group [71,72].
T395 37350-37430 Sentence denotes However, influenza HA cannot bind to 9-O-acetyl-SAs but can bind to NeuGcs [73].
T396 37431-37740 Sentence denotes The HCoV-OC43 S glycoprotein, HCoV-HKU1 S glycoprotein, BCoV S glycoprotein and PHEV S glycoprotein, therefore, share the ligand-binding specificity of influenza C/D HEF enzyme, although they are functionally more similar to influenza virus A/B HA, whereas CoV HE or influenza virus A/B NA have RDE activities
T397 37741-37815 Sentence denotes CoV HEs are functionally similar to influenza virus C/D HEF glycoproteins.
T398 37816-37990 Sentence denotes In CoV, the S glycoprotein recognizes the 9-O-Ac-SA sugar, while the HE acts as the RDE enzyme with SA-O-acetyl-esterase activity to release virions from infected host cells.
T399 37991-38051 Sentence denotes For example, HCoV-OC43 also has a similar HE as an RDE [71].
T400 38052-38133 Sentence denotes In influenza C and D viruses, HEF glycoproteins act similarly to the CoV HE [74].
T401 38134-38196 Sentence denotes In influenza A virus, RDE NA releases virions from host cells.
T402 38197-38618 Sentence denotes However, MERS-CoV does not have a similar enzyme and thus MER-CoV binding to SA receptors is mediated by energetically reversible interactions of the lipid rafts with increased SA receptors [75], thus enhancing dipeptidyl peptidase 4 (DPP4) or carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) recognition power and viral entry [76] and membrane-associated 78-kDa glucose-regulated protein (GRP78) [77].
T403 38619-38746 Sentence denotes MERS-CoV S glycoprotein can hemagglutinate human erythrocytes and mediates virus entry into human respiratory epithelial cells.
T404 38747-38896 Sentence denotes MERS-CoV S glycoprotein attachment is not observed for 9-O-acetylated or 5-N-glycolyl SAs, but is observed for α2,3-SA linkage over α2,6-SA linkages.
T405 38897-39060 Sentence denotes SA-binding sites of MERS-CoV S glycoprotein and HCoV-OC43 S glycoprotein are not conserved [78], although they engage α2,3-SAs on the avian host cell surface [79].
T406 39061-39166 Sentence denotes MERS-CoV recognizes α2,3-SA and to a lesser extent the α2,6-SAs and sulfated SLeX for binding preference.
T407 39167-39235 Sentence denotes Thus, S glycoproteins may have independently evolved SA recognition.
T408 39236-39519 Sentence denotes The acquisition of SA-binding ability of MERS-CoV S seems to be an evolutionarily recent event, because HKU4 S1 and HKU5 S1 cannot hemagglutinate human erythrocytes [75], indicating flexible evolutionary exchange allowing cross-species transmission towards host cell tropism of CoVs.
T409 39520-39695 Sentence denotes In conclusion, CoV recognition of 9-O-Ac-SAs for infection is based on a conserved sequence for engagement of SA-related carbohydrate ligands across CoVs and orthomyxoviruses.
T410 39697-39701 Sentence denotes 6.3.
T411 39702-39724 Sentence denotes Host Receptors of CoVs
T412 39725-39806 Sentence denotes CoV S spikes recognize diverse surface molecules as the attachment or entry site.
T413 39807-39963 Sentence denotes Animal and human coronaviruses evolve to acquire the same host receptors and attachment factors and overcome the interspecies barrier from animals to human.
T414 39964-40097 Sentence denotes Specifically, S glycoprotein interaction with its binding receptor determines host tropism, pathogenicity and therapeutic clues [80].
T415 40098-40160 Sentence denotes CoVs recognize multiple host receptors via distinct S domains.
T416 40161-40247 Sentence denotes The host receptors for β-CoV SARS-CoV includes angiotensin-converting enzyme 2 (ACE2).
T417 40248-40323 Sentence denotes As a lineage C β-CoV, the MERS-CoV S glycoprotein binds to DPP4 [81,82,83].
T418 40324-40398 Sentence denotes MERS-CoV S glycoprotein recognizes α2,3-SA over α2,6-SA-bearing receptors.
T419 40399-40480 Sentence denotes The N-terminal subunits of the S1/S1A/S1B/S1D complex of MERS-CoV recognize DPP4.
T420 40481-40549 Sentence denotes MERS-CoV recognizes CEACAM5 as the attachment factor for entry [78].
T421 40550-40713 Sentence denotes Among the six HCoVs, the α-CoV HCoV-229E S protein recognizes human APN (hAPN) [84]. α-CoV HCoV-NL63 and the lineage B β-CoV SARS-CoV S glycoproteins bind to ACE2.
T422 40714-40826 Sentence denotes Meanwhile the protein receptors specific for lineage A β-CoVs such as HCoV-HKU1 and HCoV-OC43 are not known yet.
T423 40827-40910 Sentence denotes BCoV, HCoV-OC43, HCoV-HKU1 and TGEV recognize O-acetyl-SAs as attachment molecules.
T424 40911-41053 Sentence denotes In addition to O-acetyl-SA, HCoV-HKU1 spikes additionally bind to major histocompatibility complex class I (MHC-I) C as attachment sites [85].
T425 41054-41189 Sentence denotes SARS-CoV uses dendritic cell (DC)-specific intercellular adhesion molecule (ICAM)-3–grabbing nonintegrin (DC-SIGN) for attachment [86].
T426 41190-41322 Sentence denotes For glycan interaction, HCoV-NL63 and mouse hepatitis virus utilize heparan sulfate (HS) proteoglycans as attachment enhancers [87].
T427 41323-41470 Sentence denotes In general, ACE2, APN, heat shock protein A5 (HSPA5), furin, heparan sulfate proteoglycans (HSPGs) and O-acetyl-SA are CoVs-recognizing candidates.
T428 41472-41478 Sentence denotes 6.3.1.
T429 41479-41547 Sentence denotes Angiotensin-Converting Enzyme 2 (ACE2) as the SARS-CoV Host Receptor
T430 41549-41602 Sentence denotes Structure and Role of the Host SARS-CoV Receptor ACE2
T431 41603-41635 Sentence denotes SARS-CoV-2 needs ACE2 for entry.
T432 41636-41766 Sentence denotes Host proteases such as human ACE2 help viral entry through removement of a barrier to enter human cells through unknown receptors.
T433 41767-41859 Sentence denotes Human ACE2 is known for its role as the SARS-CoV-2 entry receptor and the SARS-CoV receptor.
T434 41860-41955 Sentence denotes The enzyme ACE-2 in the renin-angiotensin system (RAS) is associated with CoV entry into lungs.
T435 41956-42056 Sentence denotes ACE2 mediates SARS-2002 entry into host cells via S glycoprotein interaction with the ACE2 receptor.
T436 42057-42129 Sentence denotes The ACE2 levels on the plasma membrane correlate with virus infectivity.
T437 42130-42201 Sentence denotes ACE2 expression is present in most tissues such as the lung epithelium.
T438 42202-42307 Sentence denotes It is highly expressed by respiratory epithelial cells and type I/II lung alveolar epithelial cells [88].
T439 42308-42370 Sentence denotes The host receptor is not linked to the classification of CoVs.
T440 42371-42427 Sentence denotes MERS-CoV, a β-CoV, does not recognize the ACE2 receptor.
T441 42428-42490 Sentence denotes In contrast, the α-CoV HCoV-NL63 recognizes the ACE2 receptor.
