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Id Subject Object Predicate Lexical cue
T1 0-127 Sentence denotes SARS-CoV-2 Evolutionary Adaptation toward Host Entry and Recognition of Receptor O-Acetyl Sialylation in Virus–Host Interaction
T2 129-137 Sentence denotes Abstract
T3 138-263 Sentence denotes The recently emerged SARS-CoV-2 is the cause of the global health crisis of the coronavirus disease 2019 (COVID-19) pandemic.
T4 264-435 Sentence denotes No evidence is yet available for CoV infection into hosts upon zoonotic disease outbreak, although the CoV epidemy resembles influenza viruses, which use sialic acid (SA).
T5 436-502 Sentence denotes Currently, information on SARS-CoV-2 and its receptors is limited.
T6 503-650 Sentence denotes O-acetylated SAs interact with the lectin-like spike glycoprotein of SARS CoV-2 for the initial attachment of viruses to enter into the host cells.
T7 651-764 Sentence denotes SARS-CoV-2 hemagglutinin-esterase (HE) acts as the classical glycan-binding lectin and receptor-degrading enzyme.
T8 765-878 Sentence denotes Most β-CoVs recognize 9-O-acetyl-SAs but switched to recognizing the 4-O-acetyl-SA form during evolution of CoVs.
T9 879-962 Sentence denotes Type I HE is specific for the 9-O-Ac-SAs and type II HE is specific for 4-O-Ac-SAs.
T10 963-1094 Sentence denotes The SA-binding shift proceeds through quasi-synchronous adaptations of the SA-recognition sites of the lectin and esterase domains.
T11 1095-1279 Sentence denotes The molecular switching of HE acquisition of 4-O-acetyl binding from 9-O-acetyl SA binding is caused by protein–carbohydrate interaction (PCI) or lectin–carbohydrate interaction (LCI).
T12 1280-1425 Sentence denotes The HE gene was transmitted to a β-CoV lineage A progenitor by horizontal gene transfer from a 9-O-Ac-SA–specific HEF, as in influenza virus C/D.
T13 1426-1516 Sentence denotes HE acquisition, and expansion takes place by cross-species transmission over HE evolution.
T14 1517-1591 Sentence denotes This reflects viral evolutionary adaptation to host SA-containing glycans.
T15 1592-1701 Sentence denotes Therefore, CoV HE receptor switching precedes virus evolution driven by the SA-glycan diversity of the hosts.
T16 1702-1834 Sentence denotes The PCI or LCI stereochemistry potentiates the SA–ligand switch by a simple conformational shift of the lectin and esterase domains.
T17 1835-1967 Sentence denotes Therefore, examination of new emerging viruses can lead to better understanding of virus evolution toward transitional host tropism.
T18 1968-2122 Sentence denotes A clear example of HE gene transfer is found in the BCoV HE, which prefers 7,9-di-O-Ac-SAs, which is also known to be a target of the bovine torovirus HE.
T19 2123-2369 Sentence denotes A more exciting case of such a switching event occurs in the murine CoVs, with the example of the β-CoV lineage A type binding with two different subtypes of the typical 9-O-Ac-SA (type I) and the exclusive 4-O-Ac-SA (type II) attachment factors.
T20 2370-2487 Sentence denotes The protein structure data for type II HE also imply the virus switching to binding 4-O acetyl SA from 9-O acetyl SA.
T21 2488-2657 Sentence denotes Principles of the protein–glycan interaction and PCI stereochemistry potentiate the SA–ligand switch via simple conformational shifts of the lectin and esterase domains.
T22 2658-2829 Sentence denotes Thus, our understanding of natural adaptation can be specified to how carbohydrate/glycan-recognizing proteins/molecules contribute to virus evolution toward host tropism.
T23 2830-2986 Sentence denotes Under the current circumstances where reliable antiviral therapeutics or vaccination tools are lacking, several trials are underway to examine viral agents.
T24 2987-3132 Sentence denotes As expected, structural and non-structural proteins of SARS-CoV-2 are currently being targeted for viral therapeutic designation and development.
T25 3133-3240 Sentence denotes However, the modern global society needs SARS-CoV-2 preventive and therapeutic drugs for infected patients.
T26 3241-3437 Sentence denotes In this review, the structure and sialobiology of SARS-CoV-2 are discussed in order to encourage and activate public research on glycan-specific interaction-based drug creation in the near future.
T27 3439-3441 Sentence denotes 1.
T28 3442-3454 Sentence denotes Introduction
T29 3455-3656 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 3657-3895 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 3896-3962 Sentence denotes To date, pneumonia is epidemiologically caused by diverse viruses.
T32 3963-4180 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 4181-4429 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 4430-4628 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 4629-4707 Sentence denotes SARS-CoV-2 is spreading and causing a global health-threatening emergency [4].
T36 4708-4861 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 4862-4958 Sentence denotes Preventive and therapeutic drugs for patients infected with SARS-CoV-2 are yet to be discovered.
T38 4959-5103 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 5104-5149 Sentence denotes CoVs can also rarely infect neural cells [7].
T40 5150-5311 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 5312-5423 Sentence denotes This is in contrast to influenza viruses, which are known to selectively utilize sialic acid (SA) linkages [8].
T42 5424-5573 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 5574-5719 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 5720-5872 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 5873-5960 Sentence denotes O-GlcNAc, a minor glycan source, is mainly found in the nucleus and cytosol (Figure 1).
T46 5961-6094 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 6095-6254 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 6255-6371 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 6372-6521 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 6522-6817 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 6818-6931 Sentence denotes Recently, 332 protein candidates were suggested to be SARS-CoV-2-human protein interacting proteins through PPIs.
T52 6932-7056 Sentence denotes Among these, 66 human proteins, as druggable host factors, were further characterized as possible FDA-approvable drugs [10].
T53 7057-7156 Sentence denotes If PPI is involved, however, carbohydrates or glycans may serve as co-receptors or co-determinants.
T54 7157-7244 Sentence denotes Previous reports suggest that carbohydrates act as receptor determinants in most cases.
T55 7245-7397 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 7398-7607 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 7608-7700 Sentence denotes The 9-carbon SAs are mainly animal-specific with anionic sugars attached to terminal sugars.
T58 7701-7741 Sentence denotes SAs exist in two forms, NeuGc and NeuAc.
T59 7742-7814 Sentence denotes NeuGc is a differentially modified form of the parental SA form, Neu5Ac.
T60 7815-7844 Sentence denotes SAs are structurally diverse.
T61 7845-8188 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 8189-8250 Sentence denotes Sialyltransferases (STs) biosynthesize different SA linkages.
T63 8251-8348 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 8349-8483 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 8484-8590 Sentence denotes The most frequent modification of SAs is O-acetylation at positions of C4, C7, C8 and C9 of SA (Figure 5).
T66 8592-8594 Sentence denotes 2.
T67 8595-8617 Sentence denotes Classification of CoVs
T68 8618-8707 Sentence denotes Mammal- and avian-infectible CoVs consist of the broad-ranged subfamily of Coronavirinae.
T69 8708-8758 Sentence denotes The ICTV recommended classification is as follows:
T70 8759-8884 Sentence denotes Riboviria (Realm)—Nidovirales (Order)— Cornidovirineae (Suborder)—coronavirida (Family)—orthocoronavirinae—Coronavirus genus.
T71 8885-8948 Sentence denotes The four CoV genera [11] are the α-CoV, β-CoV, γ-CoV and δ-CoV.
T72 8949-9097 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 9098-9210 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 9211-9254 Sentence denotes The β-CoV genus has A, B, C and D lineages.
T75 9255-9311 Sentence denotes Among these, lineage B includes SARS-CoV and SARS-CoV-2.
T76 9312-9340 Sentence denotes Lineage C includes MERS-CoV.
T77 9341-9480 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 9481-9686 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 9687-9843 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 9844-9889 Sentence denotes CoV RNA sequences mutate at a high frequency.
T81 9890-9980 Sentence denotes Among the known RNA viruses, CoVs bear the longest genome sizes of 26 to 32 kb length RNA.
T82 9981-10212 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 10213-10325 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 10326-10404 Sentence denotes SARS-CoV-2 infects human respiratory tracts and causes outbreaks of pneumonia.
T85 10405-10479 Sentence denotes SARS-CoV-2 is a novel CoV and originates from the Wuhan district in China.
T86 10480-10616 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 10618-10620 Sentence denotes 3.
T88 10621-10665 Sentence denotes Structure, Components and Life Cycle of CoVs
T89 10666-10833 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 10834-11008 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 11009-11084 Sentence denotes The SARS-CoV-2 genome is 29,891 bp in size, which encodes 9860 amino acids.
T92 11085-11179 Sentence denotes The ssRNA are capped and tailed with a 5′-capping structure and 3′-poly A tail at the termini.
T93 11180-11345 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 11346-11352 Sentence denotes 6M71).
T95 11353-11473 Sentence denotes Generally, viral families are determined by the genome structure and virion morphologies of an envelope or naked capsid.
T96 11474-11566 Sentence denotes A virus with a naked capsid has a coat of nucleocapsid protein (N) coating the viral genome.
T97 11567-11659 Sentence denotes Viruses with an envelope have lipid envelopes further surrounding the outmost protein layer.
T98 11660-11795 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 11796-11945 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 11946-12086 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 12087-12248 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 12249-12334 Sentence denotes The RNA genome linked with nucleoprotein buds into the ERGIC to form virus particles.
T103 12335-12446 Sentence denotes Assembled virions transported to the vesicular surface are released to the extracellular milieu via exocytosis.
T104 12447-12515 Sentence denotes The RNA generates the replicase as two polyproteins, pp1a and pp1ab.
T105 12516-12691 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 12692-12799 Sentence denotes These enzymes including RTC synthesize RNAs for replication and transcription to generate viral RNA genome.
T107 12800-12890 Sentence denotes CoV genomes bear two or three protease genes and the coding enzymes cleave the replicases.
T108 12891-12988 Sentence denotes Together with the replicases, nonstructural proteins, termed Nsps, assemble into the RTC complex.
T109 12989-13045 Sentence denotes Nsp1 to Nsp16 are known to have multiple enzyme regions.
T110 13046-13175 Sentence denotes For example, Nsp1 degrades cellular mRNAs and, consequently blocks protein translation in host cells and innate immune responses.
T111 13176-13231 Sentence denotes Nsp2 recognizes the specific protein called prohibitin.
T112 13232-13306 Sentence denotes Nsp3 is a multi-domain transmembrane (TM) protein with diverse activities.
T113 13307-13435 Sentence denotes Ubiquitin-like 1 and acidic domains bind to N protein and ADP-ribose-1′-phosphatase (ADRP) activity induces cytokine expression.
T114 13436-13537 Sentence denotes The papain-like protease (PLpro)(PDB:6WX4)/ deubiquitinase domain cleaves virus-produced polyprotein.
