Epistemic_Statements  

CORD-19:12af81d8d81c5da78255316d73ab6564cc2e835e JSONTXT 8 Projects

Annnotations TAB TSV DIC JSON TextAE

Id Subject Object Predicate Lexical cue
T1 176-269 Epistemic_statement denotes For many viruses, these receptors are glycans that are linked to either a protein or a lipid.
T2 605-736 Epistemic_statement denotes Here, we compare the currently available structural data on viral attachment proteins in complex with sialic acid and its variants.
T3 874-1032 Epistemic_statement denotes This information could be of use for the prediction of the location of sialic acid binding sites in viruses for which structural information is still lacking.
T4 1033-1217 Epistemic_statement denotes An improved understanding of the principles that govern the recognition of sialic acid and sialylated oligosaccharides would also advance efforts to develop efficient antiviral agents.
T5 1696-1868 Epistemic_statement denotes Coxsackievirus A24 variant and Enterovirus 70, which cause Acute Hemorrhagic Conjunctivitis and have pandemic potential, also attach to sialylated oligosaccharides [5, 6] .
T6 1869-2046 Epistemic_statement denotes Epidemic Keratoconjunctivitis (EKC) has been linked to several human D-type Adenoviruses, and one of these has recently been shown to attach to the disialylated GD1a motif [7] .
T7 2297-2609 Epistemic_statement denotes Moreover, the recently identified Merkel Cell Polyomavirus, a human oncovirus, likely uses the trisialylated ganglioside GT1b as a receptor [10, 11] , and other mammalian polyomaviruses such as Simian Virus 40 (SV40) and murine Polyomavirus (Polyoma) also bind glycans terminating in sialic acid [12] [13] [14] .
T8 2831-2944 Epistemic_statement denotes However, some strains of human noroviruses were recently shown to bind to the sialyl-Lewis X motif as well [16] .
T9 2999-3203 Epistemic_statement denotes They have long been classified into strains that can be inhibited by neuraminidase treatment, which cleaves sialic acid from glycan sequences on host cells, and those that are insensitive to it [17, 18] .
T10 3285-3449 Epistemic_statement denotes Interestingly, the "neuraminidase-insensitive" rotavirus strain Wa was recently shown to attach to the ganglioside GM1, which carries a branching sialic acid [19] .
T11 3450-3563 Epistemic_statement denotes Due to its branched structure, this particular carbohydrate is difficult to cleave with neuraminidases [20, 21] .
T12 3703-3890 Epistemic_statement denotes Sialic acid therefore has to be considered as a possible receptor component even for viruses whose infectivity cannot be modulated by treatment of cells with commonly used neuraminidases.
T13 4410-4739 Epistemic_statement denotes Perhaps it is not surprising, therefore, that the sialic acid itself serves as the major point of contact with the glycan-binding viral attachment protein in all cases where structural information of sufficient resolution is available [8, 13, [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] .
T14 4972-5181 Epistemic_statement denotes Such parameters could be useful for the prediction of new sialic acid binding sites in viral proteins, or of altered modes of sialic acid (and its derivatives) binding in different viral serotypes and strains.
T15 5182-5403 Epistemic_statement denotes Several structures of viral attachment proteins in complex with sialylated compounds have been determined recently, providing new insights into viral specificity for glycan receptors [8, 13, [35] [36] [37] [38] [39] 41] .
T16 6773-7065 Epistemic_statement denotes In cases where the attachment protein also has receptor-destroying enzymatic activity, such as in the HN and HE(F) proteins, only the sites that can clearly be attributed to attachment are considered here, thus excluding the dual function neuraminidase site of some HN proteins [32, 42, 43] .
T17 7565-7783 Epistemic_statement denotes Interestingly, all attachment proteins, including the ones that bind to O-acetylated compounds, make extensive contacts with one face of the sialic acid ring, while the other face is engaged by only few contacts (Figs.
T18 7795-7921 Epistemic_statement denotes A likely reason for this preference is the formation of two key contacts that are formed in all complexes in a similar manner.
T19 9127-9239 Epistemic_statement denotes However, the different proteins interacting with Neu5Ac sample different epitopes on the Neu5Ac contact surface.
T20 9829-10056 Epistemic_statement denotes As the contact areas are quite small and the sialic acids are partially exposed to solvent, adding or removing a single contact can thus have significant effects on the affinity of a given virus for sialic acid or its variants.
T21 10057-10213 Epistemic_statement denotes The parent compound of Neu5Ac, neuraminic acid, can feature numerous modifications that give rise to over 40 different known sialic acid variants [44, 45] .
T22 10329-10472 Epistemic_statement denotes It is perhaps not surprising, therefore, that some viruses exploit this divergence and preferentially recognize sialic acids other than Neu5Ac.
T23 11203-11301 Epistemic_statement denotes Recognition of different sialic acids is also a likely cause of changes in tropism and host range.
T24 11548-11675 Epistemic_statement denotes 1F, 3B) , and it is tempting to speculate that this pocket serves to accommodate the additional hydroxyl group of Neu5Gc [13] .
T25 11703-11883 Epistemic_statement denotes 1E, 3A) , whose sialic acid binding site is largely similar to that of SV40 VP1, features a much smaller pocket that likely prefers the smaller human Neu5Ac over the simian Neu5Gc.
T26 12284-12424 Epistemic_statement denotes However, at least one example exists where homologous proteins, the Ad37 and cAd2 fiber knobs, bind sialic acid at different locations (Fig.
T27 12434-12575 Epistemic_statement denotes Interestingly, there are several examples of highly homologous proteins that bind sialic acid at the same site but in different orientations.