T442 42491-42594 Sentence denotes ACE2 is a membrane-anchored carboxypeptidase with 805 amino acid residues and is captopril-insensitive.
T443 42595-42889 Sentence denotes It contains 17 amino acid residues as a signal peptide in the N-terminal region, a type I membrane-anchored domain in the C-terminal region, an extracellular N-terminal domain with heavy N-glycans, a N-terminal SARS-CoV-binding and carboxypeptidase site and a short C-terminal cytoplasmic tail.
T444 42890-42934 Sentence denotes The ACE2 gene is located on chromosome Xp22.
T445 42935-43002 Sentence denotes Two ACE2 forms are known, a membrane-bound form and a soluble form.
T446 43003-43057 Sentence denotes ACE cleaves angiotensin I (Ang I) substrate to Ang II.
T447 43058-43211 Sentence denotes Ang II recognizes the Ang II receptor type 1 (AT1R), contributing to systemic and local vasoconstriction, fibrosis and salt retention in vascular organs.
T448 43212-43250 Sentence denotes ACE2 has the opposite function of ACE.
T449 43251-43288 Sentence denotes ACE2 is a close homolog to human ACE.
T450 43289-43357 Sentence denotes ACE2 activity on Ang II is about 400-fold higher than that on Ang I.
T451 43358-43536 Sentence denotes Ang-1 to Ang-7 recognize the G protein-coupled receptor (GPCR) Mas to activate vasorelaxation, cardioprotection, antioxidative action, antiinflammation and anti-Ang II-signaling.
T452 43537-43627 Sentence denotes Therefore, the ACE2-Ang-1 to Ang-7 axis is a target candidate for cardiovascular diseases.
T453 43628-43692 Sentence denotes ACE2 shows similar binding structures between nCoV and SARS-CoV.
T454 43693-43787 Sentence denotes The three proteins of ACE, Ang II and AT1R contribute to progression of lung injury in humans.
T455 43788-43885 Sentence denotes ACE2 removes a single amino acid residue from Ang II to yield the vasodilator, named Ang 1-Ang 7.
T456 43886-43949 Sentence denotes ACE2 cleaves Ang-I to Ang 1–Ang 9 and Ang II to Ang-1 to Ang-7.
T457 43950-44055 Sentence denotes The biggest difference between ACE2 and ACE is that ACE2 has a non-inhibitory property by ACE inhibitors.
T458 44056-44147 Sentence denotes Pulmonary ACE2 is potentially a candidate target in CoV-involved inflammatory pathogenesis.
T459 44148-44230 Sentence denotes If ACE inhibitors and Ang II-AT1 blockers are dosed, ACE2 expression is increased.
T460 44231-44335 Sentence denotes However, currently we have no conclusive evidence that the inhibitors help SARS-CoV or SARS-CoV-2 entry.
T461 44336-44387 Sentence denotes Rather, SARS-CoV infection reduces ACE2 expression.
T462 44388-44457 Sentence denotes Therefore, SARS-CoV-2 host tropism is not related to ACE2 expression.
T463 44458-44532 Sentence denotes ACE2 levels and ANG II/ANG 1–7 levels regulate the pathogenic progression.
T464 44533-44657 Sentence denotes ACE2 expression is upregulated by gene polymorphisms and ACE inhibitors or Angiotensin II receptor blockers such as sartans.
T465 44659-44713 Sentence denotes Host Cell ADAM17 and TMPRSS2 Competitively Cleave ACE2
T466 44714-44824 Sentence denotes A disintegrin and metallopeptidase domain (ADAM) family of Zn-metalloproteinases belongs to membrane proteins.
T467 44825-44914 Sentence denotes The well-known ADAM17 is a TNF-α-converting enzyme (TACE), called the sheddase for TNF-α.
T468 44915-44983 Sentence denotes Other ADAM sheddase family members include ADAM9, ADAM10 and ADAM12.
T469 44984-45014 Sentence denotes ADAM17 mediates ACE2 shedding.
T470 45015-45104 Sentence denotes SARS-CoV S glycoprotein activates cellular TACE and consequently facilitates virus entry.
T471 45105-45254 Sentence denotes Soluble ACE2 as the N-terminal carboxypeptidase domain form is derived from the original ACE2 form by an ADAM17 metalloprotease in the membrane [89].
T472 45255-45379 Sentence denotes ADAM17 is indeed an enzyme that can convert membrane type pro-TNF-α to soluble TNF-α, a functional proinflammatory cytokine.
T473 45380-45536 Sentence denotes Therefore, ADAM17 inhibition indicates an anti-inflammatory response and ADAM17 inhibitors are promising candidates for TNF-α-induced inflammatory diseases.
T474 45537-45606 Sentence denotes The short C-terminal domain of ACE2 is removed by ADAM17 and TMPRSS2.
T475 45607-45683 Sentence denotes However, TMPRSS2 cleaves ACE2 competitively with the ADAM17 metalloprotease.
T476 45684-45872 Sentence denotes SARS-S protein-ACE2 binding leads to ADAM17/TNF-α-converting enzyme (TACE)-cleavage of ACE2, facilitating extracellular ACE2 shedding and consequent SARS-CoV entry into host cells [90,91].
T477 45873-45964 Sentence denotes Only TMPRSS2 cleavage allows SARS-CoV entry into host cells through endocytosis and fusion.
T478 45965-46038 Sentence denotes Soluble ACE2 also recognizes the virus and prevents SARS-CoV-2 infection.
T479 46039-46095 Sentence denotes SARS-CoV-2 infection requires membrane ACE2 and TMPRSS2.
T480 46096-46161 Sentence denotes The ACE2–B0AT1 complex binds to the S glycoprotein of SARS-CoV-2.
T481 46162-46267 Sentence denotes Intestinal membrane ACE2 and lung TMPRSS2-shedded ACE2 can act as alternative entry sites for SARS-CoV-2.
T482 46268-46336 Sentence denotes SARS-CoV-2 infects the lungs and intestine via TMPRSS2-cleaved ACE2.
T483 46337-46457 Sentence denotes If TMPRSS2 is engaged in SARS-CoV-2 entry and ACE2 downregulation, TMPRSS2 inhibition would lead to COVID-19 prevention.
T484 46458-46641 Sentence denotes Although ACE2 is expressed both in type I and type II lung alveolar epithelial cells, SARS-CoV and SARS-CoV-2 target only type II epithelial cells due to the ACE2–TMPRSS2 interaction.
T485 46642-46764 Sentence denotes Therefore, supplementation of ACE2 (soluble ACE2) or Ang-1 to Ang-7 should be a way to reduce SARS-CoV-2-related symptoms.
T486 46765-46834 Sentence denotes TMPRSS2-cleaved ACE2 is involved in SARS-CoV and MERS-CoV infections.
T487 46835-46928 Sentence denotes SARS-CoV-2 uses ACE2 for cell entry through TMPRSS2 priming of the S glycoprotein (Figure 7).
T488 46929-47040 Sentence denotes Infection of the H7N9 influenza and H1N1 influenza A subtype viruses are also mediated by TMPRSS2-cleaved ACE2.
T489 47041-47121 Sentence denotes This implies that TMPRSS2 can be targeted as a strategic antiviral therapy [92].
T490 47122-47223 Sentence denotes Transmembrane protease serine 2, termed TMPRSS2, a type II TM Ser protease (TTSP), also cleaves ACE2.