T115 13538-13606 Sentence denotes Nsp4 is a TM scaffold protein for double-membrane vesicle structure.
T116 13607-13724 Sentence denotes Nsp5 has a main protease domain which also cleaves virus-produced polyprotein and Nsp6 acts as a TM scaffold protein.
T117 13725-13867 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 13868-13969 Sentence denotes Nsp9 is an RNA-binding protein that activates ExoN and 2-O-methyltrnasferase (MTase) enzyme activity.
T119 13970-14033 Sentence denotes Nsp10 binds to Nsp16 and Nsp14 to form a heterodimeric complex.
T120 14034-14105 Sentence denotes Nsp12 is the RdRp and Nsps13 is the RNA helicase and 5′ triphosphatase.
T121 14106-14153 Sentence denotes Nsps14 is a N7 MTase and 3′-5′ exoribonuclease.
T122 14154-14227 Sentence denotes ExoN of Nsap14 acts as an N7 MTase and attaches the 5′ cap to viral RNAs.
T123 14228-14335 Sentence denotes Viral exoribonuclease enzyme proofreads the viral RNA genome, where Nsp15 is a viral endoribonuclease (PDB:
T124 14336-14342 Sentence denotes 6VWW).
T125 14343-14467 Sentence denotes Nsp16 has 2-O-MTase enzyme activity, which shields viral RNA from melanoma differentiation associated protein-5 recognition.
T126 14469-14473 Sentence denotes 3.1.
T127 14474-14510 Sentence denotes Spike (S) Transmembrane Glycoprotein
T128 14511-14551 Sentence denotes In RNA viruses, the S glycoprotein (PDB:
T129 14552-14701 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 14702-14771 Sentence denotes SARS-CoV-2 S-glycoprotein bears 22 N-glycan sequons in each protomer.
T131 14772-14848 Sentence denotes Therefore, the trimeric S glycoprotein surface is dominated by 66 N-glycans.
T132 14849-14957 Sentence denotes The S glycoprotein mediates direct and indirect interaction of virus with host cells in the infection cycle.
T133 14958-15047 Sentence denotes All CoVs exhibit a surface S glycoprotein, which bears the receptor-binding domain (RBD).
T134 15048-15098 Sentence denotes The S glycoprotein has a distinct spike structure.
T135 15099-15297 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 15298-15475 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 15476-15594 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 15595-15676 Sentence denotes The S1 NTD binds to carbohydrate receptors because the S1 domains act as the RBD.
T139 15677-15729 Sentence denotes The CTD of S1 recognizes protein receptors via RBDs.
T140 15731-15735 Sentence denotes 3.2.
T141 15736-15760 Sentence denotes Nucleocapsid (N) Protein
T142 15761-15823 Sentence denotes In RNA viruses, the N protein recognizes the viral RNA genome.
T143 15824-15843 Sentence denotes The N protein (PDB:
T144 15844-15894 Sentence denotes 6M3M) binds to the RNA genome via the NTD and CTD.
T145 15895-15976 Sentence denotes The N protein tethers to the viral RNA and replicase–transcriptase complex (RTC).
T146 15977-15987 Sentence denotes NSP3 (PDB:
T147 15988-16045 Sentence denotes 6VXS) of CoV blocks the innate immune responses of hosts.
T148 16046-16228 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 16229-16299 Sentence denotes Representatively, the N protein is known as the RNA chaperone protein.
T150 16300-16472 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 16473-16749 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 16751-16755 Sentence denotes 3.3.
T153 16756-16776 Sentence denotes Envelope (E) Protein
T154 16777-16877 Sentence denotes E protein is the most abundant structural protein needed to assemble virus particles in the cytosol.
T155 16878-16960 Sentence denotes As a TM protein, E protein is the smallest structural protein with a MW of 12 kDa.
T156 16961-17048 Sentence denotes The E protein has an NTD in the extracellular region and a CTD in the cytosolic region.
T157 17049-17123 Sentence denotes The E protein bears an ectodomain in the NTD and an endodomain in the CTD.
T158 17124-17158 Sentence denotes It has also an ion channel domain.
T159 17159-17298 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 17299-17355 Sentence denotes Most E proteins assemble and bud in new virus particles.
T161 17357-17361 Sentence denotes 3.4.
T162 17362-17387 Sentence denotes Membrane Glycoprotein (M)
T163 17388-17486 Sentence denotes The M protein contains three TM domains and is an abundant structural protein with a MW of 30 kDa.
T164 17487-17589 Sentence denotes It consists of a small glycosylated NTD in the extracellular region and CTD in the cytoplasmic region.
T165 17590-17704 Sentence denotes The M protein forms a scaffold for virus assembly in the cytosol via binding to S glycoprotein and N protein [22].
T166 17705-17896 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 17897-18022 Sentence denotes Then, CoVs bud into the ERGIC, trafficking by membrane vesicles and transported via the exocytosis-secretory pathway [23,24].
T168 18023-18162 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 18163-18362 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 18364-18368 Sentence denotes 3.5.
T171 18369-18412 Sentence denotes Hemagglutinin-Esterase (HE) Dimeric Protein
T172 18413-18455 Sentence denotes HE hemagglutinates and destroys receptors.
T173 18456-18584 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 18585-18651 Sentence denotes For example, enveloped RNA viruses evade the hosts via their RDEs.
T175 18652-18756 Sentence denotes Currently, RDE-related functional enzymes such as neuraminidase (NA) and SA-O-acetyl-esterase are known.
T176 18757-18923 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 18924-19009 Sentence denotes The origin and evolution of CoV SA-O-acetylesterases are correlated to other viruses.
T178 19010-19128 Sentence denotes The fusion event of S glycoprotein and HE is specific for HCoV attachment to SA-associated receptors in the host [25].
T179 19129-19169 Sentence denotes The HE has acetylesterase activity [26].
T180 19170-19279 Sentence denotes In early SA-related biology, influenza A/B viruses were found to recognize chicken erythrocytes in 1942 [27].
T181 19280-19355 Sentence denotes They caused hemagglutination through clumping by virus-borne hemagglutinin.
T182 19356-19469 Sentence denotes These phenomena were widely found in influenza viruses, paramyxoviruses, Newcastle disease (NDV) and mumps virus.
T183 19471-19473 Sentence denotes 4.
T184 19474-19564 Sentence denotes Relationship between C4-O- and C9-O-Acetyl SA Preferences of CoVs in Host Cell Recognition
T185 19566-19570 Sentence denotes 4.1.
T186 19571-19598 Sentence denotes General O-Acetylation of SA
T187 19599-19788 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 19789-19897 Sentence denotes SA are modified by acetyl-, lactyl-, methyl- and sulfo-groups individually or in multiple combinations [28].
T189 19898-19954 Sentence denotes Multiple enzymes are involved in the modifications [29].
T190 19955-20093 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 20094-20128 Sentence denotes It consisted of two acetyl groups.
T192 20129-20194 Sentence denotes Among these, only one acetyl group was attached to nitrogen [30].
T193 20195-20347 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 20348-20423 Sentence denotes Neu5,9Ac2, Neu5Ac and Neu5Gc are naturally occurring SA species in mammals.
T195 20424-20463 Sentence denotes A common modification is O-acetylation.
T196 20464-20517 Sentence denotes In fact, O-acetylation of SAs is common in organisms.
T197 20518-20687 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 20688-20763 Sentence denotes Neu5Ac9NAc is a chemical and biologic mimic of Neu5,9Ac2 in the SA-glycans.
T199 20764-20894 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 20895-21000 Sentence denotes CasD1 catalyzes the addition of acetyl groups to the SA C-7 at the late Golgi apparatus compartment [31].
T201 21001-21145 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 21146-21274 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 21275-21429 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 21430-21592 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 21593-21692 Sentence denotes The chemical structure of the O-acetyl group is quite unstable and susceptible to esterase enzymes.
T206 21693-21826 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 21827-21936 Sentence denotes The O-acetylated glycan modification invites interaction with viruses, antibodies and mammalian lectins [32].
T208 21937-22022 Sentence denotes Therefore, the SA O-acetylation modification confers specific functions to organisms.
T209 22024-22028 Sentence denotes 4.2.
T210 22029-22113 Sentence denotes Evolutionary Acquisition of C4-O-Acetyl and C9-O-Acetyl SA Recognition by HE Enzymes
T211 22115-22121 Sentence denotes 4.2.1.
T212 22122-22146 Sentence denotes C4-O-Acetyl Modification
T213 22147-22261 Sentence denotes For example, in the horse, C4-O-acetyl modification of Neu5Ac (SA) occupies more than 50% of the total SA content.
T214 22262-22336 Sentence denotes The C4-O-acetylated Neu5Ac, Neu4,5Ac2, inhibits the influenza A2 virus HA.
T215 22337-22474 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 22475-22612 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 22613-22698 Sentence denotes C4-O-acetylated Neu5Ac facilitates the initial attachment of viruses to target cells.
T218 22699-22868 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 22869-23022 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 23023-23214 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 23215-23354 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 23355-23484 Sentence denotes Previous development of O-Ac site-selective NA inhibitors were based on the conceptual consideration of different O-Ac positions.
T223 23485-23593 Sentence denotes The O-Ac of SAs is site-specific, as C4 of Neu5Ac is considered to be a potential position for modification.
T224 23594-23702 Sentence denotes Historically, inhibitors of influenza A and B viruses-sialidases were designed by Von-Itzstein in 1993 [39].
T225 23703-23812 Sentence denotes The Ac group-based C4 substitution interacts with amino acid Glu-119 present in the active site of sialidase.
T226 23813-23982 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 23983-24117 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 24118-24196 Sentence denotes The C4 of Neu5Ac2en was substituted by alkyl groups such as the O-ethyl group.
T229 24197-24286 Sentence denotes For example, Zanamivir has a substitution with a 4-guanidino group with an IC50 of 25 μM.
T230 24287-24360 Sentence denotes Thus, sialidase inhibition is important for C4 modification of Neu5Ac2en.
T231 24361-24504 Sentence denotes Later, oseltamivir with the tradename Tamiflu (Basel, Switzerland) and zanamivir with the tradename Relenza (London, UK) were established [41].
T232 24505-24578 Sentence denotes These drugs exhibit some adverse side effects that restrict clinical use.
T233 24580-24586 Sentence denotes 4.2.2.
T234 24587-24614 Sentence denotes SA C9-O-Acetyl Modification
T235 24615-24793 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 24794-24923 Sentence denotes Instead, the influenza C virus HA recognizes the hosts. β-elimination and permethylation eliminate the 9-O-acetyl group from SAs.
T237 24924-25166 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 25167-25233 Sentence denotes SA O-acetylesterase regulates the presence of 7,9-O-Ac and 9-O-Ac.
T239 25234-25320 Sentence denotes SA O-acetylation and deacetylation are involved in development, cancer and immunology.
T240 25321-25387 Sentence denotes SA O-acetylation alters host lectin bindings such as siglecs [29].