T28 12752-12825 Epistemic_statement denotes However, the orientations of the bound sialic acids differ markedly (Fig.
T29 13444-13694 Epistemic_statement denotes The critical role of the context of the sialic acid -linkage type, as well as length, sequence and conformational preferences of the remaining oligosaccharide chain -is perhaps best illustrated by its influence on the host range of Influenza viruses.
T30 14059-14297 Epistemic_statement denotes The vast database on Influenza A HA structures in complex with sialylated ligands, and concurrent glycan array analyses, has been the subject of several excellent recent reviews [2, 3] , and will therefore not be discussed in detail here.
T31 14298-14521 Epistemic_statement denotes However, glycan array screening has recently helped to unravel the identities of sialylated glycan receptors for two pathogenic human viruses, and structural biology has defined the nature of interaction in both cases [8] .
T32 14747-15136 Epistemic_statement denotes Crystal structures of two members of the family in complex with their cognate receptors have been determined recently: SV40 VP1 has been crystallized in complex with the oligosaccharide portion of its ganglioside receptor GM1 [13] , whereas the structure of the VP1 protein of human JCV has been solved with the pentasaccharide receptor fragment LSTc (Lacto-series tetrasaccharide c) [8] .
T33 15384-15540 Epistemic_statement denotes Moreover, although both GM1 and LSTc were present on the arrays, JCV VP1 failed to interact with GM1, and SV40 VP1 also did not recognize the LSTc compound.
T34 15793-15925 Epistemic_statement denotes The remarkable specificity for each receptor can be attributed to contacts that involve the remaining parts of the oligosaccharides.
T35 16079-16264 Epistemic_statement denotes An α2,3-linked Neu5Ac would not adopt a similarly bent conformation, explaining why sialylparagloboside, which is identical to LSTc except for its α2,3-linked Neu5Ac, does not bind JCV.
T36 16265-16404 Epistemic_statement denotes Modeling LSTc into the SV40 VP1 binding site by superimposing the two sialic acid structures suggests that LSTc could be tolerated by SV40.
T37 16405-16550 Epistemic_statement denotes However, as the residue equivalent to N123 in JCV is a glycine (G131) in SV40, no favorable contacts to the GlcNAc residue can be generated (Fig.
T38 16557-16646 Epistemic_statement denotes The inability to form such an interaction most likely explains why SV40 cannot bind LSTc.
T39 16647-16790 Epistemic_statement denotes It therefore appears that the formation of a very small number of contacts is largely responsible for defining the specificity of VP1 for LSTc.
T40 16791-16946 Epistemic_statement denotes The reverse combination, a GM1 ligand bound to JCV, would likely be disfavored due to steric clashes with JCV VP1 residue S62, which is an alanine in SV40.
T41 17343-17431 Epistemic_statement denotes However, receptor clustering is not always necessary to achieve higher-affinity binding.
T42 17897-18162 Epistemic_statement denotes A structural analysis of the trimeric Ad37 fiber knob in complex with GD1a established that the two terminal sialic acid residues bind to two different Ad37 fiber knob protomers in an identical manner, thus engaging two of the three possible binding sites [7] (Fig.
T43 18331-18607 Epistemic_statement denotes Thus, although each protomer in an Ad37 fiber knob would be able to bind sialic acid attached to different oligosaccharide structures, specificity for GD1a is generated by a multivalent interaction in which two protomers interact with the same receptor in an identical manner.
T44 18608-18814 Epistemic_statement denotes It is conceivable that trivalent compounds that engage all three binding sites of the Ad37 fiber knobs would have even higher affinity, thus providing a platform for the development of antiviral inhibitors.
T45 18970-19120 Epistemic_statement denotes A similar strategy could be useful to develop molecules that inhibit viral attachment proteins, which usually occur as multimers at the viral surface.
T46 19242-19358 Epistemic_statement denotes Common principles of interaction can be established by comparing the sialic acid binding modes of different viruses.
T47 19706-20009 Epistemic_statement denotes Nevertheless, many of the viruses discussed here achieve remarkable specificity for a single type of sialylated oligosaccharide by establishing a small number of auxiliary interactions with functional groups that lie beyond the sialic acid, and by excluding some possible ligands through steric clashes.
T48 20179-20428 Epistemic_statement denotes It thus appears that many viruses use the unique properties of sialic acid as a "hook" that allows them to adhere to the cell, and modulate binding in different strains or families by subtly altering structural elements in the vicinity of this hook.
T49 20703-20807 Epistemic_statement denotes The prominence of sialic acid in viral attachment may form a basis for new approaches to combat viruses.
T50 20808-21028 Epistemic_statement denotes Compounds that mimic sialic acid have already proved useful as inhibitors of the Influenza virus neuraminidase [53] and can also efficiently inhibit the receptor-binding site of the Influenza A virus hemagglutinin [54] .
T51 21393-21525 Epistemic_statement denotes However, proper interpretation of the information provided by glycan array screening and structural analyses requires affinity data.
T52 21526-21629 Epistemic_statement denotes Such data are often difficult to obtain and compare, and they are currently lacking for many complexes.
T53 21630-21839 Epistemic_statement denotes Being able to correlate affinity measurements with structural data would significantly advance the design of antiviral agents, and, together with oligosaccharide expression data, help to explain viral tropism.