T491 47224-47358 Sentence denotes The human TMPRSS2 gene, located on chromosome 21, comprises androgen receptor elements (AREs) in the upstream 5′-flanking region [93].
T492 47359-47423 Sentence denotes TMPRSS2 expression is regulated in an androgen-dependent manner.
T493 47424-47465 Sentence denotes The TMPRSS2 gene encodes 492 amino acids.
T494 47466-47551 Sentence denotes The original form is cleaved into the major membrane form and the minor soluble form.
T495 47552-47685 Sentence denotes TMPRSS2 activates protease activated receptor 2 (PAR-2) and activated PAR-2 upregulates matrix metalloproteinase-2 (MMP-2) and MMP-9.
T496 47686-47768 Sentence denotes TMPRSS2-activated hepatocyte growth factor (HGF) induces c-Met receptor signaling.
T497 47769-47809 Sentence denotes TMPRSS2 activates SARS-CoV and MERS-CoV.
T498 47810-48021 Sentence denotes The SARS-CoV S glycoprotein is cleaved by host-borne TMPRSS2, human airway trypsin-like protease (HAT), TM protease, serine 13 (MSPL), serine protease DESC1 (DESC1), furin, factor Xa and endosomal cathepsin L/B.
T499 48022-48113 Sentence denotes SARS-CoV can enter cells upon cleavage by protease TMPRSS2 or endosomal cathepsin L/B [90].
T500 48114-48169 Sentence denotes Virus S protein precursor is cleaved by host proteases.
T501 48170-48306 Sentence denotes The spikes are cleaved by endosomal cathepsin and by Golgi or plasma membrane TMPRSS2 in the step of assembly or attachment and release.
T502 48307-48399 Sentence denotes The serine protease inhibitor camostat effectively blocks lethal SARS-CoV infection to mice.
T503 48400-48468 Sentence denotes However, serine protease and cathepsin inhibitors are not effective.
T504 48469-48578 Sentence denotes Thus, TMPRSS2 is suggested to be an acting protease for SARS-CoV entry into host cells, but not by cathepsin.
T505 48579-48671 Sentence denotes Cis-cleavage liberates SARS-CoV S glycoprotein fragments into the extracellular supernatant.
T506 48672-48813 Sentence denotes Trans-cleavage activates the SARS-CoV S glycoprotein on the target cells, potentiating efficient SARS-CoV S glycoprotein-driven viral fusion.
T507 48814-48886 Sentence denotes TMPRSS2-activated SARS-CoV facilitates enveloped virus entry into cells.
T508 48887-48955 Sentence denotes TMPRSS2 is important for SARS-CoV entry and infection [81,94,95,96].
T509 48956-49095 Sentence denotes The fact that SARS- and MERS-CoV infections are potentiated by TMPRSS2 indicates that TMPRSS2 is a promising target for therapeutic agents.
T510 49096-49445 Sentence denotes For example, several Ser protease inhibitors such as camostat mesylate inhibit TMPRSS2–ACE2-involved SARS-CoV-2 entry. camostat, a serine protease inhibitor, reduces influenza virus titers in cell culture. camostat-treated TMPRSS2 inhibition in Calu-3 cells greatly reduces SARS-CoV viral titers and improves survival rate in SARS-CoV infected mice.
T511 49446-49621 Sentence denotes A treatment of 10-μM camostat blocks MERS-CoV entry to African green monkey kidney (Vero)-TMPRSS2 cells and blocks viral RNA synthesis in Calu-3 cells upon MERS-CoV infection.
T512 49622-49713 Sentence denotes Aprotinin is a polypeptide with 58 amino acid residues that was isolated from bovine lungs.
T513 49714-50023 Sentence denotes Another serine protease inhibitor, nafamostat, inhibits MERS-CoV entry and infection by TMPRSS2 inhibition [93]. nafamostat mesylate blocks the TMPRSS2–ACE2-involved SARS-CoV-2 envelope–PM fusion and prevents SARS-CoV-2 entry [95]. nafamostat mesylate inhibits viral entry and thrombosis in COVID-19 patients.
T514 50024-50198 Sentence denotes Similarly, an FDA-approved mucolytic cough suppressant, Bromhexine hydrochloride (BHH), inhibits TMPRSS2 (IC50 0.75 μM) and hence blocks infection of CoV and influenza virus.
T515 50199-50280 Sentence denotes MPRSS2 as a host factor plays a pivotal role in SARS-CoV and MERS-CoV infections.
T516 50281-50339 Sentence denotes FDA-approved TMPRSS2 inhibitors are yet under development.
T517 50340-50479 Sentence denotes Because TMPRSS2 mediates efficient viral entry and replication, it should be a promising target for new therapeutics against CoV infection.
T518 50481-50487 Sentence denotes 6.3.2.
T519 50488-50538 Sentence denotes Dipeptidyl peptidase-4 (DPP4) as MERS-CoV Receptor
T520 50539-50582 Sentence denotes The Ser exopeptidase DPP-4/human CD26 (PDB:
T521 50583-50665 Sentence denotes 4L72), a type II TM ectopeptidase, functions as a host cell receptor for MERS-CoV.
T522 50666-50776 Sentence denotes The RBD structure was characterized by crystallography approaches of the MERS-CoV S glycoprotein–DPP4 complex.
T523 50777-50910 Sentence denotes DPP4 is a single type II TM glycoprotein with a small cytoplasmic tail in the N-terminal region and is present as a homodimeric form.
T524 50911-50972 Sentence denotes DPP4 cleaves X-proline dipeptides from the N-terminal region.
T525 50973-51072 Sentence denotes S glycoprotein recognizes SA species and DPP44 as the attachment and entry receptors, respectively.
T526 51073-51150 Sentence denotes The MERS-CoV S1 N-terminal domain attaches to DPP4 as the host receptor [81].
T527 51151-51220 Sentence denotes The S2 C-terminal domain of MERS-CoV anchors to cellular PM to enter.
T528 51221-51305 Sentence denotes MERS-CoV S glycoprotein is cleaved at a sequence between the S1 and S2 domains [96].
T529 51306-51360 Sentence denotes Another cleavage site S2′ is present in the S2 domain.
T530 51361-51529 Sentence denotes MERS CoV S glycoprotein sialyl receptors are expressed in the camel nasal respiratory epithelial cells and the human lung alveolar epithelial cells, which express DPP4.
T531 51530-51619 Sentence denotes Binding capacities are hindered by the SA 9-O-acetyl group or SA 5-N-glycolyl group [75].
T532 51621-51627 Sentence denotes 6.3.3.
T533 51628-51643 Sentence denotes CEACAM Receptor
T534 51644-51764 Sentence denotes Entry of host cells needs binding of S glycoproteins to the CEACAM receptor, forming S-protein-mediated membrane fusion.
T535 51765-51823 Sentence denotes The trimeric S glycoprotein bears three S1 receptor heads.
T536 51824-51906 Sentence denotes The three S1 heads of the virus bind to three receptor molecules on the host cell.
T537 51907-52116 Sentence denotes Cholesterol is indirectly involved in membrane fusion through CEACAM engagement into “lipid raft” microdomains, increasing multiple S protein interaction with the receptors and triggering membrane fusion [97].
T538 52117-52209 Sentence denotes The enveloped CoV, MHV, binds to CEACAMs on cholesterol-depleted cells in BHK cell cultures.
T539 52210-52243 Sentence denotes The NTD of S1 recognizes CEACAM1.