T241 25388-25452 Sentence denotes The presence of 9-O-Ac can also reduce the activity of NAs [43].
T242 25453-25512 Sentence denotes SA modifications regulate pathogen binding or pathogen NAs.
T243 25513-25571 Sentence denotes Influenza A/B/C/D viruses use SA as their entry receptors.
T244 25572-25707 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 25708-25818 Sentence denotes In contrast, influenza C and D subtypes bear only one coated glycoprotein, termed the HE fusion protein (HEF).
T246 25819-25849 Sentence denotes The HEF acts as the HA and NA.
T247 25850-26037 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 26038-26133 Sentence denotes The 9-O-Ac on cells prevents the NA activity and HA binding of the influenza A type virus [44].
T249 26135-26137 Sentence denotes 5.
T250 26138-26148 Sentence denotes HE of CoVs
T251 26150-26154 Sentence denotes 5.1.
T252 26155-26207 Sentence denotes Evolutionary Origin and Classification of the CoV HE
T253 26208-26309 Sentence denotes Certain viruses use glycoproteins such as HA, HE, S and HEF for host receptor binding or destruction.
T254 26310-26434 Sentence denotes Coronaviridae, Orthomyxoviridae, Paramyxoviridae and Adenoviridae utilize SAs as binding molecules for attachment and entry.
T255 26435-26491 Sentence denotes However, only limited human pathogens recognize O-Ac SA.
T256 26493-26499 Sentence denotes 5.1.1.
T257 26500-26551 Sentence denotes Influenza Virus A and B Spike Proteins of HA and NA
T258 26552-26629 Sentence denotes Influenza A and B viruses bear two spikes of receptor-binding HA and NA [45].
T259 26631-26637 Sentence denotes 5.1.2.
T260 26638-26662 Sentence denotes Influenza C virus HA-HEF
T261 26663-26716 Sentence denotes HEF is indeed an ancient type of SA-O-acetylesterase.
T262 26717-26825 Sentence denotes In contrast to A/B, the influenza C virus bears one spike with triple functions of HEF as a homotrimer [46].
T263 26826-26911 Sentence denotes Each HEF subunit bears two Neu5,9Ac2-binding sites and binds to the 9-O-acetyl group.
T264 26912-26972 Sentence denotes In parallel, another modification of O-acetylation is found.
T265 26973-27091 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 27092-27247 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 27248-27340 Sentence denotes Neu5,9Ac2 is an essential determinant for influenza virus C type-specific host cell tropism.
T268 27341-27400 Sentence denotes NAs cleave the α-ketosidic linkages to the D-Gal or GalNAc.
T269 27401-27468 Sentence denotes SA-O-acetylesterases cleave different O-acetyl linkages (Figure 5).
T270 27469-27571 Sentence denotes The OH-group of Tyr224 and the guanidino group of Arg236 interact with the CH3CO-carbonyl oxygen [49].
T271 27572-27711 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 27712-27890 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 27892-27898 Sentence denotes 5.1.3.
T274 27899-27925 Sentence denotes CoV SA-O-Acetylesterase HE
T275 27926-28014 Sentence denotes CoVs and toroviruses of the Coronaviridae family are specific for the O-Ac SA receptors.
T276 28015-28081 Sentence denotes Their S and HE glycoproteins are similar to influenza C virus HEF.
T277 28082-28239 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 28240-28272 Sentence denotes HE multimer forms enter virions.
T279 28273-28391 Sentence denotes Bovine CoV (BCoV) and HCoV-OC43, similar to influenza C virus, recognize Neu5,9Ac2 and bear SA-9-O-acetylesterase [8].
T280 28392-28426 Sentence denotes CoV HEs are all O-acetylesterases.
T281 28427-28620 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 28621-28684 Sentence denotes Therefore, viral HEs are diverse and widespread over evolution.
T283 28686-28690 Sentence denotes 5.2.
T284 28691-28725 Sentence denotes Substrate Diversity of the CoV HEs
T285 28726-28803 Sentence denotes HEs as envelope proteins are found in CoVs, orthomyxoviruses and toroviruses.
T286 28804-28867 Sentence denotes Coronaviral HEs are involved in virus attachment to SA species.
T287 28868-28976 Sentence denotes HE protein in β-CoVs binds to Neu5,9Ac2 form SA and agglutinates the red blood cells (RBCs) of rodents [52].
T288 28977-29090 Sentence denotes As with SA-O-acetylesterase, HE potentiates viral entry with the S protein and spreading via the mucosal glycans.
T289 29091-29159 Sentence denotes It contains a carbohydrate-recognizing domain (CRD) known in lectin.
T290 29160-29242 Sentence denotes The HE glycan-binding domain (GBD) mediates virus attachment to SAs on host cells.
T291 29243-29261 Sentence denotes HE is the only HA.
T292 29262-29395 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 29396-29618 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 29619-29696 Sentence denotes Murine CoVs HEs acquired by horizontal gene transfer, bind to C9-O-Ac Neu5Ac.
T295 29697-29756 Sentence denotes However, some murine CoV HEs cannot bind to C4-O-Ac Neu5Ac.
T296 29757-29907 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 29908-30059 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 30060-30122 Sentence denotes Type I HE is specific for the 9-O-acetylated SAs (9-O-Ac-SAs).
T299 30123-30161 Sentence denotes Type II HE is specific for 4-O-Ac-SAs.
T300 30162-30286 Sentence denotes The SA-binding shift indicates quasi-synchronous adaptations of the SA-recognition sites of the lectin and esterase domains.
T301 30287-30422 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 30423-30627 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 30628-30784 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 30785-30960 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 30961-31073 Sentence denotes Therefore, CoV HE receptor switching precedes virus evolution driven by SA-containing glycan diversity of hosts.
T306 31074-31175 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 31176-31319 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 31320-31564 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 31565-31754 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 31755-31840 Sentence denotes Rat CoV (RCoV) has SA-4-O-acetylesterases, converting Neu4,5Ac2 to Neu5Ac [53,57,58].
T311 31841-31898 Sentence denotes Some murine CoVs prefer 4-O-Ac-SAs and others 9-O-Ac-SAs.
T312 31899-31980 Sentence denotes HCoV-OC43 and BCoV prefer α2-6-SA 9-O-acetylation by their SA-O-acetyleseterases.
T313 31981-32153 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 32154-32237 Sentence denotes BCoV and HCoV-OC43 adapted to SA receptor determinants of 9-O-Ac-SA receptors [59].
T315 32238-32347 Sentence denotes For a second receptor, the binding of S glycoprotein to Neu5,9Ac2 receptor is essential for entry into cells.
T316 32348-32535 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 32537-32539 Sentence denotes 6.
T318 32540-32569 Sentence denotes CoVs Infection of Human Hosts
T319 32571-32575 Sentence denotes 6.1.
T320 32576-32658 Sentence denotes CoVs Utilize SAs and SA Linkages as Attachment and Entry Sites to Human Host Cells
T321 32659-32778 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 32779-32914 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 32915-33007 Sentence denotes Infectious bronchitis virus (IBV) and transmissible gastroenteritis virus are such examples.
T324 33008-33109 Sentence denotes Additionally, both α-CoV and γ-CoV also include sub-members deficient of any SA-recognizing activity.
T325 33110-33197 Sentence denotes During evolution, some subtypes of SARS-CoV and HCoV-229E acquired SA-binding capacity.
T326 33198-33310 Sentence denotes The SA-binding activities of BCoV, transmissible gastroenteritis coronavirus (TGEV) and IBV are well known [60].
T327 33312-33332 Sentence denotes 6.1.1. α-Coronavirus
T328 33333-33436 Sentence denotes In α-CoVs such as TGEV, HA-activity is attributed to the SA-recognizing activity to α2,3-NeuGc [61,62].
T329 33437-33523 Sentence denotes The SA-binding site is present on the N-terminal region of the S-glycoprotein of TGEV.
T330 33524-33580 Sentence denotes TGEV has two types with enteric and respiratory tropism.
T331 33581-33679 Sentence denotes The respiratory TGEV has the porcine aminopeptidase N (pAPN)-binding domain and SA-binding domain.
T332 33680-33836 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 33837-34005 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 34006-34165 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 34166-34250 Sentence denotes MGP SA-binding allows virus entry via the mucus layer to the intestinal enterocytes.
T336 34251-34405 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 34406-34483 Sentence denotes The loss of SA-binding activity is correlated to the non-enteropathogenicity.
T338 34484-34673 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 34674-34783 Sentence denotes SA-binding activity-deficient TGEV can propagate in cells through pAPN, known as CD13, as a receptor [62,63].
T340 34784-34870 Sentence denotes The SA-binding activity potentiates infection and is crucial for intestinal infection.
T341 34872-34892 Sentence denotes 6.1.2. β-Coronavirus
T342 34893-35004 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 35005-35122 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 35123-35272 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 35273-35334 Sentence denotes The SA-acetylesterase is the HE surface glycoprotein in BCoV.
T346 35335-35418 Sentence denotes The three-dimensional structure of BCoV HE is similar to other viral esterases [9].
T347 35419-35464 Sentence denotes The HE gene is found only in the β-CoV genus.
T348 35465-35636 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 35637-35690 Sentence denotes Murine CoVs prefer to esterize 4-O-acetyl-NeuAc [64].
T350 35691-35800 Sentence denotes The β-CoV acetylesterase destroys the receptors and this specificity is similar to that of influenza viruses.
T351 35801-35926 Sentence denotes Acetylesterase activity can be inhibited by diisopropyl fluorophosphate and this agent decreases viral infection levels [65].
T352 35927-36082 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 36083-36150 Sentence denotes The BCoV HE protein has dual activity of acetylesterase and HA [9].
T354 36151-36272 Sentence denotes BCoV widely agglutinates erythrocytes and purified HE only agglutinates Neu5,9Ac2-enriched erythrocytes of rats and mice.
T355 36273-36355 Sentence denotes BCoV and HCoV-OC43 can agglutinate chicken erythrocytes, while purified HE cannot.
T356 36356-36543 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 36544-36719 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 36721-36741 Sentence denotes 6.1.3. γ-Coronavirus
T359 36742-36846 Sentence denotes In γ-CoVs, IBV strains, known as poultry respiratory infectious pathogens, can agglutinate erythrocytes.
T360 36847-36948 Sentence denotes IBV prefers to recognize α2,3-NeuAc and the SA functions as a host entry receptor for infection [66].
T361 36949-37127 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 37128-37186 Sentence denotes The heavy glycosylated M41 RBD has 10 glycosylation sites.
T363 37187-37242 Sentence denotes N-glycosylation of IBV determines receptor specificity.
T364 37243-37293 Sentence denotes However, the host receptor has not yet been found.
T365 37294-37380 Sentence denotes NA treatment reduces the binding of soluble S to kidney and tracheal epithelial cells.
T366 37381-37452 Sentence denotes The IBV S protein recognizes epithelial cells in a SA-dependent manner.