T540 52244-52328 Sentence denotes For MERS-CoV, another CEACAM5 isoform is the attachment factor for virus entry [75].
T541 52329-52418 Sentence denotes The CoV S1 NTD has a similar tertiary structure to human galactose-recognizing galectins.
T542 52419-52492 Sentence denotes MHV S1 NTD binds murine CEACAM1a and BCoV S1 NTD binds sugar [98,99,100].
T543 52493-52573 Sentence denotes CEACAM1a is a cell adhesion protein (CAM) and its mRNA is alternatively spliced.
T544 52574-52650 Sentence denotes The cryo-EM structure of MHV S complexed with CEACAM1a was elucidated [101].
T545 52651-52863 Sentence denotes Thus, HCoVs evolutionarily combined the galectin gene of hosts into their S1 glycoprotein gene, while BCoV S1 protein is present without such gene recombination but contains the sugar-recognizing lectin capacity.
T546 52864-52951 Sentence denotes MHV S1 protein also evolutionarily acquired murine CEACAM1a-recognizing activity [102].
T547 52952-53068 Sentence denotes Therefore, CoVs are under evolution to adapt their host receptor interaction to infect cross-species hosts [80,103].
T548 53069-53256 Sentence denotes On the host side, to escape the lethal pressure from CoV infections, hosts have also evolved to acquire SA-binding proteins such as siglecs to inhibit or activate the innate immune cells.
T549 53257-53341 Sentence denotes Both raft and non-raft CEACAMs are involved in the virus–cell membrane fusion event.
T550 53342-53502 Sentence denotes Formation of CEACAM-associated MHV particles or CEACAM-induced MHV fusion is possible by GPI-anchored CEACAMs through the binding between CEACAM and S proteins.
T551 53503-53640 Sentence denotes However, MHV can bind to both GPI- and TM-anchored CEACAMs. In addition, soluble CEACAMs also mediate S glycoprotein-driven fusion [104].
T552 53641-53708 Sentence denotes This implies that membrane anchors are not intrinsically necessary.
T553 53709-53782 Sentence denotes In fact, CEACAMs are present in different tissue-specific isoforms [105].
T554 53783-54034 Sentence denotes Nevertheless, GPI-anchored CEACAMs are more effective for MHV infection than TM-anchored CEACAMs. Soluble CEACAM receptors can bind to viral S glycoproteins and induce conformational shifts to acceptable S glycoprotein-involved membrane fusions [106].
T555 54035-54188 Sentence denotes For example, soluble CEACAM forms interacts with S1 fragments [107] and alters the S1–S2 association stability [108] and S1 oxidation confirmation [109].
T556 54189-54250 Sentence denotes S proteins are structurally shifted prior to membrane fusion.
T557 54251-54407 Sentence denotes For the cross-linking of viruses and cells, integral hydrophobic peptides of the S2 chain are embedded into membranes via membrane hydrophobic cholesterols.
T558 54409-54415 Sentence denotes 6.3.4.
T559 54416-54485 Sentence denotes Membrane-Associated 78-kDa Glucose-Regulated Protein (GRP78) or HSPA5
T560 54486-54710 Sentence denotes MERS-CoV S glycoprotein also recognizes a 78-kDa glucose–regulated protein (GRP78) or heat shock 70 kDa protein 5 (HSPA5), known as binding immunoglobulin protein (BiP) or Byun1, which is encoded by the HSPA5 gene in humans.
T561 54711-54774 Sentence denotes HSP5A is a ER-resident unfolded protein response (UPR) protein.
T562 54775-54912 Sentence denotes Stressed cell status such as viral infection increase expression and translocation of HSPA5 to the PM to form a membrane protein complex.
T563 54913-54996 Sentence denotes GRP78 modulates MERS-CoV entry in the presence of the DPP4 as a host cell receptor.
T564 54997-55080 Sentence denotes Additionally, lineage D β-CoV and bat CoV HKU9 (bCoV-HKU9) also bind to GRP78 [76].
T565 55081-55199 Sentence denotes A cell surface receptor, GRP78, was predicted to be another COVID-19 receptor as an S glycoprotein binding site [110].
T566 55200-55315 Sentence denotes The prediction was made using the combined technology of molecular modeling docking with structural bioinformatics.
T567 55316-55382 Sentence denotes GRP78 or BiP is a chaperone protein located in the ER lumen [111].
T568 55383-55548 Sentence denotes Known ER-bound enzymes include activating transcription factor 6 (ATF6), inositol-requiring enzyme 1 (IRE1) and protein kinase RNA (PKR)-like ER kinase (PERK) [112].
T569 55549-55710 Sentence denotes Depending on threshold of unfolded protein accumulation, GRP78 releases IRE1, ATF6 and PERK, and is activated, resulting in translation inhibition and refolding.
T570 55711-55797 Sentence denotes Stress-overexpressed GRP78 can avoid ER retention and is translocated to the membrane.
T571 55798-55933 Sentence denotes GRP78 translocated to the cell PM can recognize viruses by its substrate-binding domain (SBD) for virus entry into the cell (Figure 8).
T572 55934-56082 Sentence denotes In sequence and structural alignments and protein–protein docking, RBD of the CoV spike protein recognizes the GRP78 SBDβ as the host cell receptor.
T573 56083-56213 Sentence denotes The predicted region III (C391–C525) and region IV (C480–C488) of the S glycoprotein and GRP78 are highly potential binding sites.
T574 56214-56259 Sentence denotes Region IV is the GRP78 binding-driving force.
T575 56260-56384 Sentence denotes These nine amino acid residues are being molecularly targeted for the designation and simulation of COVID-19-specific drugs.
T576 56385-56518 Sentence denotes This process is the mechanism underlying the cell surface HSPA5 (GRP78) exposure and this is exploited to be used for pathogen entry.
T577 56519-56749 Sentence denotes Such pathogenic entry into host cells has been observed in multiple infections including pathogenic human viruses such as human papillomavirus, Ebola virus, Zika virus and HcoVs—as well as fungal Rhizopus oryzae [113,114,115,116].
T578 56750-56849 Sentence denotes Therefore, natural products can inhibit cell-surface HSPA5 recognition of the viral S glycoprotein.
T579 56851-56857 Sentence denotes 6.3.5.
T580 56858-56913 Sentence denotes Aminopeptidase N (APN) is a Receptor of α-CoV HCoV-229E
T581 56914-57043 Sentence denotes Among the six HCoVs, the α-CoV HCoV-229E S protein recognizes hAPN known as CD13 or membrane alanyl aminopeptidase (EC 3.4.11.2).
T582 57044-57176 Sentence denotes Porcine epidemic diarrhea coronavirus virus (PEDV) binds to protein receptor APN of human- and pig NeuAc species as its co-receptor.
T583 57177-57316 Sentence denotes Apart from hAPN, TGEV and PEDV bind to SA species [117], although SA recognition by TGEV is not essential in the first step of entry cycle.
T584 57317-57391 Sentence denotes HCoV-229E recognizes hAPN known as CD13 for its entry receptor. hAPN (PDB:
T585 57392-57500 Sentence denotes 4FYQ) or CD13 (EC 3.4.11.2), which is a Zn-dependent metalloprotease, has a MW 150 kDa with 967 amino acids.
T586 57501-57628 Sentence denotes CD13 is a type II TM protein with a short cytoplasmic domain in the N-terminal region and long extracellular region in the CTD.
T587 57629-57692 Sentence denotes The CTD has a pentapeptide sequence specific for the Zinc–MMPs.