T367 37453-37582 Sentence denotes The SA-binding ability of IBV is necessary for infection of tracheal epithelial cells and lung respiratory epithelial cells [67].
T368 37583-37698 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 37699-37750 Sentence denotes In contrast to BCoV or HCoV-OC43, IBV lacks an RDE.
T370 37751-37829 Sentence denotes SA binding of IBV is likely more essential than in other viruses such as TGEV.
T371 37831-37837 Sentence denotes 6.1.4.
T372 37838-37847 Sentence denotes Torovirus
T373 37848-37988 Sentence denotes In torovirus, which belongs to the family Coronaviridae, the toroviruses are grouped into the Torovirinae subfamily and the Torovirus genus.
T374 37989-38104 Sentence denotes The known toroviruses can infect four species of hosts, constituting bovine, equine, porcine and human toroviruses.
T375 38105-38211 Sentence denotes They mildly infect swine and cattle through the HE protein, which is similar to the β-CoV HE protein [68].
T376 38212-38305 Sentence denotes The HE protein is a class I membrane glycoprotein which forms homodimers with a MW of 65 kDa.
T377 38306-38381 Sentence denotes The RDE protein HE reversibly binds to glycans [15] through binding to SAs.
T378 38382-38431 Sentence denotes The acetyl-esterase activity disrupts SA binding.
T379 38432-38587 Sentence denotes HE hemagglutinates mouse erythrocytes and cleaves the acetyl-ester linkage of glycans and acetylated synthetic substrate p-nitrophenyl acetate (pNPA) [69].
T380 38588-38751 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 38752-39004 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 39006-39010 Sentence denotes 6.2.
T383 39011-39104 Sentence denotes SARS-CoV-2 Recognizes 9-O-Acetyl-SAs and MERS-CoV Recognizes α2,3-SAs as Attachment Receptors
T384 39105-39173 Sentence denotes The S glycoprotein SARS-CoV-2 initiates infection of the host cells.
T385 39174-39396 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 39397-39619 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 39620-39873 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 39874-40015 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 40016-40055 Sentence denotes HCoV-OC43 and BCoV recognize 9-O-Ac-SA.
T390 40056-40094 Sentence denotes S glycoproteins engage 9-O-acetyl-SAs.
T391 40095-40336 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 40337-40397 Sentence denotes Thus, CoVs use two different entry and attachment receptors.
T393 40398-40534 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 40535-40788 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 40789-40869 Sentence denotes However, influenza HA cannot bind to 9-O-acetyl-SAs but can bind to NeuGcs [73].
T396 40870-41179 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 41180-41254 Sentence denotes CoV HEs are functionally similar to influenza virus C/D HEF glycoproteins.
T398 41255-41429 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 41430-41490 Sentence denotes For example, HCoV-OC43 also has a similar HE as an RDE [71].
T400 41491-41572 Sentence denotes In influenza C and D viruses, HEF glycoproteins act similarly to the CoV HE [74].
T401 41573-41635 Sentence denotes In influenza A virus, RDE NA releases virions from host cells.
T402 41636-42057 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 42058-42185 Sentence denotes MERS-CoV S glycoprotein can hemagglutinate human erythrocytes and mediates virus entry into human respiratory epithelial cells.
T404 42186-42335 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 42336-42499 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 42500-42605 Sentence denotes MERS-CoV recognizes α2,3-SA and to a lesser extent the α2,6-SAs and sulfated SLeX for binding preference.
T407 42606-42674 Sentence denotes Thus, S glycoproteins may have independently evolved SA recognition.
T408 42675-42958 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 42959-43134 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 43136-43140 Sentence denotes 6.3.
T411 43141-43163 Sentence denotes Host Receptors of CoVs
T412 43164-43245 Sentence denotes CoV S spikes recognize diverse surface molecules as the attachment or entry site.
T413 43246-43402 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 43403-43536 Sentence denotes Specifically, S glycoprotein interaction with its binding receptor determines host tropism, pathogenicity and therapeutic clues [80].
T415 43537-43599 Sentence denotes CoVs recognize multiple host receptors via distinct S domains.
T416 43600-43686 Sentence denotes The host receptors for β-CoV SARS-CoV includes angiotensin-converting enzyme 2 (ACE2).
T417 43687-43762 Sentence denotes As a lineage C β-CoV, the MERS-CoV S glycoprotein binds to DPP4 [81,82,83].
T418 43763-43837 Sentence denotes MERS-CoV S glycoprotein recognizes α2,3-SA over α2,6-SA-bearing receptors.
T419 43838-43919 Sentence denotes The N-terminal subunits of the S1/S1A/S1B/S1D complex of MERS-CoV recognize DPP4.
T420 43920-43988 Sentence denotes MERS-CoV recognizes CEACAM5 as the attachment factor for entry [78].
T421 43989-44152 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 44153-44265 Sentence denotes Meanwhile the protein receptors specific for lineage A β-CoVs such as HCoV-HKU1 and HCoV-OC43 are not known yet.
T423 44266-44349 Sentence denotes BCoV, HCoV-OC43, HCoV-HKU1 and TGEV recognize O-acetyl-SAs as attachment molecules.
T424 44350-44492 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 44493-44628 Sentence denotes SARS-CoV uses dendritic cell (DC)-specific intercellular adhesion molecule (ICAM)-3–grabbing nonintegrin (DC-SIGN) for attachment [86].
T426 44629-44761 Sentence denotes For glycan interaction, HCoV-NL63 and mouse hepatitis virus utilize heparan sulfate (HS) proteoglycans as attachment enhancers [87].
T427 44762-44909 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 44911-44917 Sentence denotes 6.3.1.
T429 44918-44986 Sentence denotes Angiotensin-Converting Enzyme 2 (ACE2) as the SARS-CoV Host Receptor
T430 44988-45041 Sentence denotes Structure and Role of the Host SARS-CoV Receptor ACE2
T431 45042-45074 Sentence denotes SARS-CoV-2 needs ACE2 for entry.
T432 45075-45205 Sentence denotes Host proteases such as human ACE2 help viral entry through removement of a barrier to enter human cells through unknown receptors.
T433 45206-45298 Sentence denotes Human ACE2 is known for its role as the SARS-CoV-2 entry receptor and the SARS-CoV receptor.
T434 45299-45394 Sentence denotes The enzyme ACE-2 in the renin-angiotensin system (RAS) is associated with CoV entry into lungs.
T435 45395-45495 Sentence denotes ACE2 mediates SARS-2002 entry into host cells via S glycoprotein interaction with the ACE2 receptor.
T436 45496-45568 Sentence denotes The ACE2 levels on the plasma membrane correlate with virus infectivity.
T437 45569-45640 Sentence denotes ACE2 expression is present in most tissues such as the lung epithelium.
T438 45641-45746 Sentence denotes It is highly expressed by respiratory epithelial cells and type I/II lung alveolar epithelial cells [88].
T439 45747-45809 Sentence denotes The host receptor is not linked to the classification of CoVs.
T440 45810-45866 Sentence denotes MERS-CoV, a β-CoV, does not recognize the ACE2 receptor.
T441 45867-45929 Sentence denotes In contrast, the α-CoV HCoV-NL63 recognizes the ACE2 receptor.
T442 45930-46033 Sentence denotes ACE2 is a membrane-anchored carboxypeptidase with 805 amino acid residues and is captopril-insensitive.
T443 46034-46328 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 46329-46373 Sentence denotes The ACE2 gene is located on chromosome Xp22.
T445 46374-46441 Sentence denotes Two ACE2 forms are known, a membrane-bound form and a soluble form.
T446 46442-46496 Sentence denotes ACE cleaves angiotensin I (Ang I) substrate to Ang II.
T447 46497-46650 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 46651-46689 Sentence denotes ACE2 has the opposite function of ACE.
T449 46690-46727 Sentence denotes ACE2 is a close homolog to human ACE.
T450 46728-46796 Sentence denotes ACE2 activity on Ang II is about 400-fold higher than that on Ang I.
T451 46797-46975 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 46976-47066 Sentence denotes Therefore, the ACE2-Ang-1 to Ang-7 axis is a target candidate for cardiovascular diseases.
T453 47067-47131 Sentence denotes ACE2 shows similar binding structures between nCoV and SARS-CoV.
T454 47132-47226 Sentence denotes The three proteins of ACE, Ang II and AT1R contribute to progression of lung injury in humans.
T455 47227-47324 Sentence denotes ACE2 removes a single amino acid residue from Ang II to yield the vasodilator, named Ang 1-Ang 7.
T456 47325-47388 Sentence denotes ACE2 cleaves Ang-I to Ang 1–Ang 9 and Ang II to Ang-1 to Ang-7.
T457 47389-47494 Sentence denotes The biggest difference between ACE2 and ACE is that ACE2 has a non-inhibitory property by ACE inhibitors.
T458 47495-47586 Sentence denotes Pulmonary ACE2 is potentially a candidate target in CoV-involved inflammatory pathogenesis.
T459 47587-47669 Sentence denotes If ACE inhibitors and Ang II-AT1 blockers are dosed, ACE2 expression is increased.
T460 47670-47774 Sentence denotes However, currently we have no conclusive evidence that the inhibitors help SARS-CoV or SARS-CoV-2 entry.
T461 47775-47826 Sentence denotes Rather, SARS-CoV infection reduces ACE2 expression.
T462 47827-47896 Sentence denotes Therefore, SARS-CoV-2 host tropism is not related to ACE2 expression.
T463 47897-47971 Sentence denotes ACE2 levels and ANG II/ANG 1–7 levels regulate the pathogenic progression.
T464 47972-48096 Sentence denotes ACE2 expression is upregulated by gene polymorphisms and ACE inhibitors or Angiotensin II receptor blockers such as sartans.
T465 48098-48152 Sentence denotes Host Cell ADAM17 and TMPRSS2 Competitively Cleave ACE2
T466 48153-48263 Sentence denotes A disintegrin and metallopeptidase domain (ADAM) family of Zn-metalloproteinases belongs to membrane proteins.
T467 48264-48353 Sentence denotes The well-known ADAM17 is a TNF-α-converting enzyme (TACE), called the sheddase for TNF-α.
T468 48354-48422 Sentence denotes Other ADAM sheddase family members include ADAM9, ADAM10 and ADAM12.
T469 48423-48453 Sentence denotes ADAM17 mediates ACE2 shedding.
T470 48454-48543 Sentence denotes SARS-CoV S glycoprotein activates cellular TACE and consequently facilitates virus entry.
T471 48544-48693 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 48694-48818 Sentence denotes ADAM17 is indeed an enzyme that can convert membrane type pro-TNF-α to soluble TNF-α, a functional proinflammatory cytokine.
T473 48819-48975 Sentence denotes Therefore, ADAM17 inhibition indicates an anti-inflammatory response and ADAM17 inhibitors are promising candidates for TNF-α-induced inflammatory diseases.