T588 57693-57887 Sentence denotes The APN binding domain is located on the CTD of PEDV S1 (amino acid 477–629 residues), while the SA-binding domain is found in the N-terminal region of PEDV S1 (amino acid 1–320 residues) [118].
T589 57888-58085 Sentence denotes CD13 is also a receptor for HCoV-229E, human cytomegalovirus, porcine CoV TGEV, feline infectious peritonitis virus (FIPV), feline enteric virus (FeCV) and canine-infectious CoVs [119,120,121,122].
T590 58086-58128 Sentence denotes Homodimeric CD13 digests luminal peptides.
T591 58129-58293 Sentence denotes The hAPN-encoding ANPEP gene is a dominant component in proximal tubular epithelial cells, small intestinal cells, macrophages, granulocytes and synaptic membranes.
T592 58294-58364 Sentence denotes If this gene is defective, leukemia or lymphoma are transformed [123].
T593 58365-58422 Sentence denotes Porcine and human APN exhibit about 80% protein identity.
T594 58423-58481 Sentence denotes FIPV and FeCV are in the same group as HCoV-229E and TGEV.
T595 58482-58575 Sentence denotes Thus, porcine APN is also an attachment site for pig TGEV with an additional second receptor.
T596 58576-58678 Sentence denotes HCoV-229E first binds to CD13 and consequently clusters CD13 in caveolae-associated lipid rafts [120].
T597 58680-58686 Sentence denotes 6.3.6.
T598 58687-58740 Sentence denotes Heparan Sulfate (HS) is the HCoV-NL63 Attachment Site
T599 58741-58862 Sentence denotes For glycan interaction, HCoV-NL63 and MHV utilize heparan sulfate proteoglycans (HSPGs) as attachment enhancers [87,124].
T600 58863-58911 Sentence denotes Viruses recognize HSPGs as attachment molecules.
T601 58912-58986 Sentence denotes In the spike (S) protein-deficient virions, the M protein recognizes HSPG.
T602 58987-59048 Sentence denotes The S proteins generally bind to the viral cellular receptor.
T603 59049-59137 Sentence denotes However, the M protein also acts as a receptor in the early step of HCoV-NL63 infection.
T604 59138-59214 Sentence denotes The M membrane protein of HCoV-NL63 recognizes the attachment site of HSPGs.
T605 59215-59391 Sentence denotes HCoV-NL63 M protein binds to HSPG for the initial attachment of virus to host cells and thereafter, the M and S proteins cooperate for virus entrance into the host cells [125].
T606 59392-59500 Sentence denotes HSPGs are glycosaminoglycan (GAG)-carrying proteins frequently used as a secondary receptor for viral entry.
T607 59501-59563 Sentence denotes HSPGs are composed of covalent-bonded HS chains as a GAG form.
T608 59564-59667 Sentence denotes The HS GAG linkage structure of tetrasaccharide exhibits GluAβ1,3GlcNAcα1,4Galβ1,3Galβ1,4Xylβ-O-serine.
T609 59668-59854 Sentence denotes Glycosyltransferases involved in HS GAG synthesis include GlcAT-II (glucuronosyltransferase) and GlcNAcT-II (N-acetylglucosaminyltransferase II) for heparan sulfate synthesis (Figure 9).
T610 59855-59933 Sentence denotes GAG is used as docking sites for virus interaction with the host cell surface.
T611 59934-59997 Sentence denotes GAGs contain negatively charged N- and O-sulfated sugars [126].
T612 59998-60189 Sentence denotes The biosynthetic pathway and biologic roles in early embryogenic morphogenesis and vulval morphogenesis of HS and chondroitin sulfate GAG have been elucidated in Caenorhabditis elegans [127].
T613 60190-60290 Sentence denotes The negative charges mediate the interaction of GAGs and their ligands through electrostatic forces.
T614 60291-60365 Sentence denotes Interaction of HSPG with ligands potentiates many virus infectious cycles.
T615 60366-60638 Sentence denotes For examples, adeno-associated virus, human T cell lymphotropic virus type 1, human papilloma virus 16, herpes viruses, hepatitis B and C viruses, Kaposi’s sarcoma-associated herpesvirus, human papilloma viruses and Merkel cell polyoma virus recognize the HSPGs [128,129].
T616 60639-60746 Sentence denotes HSPGs increase virulence upon interaction with viral factors required for viral attachment and replication.
T617 60748-60754 Sentence denotes 6.3.7.
T618 60755-60841 Sentence denotes Major Histocompatibility Complex Class I (MHC-I) C is an Attachment Site for HCoV-HKU1
T619 60842-61006 Sentence denotes Although HCoV-HKU1 utilizes O-acetyl-SAs as attachment sites, the HCoV-HKU1 S protein also interacts with MHC-I C (HLA-C) as an additional attachment molecule [85].
T620 61008-61014 Sentence denotes 6.3.8.
T621 61015-61072 Sentence denotes DC-SIGN (CD209) is a Binding Candidate for SARS-CoV Entry
T622 61073-61168 Sentence denotes SARS-CoV uses the C-type lectins of DC-SIGN and DC-L-SIGN as additional or secondary receptors.
T623 61169-61258 Sentence denotes Glycans on the S glycoprotein are recognized by DC/L-SIGN for virus attachment and entry.
T624 61259-61381 Sentence denotes Seven glycosylation sites of the S glycoprotein have been found to be essential for DC/L-SIGN-driven virus entry [86,130].
T625 61383-61389 Sentence denotes 6.3.9.
T626 61390-61486 Sentence denotes Tetraspanin CD9 is a Surface factor for MERS-CoV Entry Via Scaffold Cell Receptors and Proteases
T627 61487-61673 Sentence denotes Tetraspanin CD9, but not tetraspanin CD81, associates with DPP4 and the type II TM serine protease (TTSP) member TMPRSS2, a CoV-activating protease, to form a cell surface complex [131].
T628 61674-61762 Sentence denotes This CD9–DPP4–TMPRSS2 complex permits MERS-CoV pseudovirus entrance into the host cells.
T629 61763-61877 Sentence denotes The tetraspanins have four TM spanning regions linked by one large and one small loop in the extracellular region.
T630 61878-61944 Sentence denotes Tetraspanins form virus entry baselines and open CoV entry routes.
T631 61945-62035 Sentence denotes To help viral entry into host cells, MERS-CoV S interacts with DPP4 receptors via the RBD.
T632 62036-62130 Sentence denotes Receptor involvement causes cleavage using proteases such as the previously described TMPRSS2.
T633 62131-62220 Sentence denotes Association of tetraspanin CD9 with the DPP4–TMPRSS2 complex triggers the S glycoprotein.
T634 62221-62306 Sentence denotes MERS-CoVs enter the cells via endocytosis and cathepsins cleave the S proteins [132].
T635 62308-62312 Sentence denotes 6.4.
T636 62313-62385 Sentence denotes Effects of Receptor and Ligand S Glycosylation on Virus–Host Interaction
T637 62386-62486 Sentence denotes SAs are predominant surface determinants for pathogen attachment, adherence and entry to host cells.
T638 62487-62599 Sentence denotes Eleven representative vertebrate virus families utilize SAs as initial entry receptors or as attachment factors.
T639 62600-62728 Sentence denotes Interaction of virus with SA-containing glycans is complex because virus SA-binding lectins are inherently of very low affinity.
T640 62729-62828 Sentence denotes Viruses acquire enzymes to catalyze virion elution by regional depletion of binding receptors [56].