T474 48976-49045 Sentence denotes The short C-terminal domain of ACE2 is removed by ADAM17 and TMPRSS2.
T475 49046-49122 Sentence denotes However, TMPRSS2 cleaves ACE2 competitively with the ADAM17 metalloprotease.
T476 49123-49311 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 49312-49403 Sentence denotes Only TMPRSS2 cleavage allows SARS-CoV entry into host cells through endocytosis and fusion.
T478 49404-49477 Sentence denotes Soluble ACE2 also recognizes the virus and prevents SARS-CoV-2 infection.
T479 49478-49534 Sentence denotes SARS-CoV-2 infection requires membrane ACE2 and TMPRSS2.
T480 49535-49600 Sentence denotes The ACE2–B0AT1 complex binds to the S glycoprotein of SARS-CoV-2.
T481 49601-49706 Sentence denotes Intestinal membrane ACE2 and lung TMPRSS2-shedded ACE2 can act as alternative entry sites for SARS-CoV-2.
T482 49707-49775 Sentence denotes SARS-CoV-2 infects the lungs and intestine via TMPRSS2-cleaved ACE2.
T483 49776-49896 Sentence denotes If TMPRSS2 is engaged in SARS-CoV-2 entry and ACE2 downregulation, TMPRSS2 inhibition would lead to COVID-19 prevention.
T484 49897-50080 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 50081-50203 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 50204-50273 Sentence denotes TMPRSS2-cleaved ACE2 is involved in SARS-CoV and MERS-CoV infections.
T487 50274-50367 Sentence denotes SARS-CoV-2 uses ACE2 for cell entry through TMPRSS2 priming of the S glycoprotein (Figure 7).
T488 50368-50479 Sentence denotes Infection of the H7N9 influenza and H1N1 influenza A subtype viruses are also mediated by TMPRSS2-cleaved ACE2.
T489 50480-50560 Sentence denotes This implies that TMPRSS2 can be targeted as a strategic antiviral therapy [92].
T490 50561-50662 Sentence denotes Transmembrane protease serine 2, termed TMPRSS2, a type II TM Ser protease (TTSP), also cleaves ACE2.
T491 50663-50797 Sentence denotes The human TMPRSS2 gene, located on chromosome 21, comprises androgen receptor elements (AREs) in the upstream 5′-flanking region [93].
T492 50798-50862 Sentence denotes TMPRSS2 expression is regulated in an androgen-dependent manner.
T493 50863-50904 Sentence denotes The TMPRSS2 gene encodes 492 amino acids.
T494 50905-50990 Sentence denotes The original form is cleaved into the major membrane form and the minor soluble form.
T495 50991-51124 Sentence denotes TMPRSS2 activates protease activated receptor 2 (PAR-2) and activated PAR-2 upregulates matrix metalloproteinase-2 (MMP-2) and MMP-9.
T496 51125-51207 Sentence denotes TMPRSS2-activated hepatocyte growth factor (HGF) induces c-Met receptor signaling.
T497 51208-51248 Sentence denotes TMPRSS2 activates SARS-CoV and MERS-CoV.
T498 51249-51460 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 51461-51552 Sentence denotes SARS-CoV can enter cells upon cleavage by protease TMPRSS2 or endosomal cathepsin L/B [90].
T500 51553-51608 Sentence denotes Virus S protein precursor is cleaved by host proteases.
T501 51609-51745 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 51746-51838 Sentence denotes The serine protease inhibitor camostat effectively blocks lethal SARS-CoV infection to mice.
T503 51839-51907 Sentence denotes However, serine protease and cathepsin inhibitors are not effective.
T504 51908-52017 Sentence denotes Thus, TMPRSS2 is suggested to be an acting protease for SARS-CoV entry into host cells, but not by cathepsin.
T505 52018-52110 Sentence denotes Cis-cleavage liberates SARS-CoV S glycoprotein fragments into the extracellular supernatant.
T506 52111-52252 Sentence denotes Trans-cleavage activates the SARS-CoV S glycoprotein on the target cells, potentiating efficient SARS-CoV S glycoprotein-driven viral fusion.
T507 52253-52325 Sentence denotes TMPRSS2-activated SARS-CoV facilitates enveloped virus entry into cells.
T508 52326-52394 Sentence denotes TMPRSS2 is important for SARS-CoV entry and infection [81,94,95,96].
T509 52395-52534 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 52535-52884 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 52885-53060 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 53061-53152 Sentence denotes Aprotinin is a polypeptide with 58 amino acid residues that was isolated from bovine lungs.
T513 53153-53462 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 53463-53637 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 53638-53719 Sentence denotes MPRSS2 as a host factor plays a pivotal role in SARS-CoV and MERS-CoV infections.
T516 53720-53778 Sentence denotes FDA-approved TMPRSS2 inhibitors are yet under development.
T517 53779-53918 Sentence denotes Because TMPRSS2 mediates efficient viral entry and replication, it should be a promising target for new therapeutics against CoV infection.
T518 53920-53926 Sentence denotes 6.3.2.
T519 53927-53977 Sentence denotes Dipeptidyl peptidase-4 (DPP4) as MERS-CoV Receptor
T520 53978-54021 Sentence denotes The Ser exopeptidase DPP-4/human CD26 (PDB:
T521 54022-54104 Sentence denotes 4L72), a type II TM ectopeptidase, functions as a host cell receptor for MERS-CoV.
T522 54105-54215 Sentence denotes The RBD structure was characterized by crystallography approaches of the MERS-CoV S glycoprotein–DPP4 complex.
T523 54216-54349 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 54350-54411 Sentence denotes DPP4 cleaves X-proline dipeptides from the N-terminal region.
T525 54412-54511 Sentence denotes S glycoprotein recognizes SA species and DPP44 as the attachment and entry receptors, respectively.
T526 54512-54589 Sentence denotes The MERS-CoV S1 N-terminal domain attaches to DPP4 as the host receptor [81].
T527 54590-54659 Sentence denotes The S2 C-terminal domain of MERS-CoV anchors to cellular PM to enter.
T528 54660-54744 Sentence denotes MERS-CoV S glycoprotein is cleaved at a sequence between the S1 and S2 domains [96].
T529 54745-54799 Sentence denotes Another cleavage site S2′ is present in the S2 domain.
T530 54800-54968 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 54969-55058 Sentence denotes Binding capacities are hindered by the SA 9-O-acetyl group or SA 5-N-glycolyl group [75].
T532 55060-55066 Sentence denotes 6.3.3.
T533 55067-55082 Sentence denotes CEACAM Receptor
T534 55083-55203 Sentence denotes Entry of host cells needs binding of S glycoproteins to the CEACAM receptor, forming S-protein-mediated membrane fusion.
T535 55204-55262 Sentence denotes The trimeric S glycoprotein bears three S1 receptor heads.
T536 55263-55345 Sentence denotes The three S1 heads of the virus bind to three receptor molecules on the host cell.
T537 55346-55555 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 55556-55648 Sentence denotes The enveloped CoV, MHV, binds to CEACAMs on cholesterol-depleted cells in BHK cell cultures.
T539 55649-55682 Sentence denotes The NTD of S1 recognizes CEACAM1.
T540 55683-55767 Sentence denotes For MERS-CoV, another CEACAM5 isoform is the attachment factor for virus entry [75].
T541 55768-55857 Sentence denotes The CoV S1 NTD has a similar tertiary structure to human galactose-recognizing galectins.
T542 55858-55931 Sentence denotes MHV S1 NTD binds murine CEACAM1a and BCoV S1 NTD binds sugar [98,99,100].
T543 55932-56012 Sentence denotes CEACAM1a is a cell adhesion protein (CAM) and its mRNA is alternatively spliced.
T544 56013-56089 Sentence denotes The cryo-EM structure of MHV S complexed with CEACAM1a was elucidated [101].
T545 56090-56302 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 56303-56390 Sentence denotes MHV S1 protein also evolutionarily acquired murine CEACAM1a-recognizing activity [102].
T547 56391-56507 Sentence denotes Therefore, CoVs are under evolution to adapt their host receptor interaction to infect cross-species hosts [80,103].
T548 56508-56695 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 56696-56780 Sentence denotes Both raft and non-raft CEACAMs are involved in the virus–cell membrane fusion event.
T550 56781-56941 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 56942-57079 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 57080-57147 Sentence denotes This implies that membrane anchors are not intrinsically necessary.
T553 57148-57221 Sentence denotes In fact, CEACAMs are present in different tissue-specific isoforms [105].
T554 57222-57473 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 57474-57627 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 57628-57689 Sentence denotes S proteins are structurally shifted prior to membrane fusion.
T557 57690-57846 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 57848-57854 Sentence denotes 6.3.4.
T559 57855-57924 Sentence denotes Membrane-Associated 78-kDa Glucose-Regulated Protein (GRP78) or HSPA5
T560 57925-58149 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 58150-58213 Sentence denotes HSP5A is a ER-resident unfolded protein response (UPR) protein.
T562 58214-58351 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 58352-58435 Sentence denotes GRP78 modulates MERS-CoV entry in the presence of the DPP4 as a host cell receptor.
T564 58436-58519 Sentence denotes Additionally, lineage D β-CoV and bat CoV HKU9 (bCoV-HKU9) also bind to GRP78 [76].
T565 58520-58638 Sentence denotes A cell surface receptor, GRP78, was predicted to be another COVID-19 receptor as an S glycoprotein binding site [110].
T566 58639-58754 Sentence denotes The prediction was made using the combined technology of molecular modeling docking with structural bioinformatics.
T567 58755-58821 Sentence denotes GRP78 or BiP is a chaperone protein located in the ER lumen [111].
T568 58822-58987 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 58988-59149 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 59150-59236 Sentence denotes Stress-overexpressed GRP78 can avoid ER retention and is translocated to the membrane.
T571 59237-59372 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 59373-59521 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 59522-59652 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 59653-59698 Sentence denotes Region IV is the GRP78 binding-driving force.
T575 59699-59823 Sentence denotes These nine amino acid residues are being molecularly targeted for the designation and simulation of COVID-19-specific drugs.
T576 59824-59957 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 59958-60188 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 60189-60288 Sentence denotes Therefore, natural products can inhibit cell-surface HSPA5 recognition of the viral S glycoprotein.
T579 60290-60296 Sentence denotes 6.3.5.
T580 60297-60352 Sentence denotes Aminopeptidase N (APN) is a Receptor of α-CoV HCoV-229E
T581 60353-60482 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 60483-60615 Sentence denotes Porcine epidemic diarrhea coronavirus virus (PEDV) binds to protein receptor APN of human- and pig NeuAc species as its co-receptor.
T583 60616-60755 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 60756-60830 Sentence denotes HCoV-229E recognizes hAPN known as CD13 for its entry receptor. hAPN (PDB:
T585 60831-60939 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 60940-61067 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 61068-61131 Sentence denotes The CTD has a pentapeptide sequence specific for the Zinc–MMPs.
T588 61132-61326 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 61327-61524 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 61525-61567 Sentence denotes Homodimeric CD13 digests luminal peptides.
T591 61568-61732 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 61733-61803 Sentence denotes If this gene is defective, leukemia or lymphoma are transformed [123].
T593 61804-61861 Sentence denotes Porcine and human APN exhibit about 80% protein identity.
T594 61862-61920 Sentence denotes FIPV and FeCV are in the same group as HCoV-229E and TGEV.
T595 61921-62014 Sentence denotes Thus, porcine APN is also an attachment site for pig TGEV with an additional second receptor.
T596 62015-62117 Sentence denotes HCoV-229E first binds to CD13 and consequently clusters CD13 in caveolae-associated lipid rafts [120].
T597 62119-62125 Sentence denotes 6.3.6.
T598 62126-62179 Sentence denotes Heparan Sulfate (HS) is the HCoV-NL63 Attachment Site
T599 62180-62301 Sentence denotes For glycan interaction, HCoV-NL63 and MHV utilize heparan sulfate proteoglycans (HSPGs) as attachment enhancers [87,124].
T600 62302-62350 Sentence denotes Viruses recognize HSPGs as attachment molecules.
T601 62351-62425 Sentence denotes In the spike (S) protein-deficient virions, the M protein recognizes HSPG.
T602 62426-62487 Sentence denotes The S proteins generally bind to the viral cellular receptor.
T603 62488-62576 Sentence denotes However, the M protein also acts as a receptor in the early step of HCoV-NL63 infection.
T604 62577-62653 Sentence denotes The M membrane protein of HCoV-NL63 recognizes the attachment site of HSPGs.
T605 62654-62830 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 62831-62939 Sentence denotes HSPGs are glycosaminoglycan (GAG)-carrying proteins frequently used as a secondary receptor for viral entry.
T607 62940-63002 Sentence denotes HSPGs are composed of covalent-bonded HS chains as a GAG form.
T608 63003-63106 Sentence denotes The HS GAG linkage structure of tetrasaccharide exhibits GluAβ1,3GlcNAcα1,4Galβ1,3Galβ1,4Xylβ-O-serine.
T609 63107-63293 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 63294-63372 Sentence denotes GAG is used as docking sites for virus interaction with the host cell surface.
T611 63373-63436 Sentence denotes GAGs contain negatively charged N- and O-sulfated sugars [126].
T612 63437-63628 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 63629-63729 Sentence denotes The negative charges mediate the interaction of GAGs and their ligands through electrostatic forces.
T614 63730-63804 Sentence denotes Interaction of HSPG with ligands potentiates many virus infectious cycles.
T615 63805-64077 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 64078-64185 Sentence denotes HSPGs increase virulence upon interaction with viral factors required for viral attachment and replication.
T617 64187-64193 Sentence denotes 6.3.7.
T618 64194-64280 Sentence denotes Major Histocompatibility Complex Class I (MHC-I) C is an Attachment Site for HCoV-HKU1
T619 64281-64445 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 64447-64453 Sentence denotes 6.3.8.
T621 64454-64511 Sentence denotes DC-SIGN (CD209) is a Binding Candidate for SARS-CoV Entry
T622 64512-64607 Sentence denotes SARS-CoV uses the C-type lectins of DC-SIGN and DC-L-SIGN as additional or secondary receptors.
T623 64608-64697 Sentence denotes Glycans on the S glycoprotein are recognized by DC/L-SIGN for virus attachment and entry.
T624 64698-64820 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 64822-64828 Sentence denotes 6.3.9.
T626 64829-64925 Sentence denotes Tetraspanin CD9 is a Surface factor for MERS-CoV Entry Via Scaffold Cell Receptors and Proteases
T627 64926-65112 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 65113-65201 Sentence denotes This CD9–DPP4–TMPRSS2 complex permits MERS-CoV pseudovirus entrance into the host cells.
T629 65202-65316 Sentence denotes The tetraspanins have four TM spanning regions linked by one large and one small loop in the extracellular region.
T630 65317-65383 Sentence denotes Tetraspanins form virus entry baselines and open CoV entry routes.
T631 65384-65474 Sentence denotes To help viral entry into host cells, MERS-CoV S interacts with DPP4 receptors via the RBD.
T632 65475-65569 Sentence denotes Receptor involvement causes cleavage using proteases such as the previously described TMPRSS2.
T633 65570-65659 Sentence denotes Association of tetraspanin CD9 with the DPP4–TMPRSS2 complex triggers the S glycoprotein.
T634 65660-65745 Sentence denotes MERS-CoVs enter the cells via endocytosis and cathepsins cleave the S proteins [132].
T635 65747-65751 Sentence denotes 6.4.
T636 65752-65824 Sentence denotes Effects of Receptor and Ligand S Glycosylation on Virus–Host Interaction
T637 65825-65925 Sentence denotes SAs are predominant surface determinants for pathogen attachment, adherence and entry to host cells.
T638 65926-66038 Sentence denotes Eleven representative vertebrate virus families utilize SAs as initial entry receptors or as attachment factors.
T639 66039-66167 Sentence denotes Interaction of virus with SA-containing glycans is complex because virus SA-binding lectins are inherently of very low affinity.
T640 66168-66267 Sentence denotes Viruses acquire enzymes to catalyze virion elution by regional depletion of binding receptors [56].
T641 66268-66323 Sentence denotes TM S glycoprotein recognizes oligosaccharide receptors.
T642 66324-66527 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 66528-66594 Sentence denotes All CoV S proteins show conservation in binding to 9-O-acetyl-SAs.
T644 66595-66646 Sentence denotes MERS-CoV also recognizes 9-carbon sugar SA species.
T645 66647-66681 Sentence denotes MERS-CoV S-1A binds to SA species.
T646 66682-66812 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 66813-66900 Sentence denotes Binding is hence blocked by SA modification to 5-N-NeuGc and 7, 9-O-NeuAc species [73].
T648 66901-67103 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 67104-67270 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 67271-67341 Sentence denotes The receptor glycan structures decide the entry of some human viruses.
T651 67342-67451 Sentence denotes Changes in ACE2 receptor sialylation influences interaction affinity between virus ligands and host receptor.
T652 67452-67549 Sentence denotes Inter-species or individual genetic variations such as drift and mutation may occur in SARS-CoVs.
T653 67550-67654 Sentence denotes This explains currently emerging differences in CoV responses within the same population such as humans.
T654 67655-67804 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 67805-67883 Sentence denotes Virus internalization requires potential glycosylation of viral glycoproteins.
T656 67884-68001 Sentence denotes Among the three viral envelope components, S and M are the major glycoproteins and E is nascent and not glycosylated.
T657 68002-68090 Sentence denotes The M glycoprotein consists of a short glycosylated ectodomain in the N-terminal region.
T658 68091-68270 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 68271-68378 Sentence denotes For example, BCoVs attach to the surface receptor of N-acetyl-9-O-NeuAc (9-O-acetylated SAs) on host cells.
T660 68379-68445 Sentence denotes TGEV and PEDV are currently known as a similar class of such CoVs.
T661 68446-68577 Sentence denotes PEDV infects multiple hosts including bat, pig, human and monkey, where bats are considered to be the evolutionary origin for PEDV.
T662 68578-68680 Sentence denotes The S glycoprotein of SARS-CoV-2 utilizes different glycosylation patterns to recognize its receptors.
T663 68681-68757 Sentence denotes The glycosylation sites in minimal RBD exhibits similar sites to other CoVs.
T664 68758-68870 Sentence denotes The trimeric SARS-CoV-2 S glycoprotein is also highly glycosylated with 66 N-glycans, but a few O-glycans [135].
T665 68871-68928 Sentence denotes Glycosylation of S glycoproteins leads to immune evasion.
T666 68929-69051 Sentence denotes In the MERS-CoV and the bat-specific CoV-HKU4, glycosylation is linked to zoonotic infection for fusion-based entry [136].
T667 69053-69055 Sentence denotes 7.
T668 69056-69109 Sentence denotes Pharmacology of Glycan-Related Anti-SARS-CoV-2 Agents
T669 69110-69263 Sentence denotes The emerging CoV-pandemic requires therapeutic agents to block the recognition, binding, replication, amplification and propagation of the CoV in humans.
T670 69264-69399 Sentence denotes Protease inhibitors, RNA synthase inhibitors and S2 inhibitors are potential targets, and several agents are currently being evaluated.
T671 69400-69470 Sentence denotes Efficient therapeutic drugs are the most reliable option for patients.
T672 69471-69607 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 69608-69647 Sentence denotes This is a potential therapeutic target.
T674 69648-69789 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 69790-69887 Sentence denotes Human TMPRSS2 enzyme influences the CoV S glycoprotein activation, to facilitate virus infection.
T676 69888-69974 Sentence denotes ACE2 binding and TMPRSS2 activation facilitate the CoVs to attach to human host cells.
T677 69975-70088 Sentence denotes Mouse, nonhuman primate and human cells have been analyzed using single-cell RNA new generation sequencing (NGS).
T678 70089-70243 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 70244-70334 Sentence denotes In the lungs, the proteins are stored in the alveoli like air sacs of type II pneumocytes.
T680 70335-70411 Sentence denotes In the intestine, the two proteins are expressed in entero-epithelial cells.
T681 70412-70477 Sentence denotes ACE2 gene expression correlates with the IFN-related genes [137].
T682 70478-70528 Sentence denotes ACE2 helps lung cells to tolerate cellular damage.
T683 70529-70654 Sentence denotes Therefore, CoVs may evolutionally take advantage of the defense mechanisms of host cells, hijacking such host-borne proteins.
T684 70655-70815 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 70816-70944 Sentence denotes SARS-CoV-2 infection is regulated by glycosylated SARS-CoV-2 viral particles and glycosylated ACE2 in the lung epithelial cells.
T686 70945-70996 Sentence denotes RBD of the CoV S glycoprotein recognizes ACE2 [82].
T687 70997-71141 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 71142-71251 Sentence denotes Trimeric viral S glycoprotein is glycosylated and cleaved by a protease, furin, into two subunits, S1 and S2.
T689 71252-71349 Sentence denotes Subunit S1 is further cleaved into the SA and SB domains and the SB domain recognizes human ACE2.
T690 71350-71430 Sentence denotes The N-glycosylated S2 subunit is involved in virus-ACE2 complex formation [139].
T691 71431-71520 Sentence denotes Therefore, the glycosylated ACE2 receptor is a key molecule for virus binding and fusion.
T692 71521-71594 Sentence denotes Plasma sera prepared from infected patients is an alternative medication.
T693 71595-71685 Sentence denotes The WHO has suggested this trial since the 2014 Ebola epidemic and 2015 MERS-CoV outbreak.
T694 71686-71729 Sentence denotes In addition, Mab therapy is another option.
T695 71730-71857 Sentence denotes For example, LCA50 Mab mimics produced by modification of plasma antibodies isolated from MERS-CoV patients was valuable [140].