T641 62829-62884 Sentence denotes TM S glycoprotein recognizes oligosaccharide receptors.
T642 62885-63088 Sentence denotes Using cryo-EM technology and observed structures of S glycoprotein trimers of CoV OC43 complexed with 9-O-acetylated SA, S glycoprotein was demonstrated to mediate virus adhesion and entry to host cells.
T643 63089-63155 Sentence denotes All CoV S proteins show conservation in binding to 9-O-acetyl-SAs.
T644 63156-63207 Sentence denotes MERS-CoV also recognizes 9-carbon sugar SA species.
T645 63208-63242 Sentence denotes MERS-CoV S-1A binds to SA species.
T646 63243-63373 Sentence denotes For example, SAα2,3- over SAα2,6-linkages expressed in human erythrocytes and mucins are preferentially targeted by MERS-CoV S-1A.
T647 63374-63461 Sentence denotes Binding is hence blocked by SA modification to 5-N-NeuGc and 7, 9-O-NeuAc species [73].
T648 63462-63664 Sentence denotes For example, impairment of ACE2 receptor glycosylation does not influence S-glycoprotein-ACE2 interaction, however, SARS-CoV-2 virus entry into respiratory epithelial host cells was downregulated [133].
T649 63665-63831 Sentence denotes Changes in ACE2 N-glycans do not apparently influence interaction with the SARS-CoV S glycoprotein, but instead, impair viral S glycoprotein-mediated membrane fusion.
T650 63832-63902 Sentence denotes The receptor glycan structures decide the entry of some human viruses.
T651 63903-64012 Sentence denotes Changes in ACE2 receptor sialylation influences interaction affinity between virus ligands and host receptor.
T652 64013-64110 Sentence denotes Inter-species or individual genetic variations such as drift and mutation may occur in SARS-CoVs.
T653 64111-64215 Sentence denotes This explains currently emerging differences in CoV responses within the same population such as humans.
T654 64216-64365 Sentence denotes On the other hand, from the aspect of virus ligand, the S glycoprotein decorates viral surfaces and is, therefore, the target for vaccination design.
T655 64366-64444 Sentence denotes Virus internalization requires potential glycosylation of viral glycoproteins.
T656 64445-64562 Sentence denotes Among the three viral envelope components, S and M are the major glycoproteins and E is nascent and not glycosylated.
T657 64563-64651 Sentence denotes The M glycoprotein consists of a short glycosylated ectodomain in the N-terminal region.
T658 64652-64831 Sentence denotes The S glycoprotein expressed in hemagglutinating encephalomyelitis virus is an HA that recognizes N-acetyl-9-O-NeuAc as a binding receptor expressed on erythrocyte surfaces [134].
T659 64832-64939 Sentence denotes For example, BCoVs attach to the surface receptor of N-acetyl-9-O-NeuAc (9-O-acetylated SAs) on host cells.
T660 64940-65006 Sentence denotes TGEV and PEDV are currently known as a similar class of such CoVs.
T661 65007-65138 Sentence denotes PEDV infects multiple hosts including bat, pig, human and monkey, where bats are considered to be the evolutionary origin for PEDV.
T662 65139-65241 Sentence denotes The S glycoprotein of SARS-CoV-2 utilizes different glycosylation patterns to recognize its receptors.
T663 65242-65318 Sentence denotes The glycosylation sites in minimal RBD exhibits similar sites to other CoVs.
T664 65319-65431 Sentence denotes The trimeric SARS-CoV-2 S glycoprotein is also highly glycosylated with 66 N-glycans, but a few O-glycans [135].
T665 65432-65489 Sentence denotes Glycosylation of S glycoproteins leads to immune evasion.
T666 65490-65612 Sentence denotes In the MERS-CoV and the bat-specific CoV-HKU4, glycosylation is linked to zoonotic infection for fusion-based entry [136].
T667 65614-65616 Sentence denotes 7.
T668 65617-65670 Sentence denotes Pharmacology of Glycan-Related Anti-SARS-CoV-2 Agents
T669 65671-65824 Sentence denotes The emerging CoV-pandemic requires therapeutic agents to block the recognition, binding, replication, amplification and propagation of the CoV in humans.
T670 65825-65960 Sentence denotes Protease inhibitors, RNA synthase inhibitors and S2 inhibitors are potential targets, and several agents are currently being evaluated.
T671 65961-66031 Sentence denotes Efficient therapeutic drugs are the most reliable option for patients.
T672 66032-66168 Sentence denotes The first attachment step of the viral amplification cycle is initiated on the respiratory cell surfaces, driven by the viral S protein.
T673 66169-66208 Sentence denotes This is a potential therapeutic target.
T674 66209-66350 Sentence denotes Soon after the SARS-CoV-2 outbreak initiated, the CoV S glycoprotein was demonstrated to recognize ACE2 as a binding receptor on human cells.
T675 66351-66448 Sentence denotes Human TMPRSS2 enzyme influences the CoV S glycoprotein activation, to facilitate virus infection.
T676 66449-66535 Sentence denotes ACE2 binding and TMPRSS2 activation facilitate the CoVs to attach to human host cells.
T677 66536-66649 Sentence denotes Mouse, nonhuman primate and human cells have been analyzed using single-cell RNA new generation sequencing (NGS).
T678 66650-66804 Sentence denotes For example, for human infection, CoVs can enter nasal goblet secretory cells, because these cells express the proteins required for SARS-CoV-2 infection.
T679 66805-66895 Sentence denotes In the lungs, the proteins are stored in the alveoli like air sacs of type II pneumocytes.
T680 66896-66972 Sentence denotes In the intestine, the two proteins are expressed in entero-epithelial cells.
T681 66973-67038 Sentence denotes ACE2 gene expression correlates with the IFN-related genes [137].
T682 67039-67089 Sentence denotes ACE2 helps lung cells to tolerate cellular damage.
T683 67090-67215 Sentence denotes Therefore, CoVs may evolutionally take advantage of the defense mechanisms of host cells, hijacking such host-borne proteins.
T684 67216-67376 Sentence denotes In SARS-CoV-2, the ACE2 receptor is an attachment, entry and infection receptor into the cell, when the S glycoprotein is cleaved by a specific serine protease.
T685 67377-67505 Sentence denotes SARS-CoV-2 infection is regulated by glycosylated SARS-CoV-2 viral particles and glycosylated ACE2 in the lung epithelial cells.
T686 67506-67557 Sentence denotes RBD of the CoV S glycoprotein recognizes ACE2 [82].
T687 67558-67702 Sentence denotes Amino acid residues 442, 472, 479, 480 and 487 located on the receptor-binding motif (RBM) of the S glycoprotein RBD recognize human ACE2 [138].
T688 67703-67812 Sentence denotes Trimeric viral S glycoprotein is glycosylated and cleaved by a protease, furin, into two subunits, S1 and S2.
T689 67813-67910 Sentence denotes Subunit S1 is further cleaved into the SA and SB domains and the SB domain recognizes human ACE2.
T690 67911-67991 Sentence denotes The N-glycosylated S2 subunit is involved in virus-ACE2 complex formation [139].
T691 67992-68081 Sentence denotes Therefore, the glycosylated ACE2 receptor is a key molecule for virus binding and fusion.
T692 68082-68155 Sentence denotes Plasma sera prepared from infected patients is an alternative medication.
T693 68156-68246 Sentence denotes The WHO has suggested this trial since the 2014 Ebola epidemic and 2015 MERS-CoV outbreak.