T696 71858-71977 Sentence denotes Low molecular molecules are being examined for anti-virus activities from alkaloids, glycan derivatives and terpenoids.
T697 71978-72081 Sentence denotes Recently, anti-CoV drugs are being approached using molecular modeling, docking and simulation methods.
T698 72082-72213 Sentence denotes Computation-assisted drugs via molecular modeling and docking toward drug targets are applied as anti-viral compounds against CoVs.
T699 72214-72249 Sentence denotes They target human ACE2, PLpro (PDB:
T700 72250-72286 Sentence denotes 3e9s), the CoV main proteinase (PDB:
T701 72287-72454 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 72455-72471 Sentence denotes CoV 3CLpro (PDB:
T703 72472-72543 Sentence denotes 6WX4) and the PLpro cleave the polyproteins to assemble virus proteins.
T704 72544-72675 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 72677-72681 Sentence denotes 7.1.
T706 72682-72761 Sentence denotes N-Glycosylation Inhibition by Chloroquine (CLQ) and Hydroxychloroquine (CLQ-OH)
T707 72762-72841 Sentence denotes CLQ and CLQ-OH are under investigation worldwide to treat COVID-19 (Figure 10).
T708 72842-72986 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 72987-73131 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 73132-73277 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 73278-73334 Sentence denotes CLQ-OH is an aminoquinoline with less toxicity than CLQ.
T712 73335-73431 Sentence denotes CLQ-OH bears an N-hydroxyethyl side chain, which increases its solubility compared to CLQ [141].
T713 73432-73534 Sentence denotes CLQ-OH modulates activated immune cells via downregulation of TLR signaling and IL-6 production [142].
T714 73535-73623 Sentence denotes Clinical trials are also under consideration for the efficacy and safety of these drugs.
T715 73624-73740 Sentence denotes Regarding the action mechanism(s), CLQ and CLQ-OH-mediated inhibition of ACE2 terminal glycosylation was considered.
T716 73741-73927 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 73928-74034 Sentence denotes The binding affinity of ACE2 to S glycoprotein is simulated to be lowered by treatment with CLQ-OH or CLQ.
T718 74035-74156 Sentence denotes CLQ may modify the binding affinity between ACE2 and S glycoprotein by alterations in ACE2 glycosylation or modification.
T719 74157-74228 Sentence denotes CLQ-OH (EC50 0.72 μM) and CLQ (EC50, 5.47 μM) inhibit SARS-CoV-2 [143].
T720 74229-74466 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 74467-74672 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 74673-74817 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 74818-75009 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 75010-75128 Sentence denotes In fact, CLQ exhibits in vitro anti-SARS-CoV-1 activity via defective glycosylation of viral ACE2 in Vero cells [149].
T725 75129-75322 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 75323-75385 Sentence denotes However, the detailed mechanisms should be further elucidated.
T727 75386-75481 Sentence denotes The CLQ treatment efficacy in Covid-19 patients has, however, not been conclusively determined.
T728 75483-75487 Sentence denotes 7.2.
T729 75488-75559 Sentence denotes Interaction of Membrane Gangliosides in Lipid Rafts with CLQ and CLQ-OH
T730 75560-75604 Sentence denotes Lipid rafts are also viral attachment sites.
T731 75605-75923 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 75924-76050 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 76051-76183 Sentence denotes HCoV-229E entry is prevented by cholesterol depleted conditions because HCoV-229E clusters in caveolae-associated lipid rafts [157].
T734 76184-76333 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 76334-76403 Sentence denotes S protein-CD13 cross-linking occurs via CD13-caveolin-1 sequestering.
T736 76404-76479 Sentence denotes HCoV-229E particles similarly exhibit a longitudinal distribution property.
T737 76480-76556 Sentence denotes HCoV-229E-colocalized caveolin-1 undergoes the next step of virus infection.
T738 76557-76677 Sentence denotes Caveolin-1 knockdown inhibited HCoV-229E endocytosis and entry and thus caveolin-1 is essential for HCoV-229E infection.
T739 76678-76753 Sentence denotes TGEV also endocytoses by a clathrin-mediated mechanism in MDCK cells [159].
T740 76754-76858 Sentence denotes Other viruses including HCoV-OC43 also use an entry receptor sequestered to cross-linked caveolae [160].
T741 76859-76968 Sentence denotes In SARS-CoV, the first entry step to host cells needs ACE2 in intact lipid rafts by the S glycoprotein [151].
T742 76969-77085 Sentence denotes ACE2 is associated with caveolin-1 and GM1 in membrane rafts depending on its cell-type specific localization [161].
T743 77086-77231 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 77232-77329 Sentence denotes C-type lectin, CD209 L (L-SIGN), can also form lipid rafts and acts as a SARS-CoV receptor [162].
T745 77330-77514 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 77515-77586 Sentence denotes CLQ binds the SAs and gangliosides in lipid rafts with a high affinity.
T747 77587-77660 Sentence denotes Therefore, CLQ or CLQ-OH prevents the S glycoprotein–ganglioside binding.
T748 77661-77754 Sentence denotes CLQ (or CLQ-OH) binding to SA consequently prevents S glycoprotein binding to host receptors.
T749 77755-77834 Sentence denotes The N-terminal region of SARS-CoV-2 S glycoprotein interacts with gangliosides.
T750 77835-77962 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 77963-78076 Sentence denotes Using molecular modeling and simulation technology, CLQ has been suggested to recognize the SAs and gangliosides.
T752 78077-78119 Sentence denotes Human type Neu5Ac binds to CLQ and CLQ-OH.
T753 78120-78168 Sentence denotes Thus, SAs are binding targets of CLQ and CLQ-OH.
T754 78169-78267 Sentence denotes CLQ and CLQ-OH have two specific recognition sites in the polar sugar residues of ganglioside GM1.
T755 78268-78373 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 78374-78517 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 78518-78638 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 78639-78795 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 78796-78909 Sentence denotes The ACE2-binding RBD is suggested to be a potential GBS located on a differential site of the S glycoprotein NTD.
T760 78910-78990 Sentence denotes The protein sequence interfacing surface of the NTD is the consensus GBDs [164].
T761 78991-79143 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 79144-79224 Sentence denotes The GBD is conserved throughout viral isolates from worldwide COVID-19 patients.
T763 79225-79349 Sentence denotes The GBD potentially increases viral attachment ability to PM lipid rafts and contact between host ACE-2 and S protein [165].
T764 79350-79458 Sentence denotes The interaction between CLQ-OH and 9-O-acetyl-NeuAc is also similar to the 9-O-acetyl-NeuAc-CLQ interaction.
T765 79459-79545 Sentence denotes The CLQ-OH OH group enhances the interaction of CLQ with SA via a hydrogen bond [163].
T766 79546-79717 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 79718-79787 Sentence denotes CLQ and CLQ-OH prevent the binding of S glycoprotein to gangliosides.
T768 79788-79959 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 79960-80055 Sentence denotes CoVs preferentially bind to 9-O-acetyl-NeuAc [60], differentiating with other viral properties.
T770 80056-80197 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 80198-80430 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 80431-80547 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 80548-80707 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 80708-80835 Sentence denotes The lipid composition of host cell PM can also be a potential target for preventive and therapeutic drugs against such viruses.
T775 80837-80839 Sentence denotes 8.
T776 80840-80851 Sentence denotes Conclusions
T777 80852-80944 Sentence denotes The SARS-CoV-2-caused COVID-19 pandemic is a global public health issue in the 21st century.
T778 80945-81160 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 81161-81268 Sentence denotes The scientists and epidemiologists exchange COVID-19 information to highlight interdisciplinary approaches.
T780 81269-81366 Sentence denotes The pandemic outbreak issue has raised interest in the pathology and epidemiology of the disease.
T781 81367-81573 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 81574-81711 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 81712-81841 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 81842-81953 Sentence denotes Originally, HE is found in other viruses such as toroviruses and orthomyxoviruses (influenza C/D and isavirus).
T785 81954-82028 Sentence denotes The exceptional β-CoV lineage A is the only one to bear HE among the CoVs.
T786 82029-82098 Sentence denotes Virus entry and replication inhibitors need to be urgently developed.
T787 82099-82183 Sentence denotes Computation-fused artificial intelligence accelerates therapeutic agent development.
T788 82184-82337 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 82338-82496 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.
T790 82498-82513 Sentence denotes Acknowledgments
T791 82514-82672 Sentence denotes This study was in part supported by a grant (NRF-2018R1D1A1A09081927 to CHK) of the Basic Science Research Program through National Research Foundation (NRF).
T792 82674-82694 Sentence denotes Author Contributions
T793 82695-82804 Sentence denotes Conceptualization, C.-H.K.; writing—original draft preparation, C.-H.K.; writing, review and editing, C.-H.K.
T794 82805-82881 Sentence denotes All authors have read and agreed to the published version of the manuscript.
T795 82883-82890 Sentence denotes Funding
T796 82891-82965 Sentence denotes Funded by the Ministry of Education, Science and Technology (MEST), Korea.
T797 82967-82988 Sentence denotes Conflicts of Interest
T798 82989-83034 Sentence denotes The author declares no conflicts of interest.
T799 83035-83048 Sentence denotes Abbreviations
T800 83049-83075 Sentence denotes HE hemagglutinin-esterase
T801 83076-83110 Sentence denotes COVID-19 coronavirus disease 2019
T802 83111-83126 Sentence denotes SA sialic acid
T803 83127-83190 Sentence denotes SARS-CoV severe acute respiratory syndrome-related coronavirus
T804 83191-83237 Sentence denotes MERS-V Middle East respiratory syndrome virus
T805 83238-83270 Sentence denotes RSV respiratory syncytial virus
T806 83271-83301 Sentence denotes WHO World Health Organization
T807 83302-83335 Sentence denotes 2019-nCoV 2019-Novel Coronavirus
T808 83336-83363 Sentence denotes GIT gastrointestinal track
T809 83364-83395 Sentence denotes RDE receptor-destroying enzyme
T810 83396-83428 Sentence denotes LRI ligand–receptor interaction
T811 83429-83465 Sentence denotes LCI lectin–carbohydrate interaction
T812 83466-83496 Sentence denotes LGI lectin–glycan interaction
T813 83497-83533 Sentence denotes LSI lectin–sphingolipid interaction
T814 83534-83565 Sentence denotes PGI protein–glycan interaction
T815 83566-83603 Sentence denotes PCI protein–carbohydrate interaction
T816 83604-83636 Sentence denotes PPI protein–protein interaction
T817 83637-83658 Sentence denotes NeuC neuraminic acid
T818 83659-83690 Sentence denotes NeuAc N-acetyl neuraminic acid
T819 83691-83724 Sentence denotes NeuGc N-glycolyl neuraminic acid
T820 83725-83746 Sentence denotes ST sialyltransferase
T821 83747-83799 Sentence denotes ICTV International Committee on Taxonomy of Viruses
T822 83800-83815 Sentence denotes HCoV human CoV
T823 83816-83839 Sentence denotes ORF open reading frame
T824 83840-83874 Sentence denotes RdRp RNA-dependent RNA polymerase
T825 83875-83886 Sentence denotes E envelope
T826 83887-83902 Sentence denotes N nucleocapsid
T827 83903-83924 Sentence denotes S spike glycoprotein
T828 83925-83956 Sentence denotes M membrane matrix glycoprotein
T829 83957-83982 Sentence denotes ER endoplasmic reticulum
T830 83983-84042 Sentence denotes ERGIC endoplasmic reticulum-Golgi intermediate compartment
T831 84043-84069 Sentence denotes Nsp nonstructural protein
T832 84070-84106 Sentence denotes RTC replicase–transcriptase complex
T833 84107-84124 Sentence denotes TM transmembrane
T834 84125-84156 Sentence denotes ADRP ADP-ribose-1′-phosphatase
T835 84157-84184 Sentence denotes PLpro papain-like protease
T836 84185-84209 Sentence denotes MTase methyltransferase
T837 84210-84232 Sentence denotes NTD N-terminal domain
T838 84233-84255 Sentence denotes CTD C-terminal domain
T839 84256-84284 Sentence denotes RBD receptor-binding domain
T840 84285-84311 Sentence denotes ssRNA single stranded RNA
T841 84312-84344 Sentence denotes GSK3 glycogen synthase kinase 3
T842 84345-84397 Sentence denotes hnRNP A1 heterogeneous nuclear ribonucleoprotein A1
T843 84398-84422 Sentence denotes VLP virus-like particle
T844 84423-84440 Sentence denotes NA neuraminidase
T845 84441-84463 Sentence denotes NDV Newcastle disease
T846 84464-84495 Sentence denotes Neu5Ac N-acetylneuraminic acid
T847 84496-84541 Sentence denotes Neu5:9Ac2 9-O-acetyl-N-acetylneuraminic acid
T848 84542-84573 Sentence denotes CasD1 Cas1 domain containing 1
T849 84574-84610 Sentence denotes ISAV infectious salmon anemia virus
T850 84611-84623 Sentence denotes FH factor H
T851 84624-84679 Sentence denotes Neu5Ac9NAc 9-acetamido-9-deoxy-N-acetylneuraminic acid
T852 84680-84702 Sentence denotes HEF HE fusion protein
T853 84703-84734 Sentence denotes Neu5:9Ac2 5-N-acetyl-9-O-NeuAc
T854 84735-84751 Sentence denotes BCoV bovine CoV
T855 84752-84771 Sentence denotes RBC red blood cell
T856 84772-84808 Sentence denotes CRD carbohydrate-recognizing domain
T857 84809-84835 Sentence denotes GBD glycan-binding domain
T858 84836-84863 Sentence denotes MHV murine hepatitis virus
T859 84864-84922 Sentence denotes CEACAM carcinoembryonic antigen cell adhesion molecule 1a
T860 84923-84951 Sentence denotes 9-O–AC-SA 9-O-acetylated SA
T861 84952-85006 Sentence denotes PHEV porcine hemagglutinating encephalomyelitis virus
T862 85007-85020 Sentence denotes RCoV rat CoV
T863 85021-85068 Sentence denotes TGEV transmissible gastroenteritis coronavirus
T864 85069-85101 Sentence denotes IBV infectious bronchitis virus
T865 85102-85132 Sentence denotes pAPN porcine aminopeptidase N
T866 85133-85161 Sentence denotes MGP mucin-like glycoprotein
T867 85162-85189 Sentence denotes pNPA p-nitrophenyl acetate
T868 85190-85209 Sentence denotes SLeX sialyl-LewisX
T869 85210-85256 Sentence denotes α2:3-SlacNAc α2,3-sialyl-N-acetyl-lactosamine
T870 85257-85285 Sentence denotes DPP4 dipeptidyl peptidase 4
T871 85286-85345 Sentence denotes GRP78 membrane-associated 78-kDa glucose-regulated protein
T872 85346-85383 Sentence denotes ACE2 angiotensin-converting enzyme 2
T873 85384-85399 Sentence denotes hAPN human APN
T874 85400-85447 Sentence denotes MHC-I major histocompatibility complex class I
T875 85448-85536 Sentence denotes DC-SIGN dendritic cells-specific intercellular adhesion molecule-3-grabbing nonintegrin
T876 85537-85571 Sentence denotes HSPG heparan sulfate proteoglycan
T877 85572-85600 Sentence denotes HSPA5 heat shock protein A5
T878 85601-85630 Sentence denotes RAS renin-angiotensin system
T879 85631-85651 Sentence denotes Ang I angiotensin I
T880 85652-85680 Sentence denotes AT1R Ang II receptor type 1
T881 85681-85713 Sentence denotes GPCR G protein-coupled receptor
T882 85714-85761 Sentence denotes ADAM A disintegrin and metallopeptidase domain
T883 85762-85791 Sentence denotes TACE TNF-α-converting enzyme
T884 85792-85829 Sentence denotes TMPRSS transmembrane protease serine
T885 85830-85859 Sentence denotes TTSP type II TM Ser protease
T886 85860-85896 Sentence denotes PAR-2 protease activated receptor 2
T887 85897-85926 Sentence denotes MMP matrix metalloproteinase
T888 85927-85956 Sentence denotes HGF hepatocyte growth factor
T889 85957-85996 Sentence denotes HAT human airway trypsin-like protease
T890 85997-86012 Sentence denotes MSPL serine 13
T891 86013-86042 Sentence denotes BHH bromhexine hydrochloride
T892 86043-86071 Sentence denotes DPP4 dipeptidyl peptidase-4
T893 86072-86099 Sentence denotes BiP immunoglobulin protein
T894 86100-86130 Sentence denotes UPR unfolded protein response
T895 86131-86170 Sentence denotes ATF6 activating transcription factor 6
T896 86171-86204 Sentence denotes IRE1 inositol-requiring enzyme 1
T897 86205-86250 Sentence denotes PERK protein kinase RNA (PKR)-like ER kinase
T898 86251-86280 Sentence denotes SBD substrate-binding domain
T899 86281-86330 Sentence denotes PEDV porcine epidemic diarrhea coronavirus virus
T900 86331-86372 Sentence denotes FIPV feline infectious peritonitis virus
T901 86373-86399 Sentence denotes FeCV feline enteric virus
T902 86400-86422 Sentence denotes GAG glycosaminoglycan
T903 86423-86456 Sentence denotes GlcAT-II glucuronosyltransferase
T904 86457-86503 Sentence denotes GlcNAcT-II N-acetylglucosaminyltransferase II
T905 86504-86534 Sentence denotes NGS new generation sequencing
T906 86535-86562 Sentence denotes RBM receptor-binding motif
T907 86563-86599 Sentence denotes 3CLpro 3-chymotrypsin-like protease
T908 86600-86616 Sentence denotes CLQ chloroquine
T909 86617-86643 Sentence denotes CLQ-OH hydroxychloroquine
T910 86644-86673 Sentence denotes GBS ganglioside-binding site
T911 86674-86705 Sentence denotes GBD ganglioside-binding domain
T912 86706-86731 Sentence denotes WEF World Economic Forum
T913 86732-86766 Sentence denotes VODAN Virus Outbreak Data Network
T914 86768-86950 Sentence denotes Figure 1 Cellular glycans are recognized by infectious agents including viruses and bacteria through protein–carbohydrate interaction (PCI) or lectin–carbohydrate interaction (LCI).
T915 86951-87025 Sentence denotes The carbohydrates are uses as cellular adhesion sites in eukaryotic cells.
T916 87026-87190 Sentence denotes Host cell surfaced and cytosolic glycans include glycoproteins, glycolipids and proteoglycans with minor glycan species of O-GlcNAc present in nucleus and cytosols.
T917 87191-87515 Sentence denotes Figure 2 Diverse structures of sialic acids (SA). (A) Neuraminic acid; (NeuC); (B) N-acetyl neuraminic acid (NeuAc); (C) N-glycolyl neuraminic acid (NeuGc); (D) N, O-diacetyl neuraminic acid (occurs in horse); (E) N, O-diacetyl neuraminic acid (occurs in bovine); (F) N-acetyl O-diacetyl neuraminic acid (occurs in bovine).
T918 87516-87592 Sentence denotes Figure 3 SA linkages of α2-3, α2-6, α2-8 or α2-9 to the SA or Gal residues.
T919 87593-87728 Sentence denotes Figure 4 Formation of α2,3 ST or α2,6 SA structures by α 2,3- and 2,6-sialyltransferase (ST) using substrates such as Galβ-1,4-GlcNAc.
T920 87729-87874 Sentence denotes Figure 5 Action sites of viral SA-O-acetylesterases (C4, C7, C8 and C9) specific for 4-O-SA-, 7-O-SA-, 8-O-SA and 9-O-SA and neuraminidases [6].
T921 87875-88025 Sentence denotes Figure 6 CasD1, SA O-acetyltransferase, transfers acetyl groups to C7 position of SA (Neu5Ac), from which it migrates to the C9 position (Neu5,9Ac2).
T922 88026-88107 Sentence denotes The additional acetyl group is added to C7 of SA (Neu5,7,9Ac3) by the same CasD1.
T923 88108-88161 Sentence denotes The SA O-acetylesterase cleaves of the acetyl groups.
T924 88162-88284 Sentence denotes Figure 7 SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) for cell entry through TMPRSS2 priming of S glycoprotein.
T925 88285-88391 Sentence denotes Figure 8 Endoplasmic-reticulum (ER) stress responses and COVID-19 receptor (S glycoprotein binding site).
T926 88392-88463 Sentence denotes Balance of ER stress and unfolded protein response (UPR) are regulated.
T927 88464-88576 Sentence denotes ER-stress sensor proteins are IRE1 (inositol requiring 1), ATF6 (activating TF 6) and PERK (PKR-like ER kinase).
T928 88577-88795 Sentence denotes Figure 9 Structure of glycosaminoglycan (GAG)-linkage tetrasaccharide, GluAβ1,3Galβ1,3Galβ1,4Xylβ-O-serine and HS; (A) HS structure; (B) Sulfation of sugar residues; (C) Synthesis and localization of HS in host cells.
T929 88796-89092 Sentence denotes Glycosyltransferases involved in GAG synthesis include (i) GlcAT-II (glucuronosyltransferase) and (ii) GlcNAcT-II (N-acetylglucosaminyltransferase II) for heparan sulfate synthesis. β-D-glucuronic acid (GlcA), α-L-iduronic acid (IdoA) and 2-O-sulfo-α-L-iduronic acid (IdoA(2S) are composed [124].
T930 89093-89200 Sentence denotes Figure 10 Structures of (A) CLQ and (B) CLQ-related CLQ-OH as predicted UDP-GlcNAc 2-epimerase inhibitors.