T694 68247-68290 Sentence denotes In addition, Mab therapy is another option.
T695 68291-68418 Sentence denotes For example, LCA50 Mab mimics produced by modification of plasma antibodies isolated from MERS-CoV patients was valuable [140].
T696 68419-68538 Sentence denotes Low molecular molecules are being examined for anti-virus activities from alkaloids, glycan derivatives and terpenoids.
T697 68539-68642 Sentence denotes Recently, anti-CoV drugs are being approached using molecular modeling, docking and simulation methods.
T698 68643-68774 Sentence denotes Computation-assisted drugs via molecular modeling and docking toward drug targets are applied as anti-viral compounds against CoVs.
T699 68775-68810 Sentence denotes They target human ACE2, PLpro (PDB:
T700 68811-68847 Sentence denotes 3e9s), the CoV main proteinase (PDB:
T701 68848-69015 Sentence denotes 6Y84), 3-chymotrypsin-like (3C-like protease; 3CLpro), RdRp, helicase, N7 methyltransferase, human DDP4, RBD, protease cathepsin L, type II TM Ser protease or TMPRSS2.
T702 69016-69032 Sentence denotes CoV 3CLpro (PDB:
T703 69033-69104 Sentence denotes 6WX4) and the PLpro cleave the polyproteins to assemble virus proteins.
T704 69105-69236 Sentence denotes For newborn RNA genomes, RdRp is used as a replicase for the complementary RNA strand synthesis, which uses the virus RNA template.
T705 69238-69242 Sentence denotes 7.1.
T706 69243-69322 Sentence denotes N-Glycosylation Inhibition by Chloroquine (CLQ) and Hydroxychloroquine (CLQ-OH)
T707 69323-69402 Sentence denotes CLQ and CLQ-OH are under investigation worldwide to treat COVID-19 (Figure 10).
T708 69403-69547 Sentence denotes CLQ and its derivative CLQ-OH block CoV replication, amplification and spread in in vitro culture via inhibition of ACE2 receptor glycosylation.
T709 69548-69692 Sentence denotes In HCoVs, interaction of the S glycoprotein with gangliosides initially occur as the first entry step during the replication cycle of the virus.
T710 69693-69838 Sentence denotes CLQ and CLQ-OH have been alternative drugs for RA and several autoimmune diseases for 70 years, although they are anti-malaria prophylaxis drugs.
T711 69839-69895 Sentence denotes CLQ-OH is an aminoquinoline with less toxicity than CLQ.
T712 69896-69992 Sentence denotes CLQ-OH bears an N-hydroxyethyl side chain, which increases its solubility compared to CLQ [141].
T713 69993-70095 Sentence denotes CLQ-OH modulates activated immune cells via downregulation of TLR signaling and IL-6 production [142].
T714 70096-70184 Sentence denotes Clinical trials are also under consideration for the efficacy and safety of these drugs.
T715 70185-70301 Sentence denotes Regarding the action mechanism(s), CLQ and CLQ-OH-mediated inhibition of ACE2 terminal glycosylation was considered.
T716 70302-70488 Sentence denotes In in vitro Vero E6 cells, CLQ significantly inhibits SARS-CoV spread by interfering with ACE2 function, acting at the entry and post-entry steps of SARS-CoV-2 replication and infection.
T717 70489-70595 Sentence denotes The binding affinity of ACE2 to S glycoprotein is simulated to be lowered by treatment with CLQ-OH or CLQ.
T718 70596-70717 Sentence denotes CLQ may modify the binding affinity between ACE2 and S glycoprotein by alterations in ACE2 glycosylation or modification.
T719 70718-70789 Sentence denotes CLQ-OH (EC50 0.72 μM) and CLQ (EC50, 5.47 μM) inhibit SARS-CoV-2 [143].
T720 70790-71027 Sentence denotes Using computer simulation techniques, CLQ and CLQ-OH have been suggested to recognize the enzymatic active site of the UDP-GlcNAc 2-epimerase, known as an essential enzyme in SA biosynthesis [144], blocking the sialylation of host cells.
T721 71028-71233 Sentence denotes The mechanism underlying the glycosylation inhibition may support the antiviral properties of CLQ and CLQ-OH through interactions of CLQ or CLQ-OH with NDP-saccharide mutases or glycosyltransferases [145].
T722 71234-71378 Sentence denotes CLQ was reported to inhibit quinone reductase 2 [146], known as a catalytic mimetic or structural neighbor of UDP-GlcNAc 2-epimerases [147,148].
T723 71379-71570 Sentence denotes If CLQ or CLQ-OH inhibits SA synthesis, the inhibitory properties may support the antiviral activity of CLQ or CLQ-OH against SARS-CoVs because the SARS-CoV receptor ACE2 contains SA species.
T724 71571-71689 Sentence denotes In fact, CLQ exhibits in vitro anti-SARS-CoV-1 activity via defective glycosylation of viral ACE2 in Vero cells [149].
T725 71690-71883 Sentence denotes In addition. the interference of CLQ or CLQ-OH with SA synthesis may broadly be applicable as an antiviral because the HcoVs or other orthomyxoviruses also utilize SAs as entry molecules [150].
T726 71884-71946 Sentence denotes However, the detailed mechanisms should be further elucidated.
T727 71947-72042 Sentence denotes The CLQ treatment efficacy in Covid-19 patients has, however, not been conclusively determined.
T728 72044-72048 Sentence denotes 7.2.
T729 72049-72120 Sentence denotes Interaction of Membrane Gangliosides in Lipid Rafts with CLQ and CLQ-OH
T730 72121-72165 Sentence denotes Lipid rafts are also viral attachment sites.
T731 72166-72484 Sentence denotes Viruses such as IBV, dengue virus, Ebola virus, hepatitis C virus, HIV, human herpes virus 6, measles virus, Newcastle disease virus, poliovirus, West Nile virus, foot-and-mouth disease virus, simian virus 40, rotavirus, influenza virus and Marburg virus also use lipid rafts for virus entry [151,152,153,154,155,156].
T732 72485-72611 Sentence denotes In avian CoV IBV, structural proteins of the IBV virus are co-localized with PM lipid rafts embedded with the ganglioside GM1.
T733 72612-72744 Sentence denotes HCoV-229E entry is prevented by cholesterol depleted conditions because HCoV-229E clusters in caveolae-associated lipid rafts [157].
T734 72745-72894 Sentence denotes Caveolae of caveolin-1, -2 and -3 are cross-linked [158] and control the molecular distribution between rafts and caveolae in a regulatory mechanism.
T735 72895-72964 Sentence denotes S protein-CD13 cross-linking occurs via CD13-caveolin-1 sequestering.
T736 72965-73040 Sentence denotes HCoV-229E particles similarly exhibit a longitudinal distribution property.
T737 73041-73117 Sentence denotes HCoV-229E-colocalized caveolin-1 undergoes the next step of virus infection.
T738 73118-73238 Sentence denotes Caveolin-1 knockdown inhibited HCoV-229E endocytosis and entry and thus caveolin-1 is essential for HCoV-229E infection.
T739 73239-73314 Sentence denotes TGEV also endocytoses by a clathrin-mediated mechanism in MDCK cells [159].
T740 73315-73419 Sentence denotes Other viruses including HCoV-OC43 also use an entry receptor sequestered to cross-linked caveolae [160].
T741 73420-73529 Sentence denotes In SARS-CoV, the first entry step to host cells needs ACE2 in intact lipid rafts by the S glycoprotein [151].
T742 73530-73646 Sentence denotes ACE2 is associated with caveolin-1 and GM1 in membrane rafts depending on its cell-type specific localization [161].
T743 73647-73792 Sentence denotes Raft integrity with cholesterol and ACE2 is necessary for SARS-CoV pseudovirus entry into Vero E6 cells and for SARS-CoV-microdomain-based entry.
T744 73793-73890 Sentence denotes C-type lectin, CD209 L (L-SIGN), can also form lipid rafts and acts as a SARS-CoV receptor [162].
T745 73891-74075 Sentence denotes Information of the CoV entry pathways is important for therapeutic designation of SARS-CoV-targeting drugs, for example, if agents disrupt lipid-raft localization of the ACE2 receptor.
T746 74076-74147 Sentence denotes CLQ binds the SAs and gangliosides in lipid rafts with a high affinity.
T747 74148-74221 Sentence denotes Therefore, CLQ or CLQ-OH prevents the S glycoprotein–ganglioside binding.
T748 74222-74315 Sentence denotes CLQ (or CLQ-OH) binding to SA consequently prevents S glycoprotein binding to host receptors.
T749 74316-74395 Sentence denotes The N-terminal region of SARS-CoV-2 S glycoprotein interacts with gangliosides.
T750 74396-74523 Sentence denotes A ganglioside-binding site (GBS) or ganglioside-binding domain (GBD) is present in the NTD of the S glycoprotein of SARS-CoV-2.
T751 74524-74637 Sentence denotes Using molecular modeling and simulation technology, CLQ has been suggested to recognize the SAs and gangliosides.
T752 74638-74680 Sentence denotes Human type Neu5Ac binds to CLQ and CLQ-OH.
T753 74681-74729 Sentence denotes Thus, SAs are binding targets of CLQ and CLQ-OH.
T754 74730-74828 Sentence denotes CLQ and CLQ-OH have two specific recognition sites in the polar sugar residues of ganglioside GM1.
T755 74829-74934 Sentence denotes The first site is found at the tip of the sugar residues of GM1 with an interaction energy of −47 kJ/mol.
T756 74935-75078 Sentence denotes The CLQ rings face the GalNAc residue of GM1, while the second site is in a large region of the sugar-ceramide junction and the sugar residues.
T757 75079-75199 Sentence denotes Several amino acid residues of the S protein NTD, which are Phe-135, Asn-137 and Arg-158, recognize the ganglioside GM1.
T758 75200-75356 Sentence denotes The S glycoprotein NTD-GM1 complex is suggested to form a trimolecular complex with two molecules of ganglioside GM1 anchored to the NTD of S protein [163].
T759 75357-75470 Sentence denotes The ACE2-binding RBD is suggested to be a potential GBS located on a differential site of the S glycoprotein NTD.
T760 75471-75551 Sentence denotes The protein sequence interfacing surface of the NTD is the consensus GBDs [164].
T761 75552-75704 Sentence denotes The amino acids Gly, Pro and/or Ser residues found in GBD motifs are in the same 111–158 amino acids of the NTD as the ganglioside-attachment interface.
T762 75705-75785 Sentence denotes The GBD is conserved throughout viral isolates from worldwide COVID-19 patients.
T763 75786-75910 Sentence denotes The GBD potentially increases viral attachment ability to PM lipid rafts and contact between host ACE-2 and S protein [165].
T764 75911-76019 Sentence denotes The interaction between CLQ-OH and 9-O-acetyl-NeuAc is also similar to the 9-O-acetyl-NeuAc-CLQ interaction.
T765 76020-76106 Sentence denotes The CLQ-OH OH group enhances the interaction of CLQ with SA via a hydrogen bond [163].
T766 76107-76278 Sentence denotes In conditions with CLQ or CLQ-OH derivative treatment, the S glycoprotein cannot bind to gangliosides in in silico studies, which are used to uncover the action mechanism.
T767 76279-76348 Sentence denotes CLQ and CLQ-OH prevent the binding of S glycoprotein to gangliosides.
T768 76349-76520 Sentence denotes The CLQ-SA complex is formed in a mixed surface and balls by the positioning of the negative charged COOH group of Neu5Ac and one of the two cationic charges of CLQ [163].
T769 76521-76616 Sentence denotes CoVs preferentially bind to 9-O-acetyl-NeuAc [60], differentiating with other viral properties.
T770 76617-76758 Sentence denotes As CLQ interacts with the GM1 sugar part, the N-terminal domain of the S protein loses viral attachment capacity to the cell receptors [166].
T771 76759-76991 Sentence denotes The S protein NTD and the CLQ/CLQ-OH maintain the same position during GM1 binding, consequently preventing GM1 binding to the S protein and the drug at the same time, because the NTD and the CLQ/CLQ-OH simultaneously recognize GM1.
T772 76992-77108 Sentence denotes Asn-167 forms a hydrogen bond with the GalNAc residue, whereas an aromatic Phe-135 stacks to the Glc residue of GM1.
T773 77109-77268 Sentence denotes Therefore, the antiviral activities of CLQ and CLQ-OH is to block the interaction between the SARS-CoV-2 S glycoprotein and gangliosides on host cell surfaces.
T774 77269-77396 Sentence denotes The lipid composition of host cell PM can also be a potential target for preventive and therapeutic drugs against such viruses.
T775 77398-77400 Sentence denotes 8.
T776 77401-77412 Sentence denotes Conclusions
T777 77413-77505 Sentence denotes The SARS-CoV-2-caused COVID-19 pandemic is a global public health issue in the 21st century.
T778 77506-77721 Sentence denotes In order to coordinate efforts against and mitigate the public health consequences of the spreading and outbreak of the disease, the international community has been exchanging independent information and knowledge.
T779 77722-77829 Sentence denotes The scientists and epidemiologists exchange COVID-19 information to highlight interdisciplinary approaches.
T780 77830-77927 Sentence denotes The pandemic outbreak issue has raised interest in the pathology and epidemiology of the disease.
T781 77928-78134 Sentence denotes The current COVID-19 pandemic resulted in establishment of the COVID Action Platform of the World Economic Forum (WEF) to perform evidence-based cutting-edge research and analyze the fast-evolving pandemic.
T782 78135-78272 Sentence denotes The Virus Outbreak Data Network (VODAN) of the GoFair Data Alliance also pursues to apply the best remedy against the pandemic infection.
T783 78273-78402 Sentence denotes In the aspect of basic biology, most β-CoVs recognize 9-O-acetyl SAs, but certain viruses have switched to binding 4-O-acetyl SA.
T784 78403-78514 Sentence denotes Originally, HE is found in other viruses such as toroviruses and orthomyxoviruses (influenza C/D and isavirus).
T785 78515-78589 Sentence denotes The exceptional β-CoV lineage A is the only one to bear HE among the CoVs.
T786 78590-78659 Sentence denotes Virus entry and replication inhibitors need to be urgently developed.
T787 78660-78744 Sentence denotes Computation-fused artificial intelligence accelerates therapeutic agent development.
T788 78745-78898 Sentence denotes The SARS-CoV-2 genome shows 80% similarity to the previous SARS-CoV and SARS-targeting agents can be commonly treated to the related SARS-CoV-2 patients.
T789 78899-79057 Sentence denotes For better understanding of the entry pathway of SARS-CoV-2, the importance of the carbohydrates including SAs on cell and virus surfaces is again emphasized.