PMC:7128678 / 22206-25005 JSON TXT

Annnotations TAB JSON ListView MergeView

LitCovid-PubTator

LitCovid-PMC-OGER-BB

LitCovid-PD-FMA-UBERON

LitCovid-PD-UBERON

{"project":"LitCovid-PD-UBERON","denotations":[{"id":"T13","span":{"begin":958,"end":962},"obj":"Body_part"},{"id":"T14","span":{"begin":1057,"end":1061},"obj":"Body_part"},{"id":"T15","span":{"begin":1418,"end":1421},"obj":"Body_part"}],"attributes":[{"id":"A13","pred":"uberon_id","subj":"T13","obj":"http://purl.obolibrary.org/obo/UBERON_0002398"},{"id":"A14","pred":"uberon_id","subj":"T14","obj":"http://purl.obolibrary.org/obo/UBERON_0002398"},{"id":"A15","pred":"uberon_id","subj":"T15","obj":"http://purl.obolibrary.org/obo/UBERON_2001840"}],"text":"3.7 Molecular mechanism of CLQ and CLQ-OH antiviral effect: preventing SARS-CoV-2 S protein access to cell surface gangliosides\nWith the aim of establishing whether CLQ and CLQ-OH could prevent the attachment of SARS-CoV-2 to plasma membrane gangliosides, the initial NTD–GM1 complex was superposed with a drug–GM1 complex (Fig. 9 ). To improve clarity, the ganglioside is not presented in Fig. 9. This superposition shows that the NTD and the drug (CLQ-OH in this case) share the same spatial position when bound to GM1, so GM1 cannot bind the viral protein and the drug simultaneously. This is due to the fact that the NTD and the drugs (CLQ and CLQ-OH) bind to GM1 with a similar mechanism controlled by a dyad of functional interactions: a hydrogen bond and a geometrically perfect CH-π stacking interaction. In the case of the NTD, the hydrogen bond involves Asn-167, whereas CH-π stacking is mediated by the aromatic ring of Phe-135 Fig. 6(b). On one hand, Asn-167 establishes a network of hydrogen bonds with the GalNAc residue of GM1. On the other hand, the flat aromatic ring of Phe-135 stacks on to the cycle of the Glc residue of GM1. In the case of CLQ and CLQ-OH, it is the nitrogen-containing ring of the drug that stacks on to the Glc ring Fig. 4(c). Note that both the Phe-135 (in red) and CLQ-OH (in green) rings are located in the same position (Fig. 9). The other CLQ-OH molecule, which covers the tip of the sugar part of the ganglioside, interacts with the GalNAc ganglioside Fig. 4(b). When the NTD is bound to the ganglioside, the side chain of Asn-137 is found in this exact position (Fig. 9). Thus, once two CLQ-OH (or two CLQ) molecules are bound to a ganglioside Fig. 4(e,f), any binding of a SARS-Cov-2 S protein to the same ganglioside is totally prevented. The energy required to overcome this steric incompatibility is estimated to be several hundred kJ.mol−1, which is far too high to occur.\nFig. 9 Mechanism of action of hydroxychloroquine (CLQ-OH). The N-terminal domain (NTD) bound to GM1 was superposed onto GM1 in interaction with two CLQ-OH molecules. The models only show the NTD and both CLQ-OH molecules (not GM1, to improve clarity). (a,b) The aromatic ring of F-135 (in red), which stacks onto the glucose cycle of GM1, overlaps the aromatic CLQ-OH rings (in green) which also bind to GM1 via a CH-π stacking mechanism. The N-137 residue of the NTD interacts with the N-acetylgalactosamine residue of GM1, but this interaction cannot occur in the presence of CLQ-OH as this part of GM1 is totally masked by the drug. (c,d) Superposition of the NTD surface (in purple) with the two CLQ-OH molecules bound to GM1, illustrating the steric impossibility that prevents NTD binding to GM1 when both CLQ-OH molecules are already interacting with the ganglioside."}

LitCovid-PD-MONDO

LitCovid-PD-CLO

LitCovid-PD-CHEBI

LitCovid-PD-GlycoEpitope

LitCovid-sentences

{"project":"LitCovid-sentences","denotations":[{"id":"T184","span":{"begin":0,"end":128},"obj":"Sentence"},{"id":"T185","span":{"begin":129,"end":334},"obj":"Sentence"},{"id":"T186","span":{"begin":335,"end":398},"obj":"Sentence"},{"id":"T187","span":{"begin":399,"end":588},"obj":"Sentence"},{"id":"T188","span":{"begin":589,"end":813},"obj":"Sentence"},{"id":"T189","span":{"begin":814,"end":950},"obj":"Sentence"},{"id":"T190","span":{"begin":951,"end":1043},"obj":"Sentence"},{"id":"T191","span":{"begin":1044,"end":1146},"obj":"Sentence"},{"id":"T192","span":{"begin":1147,"end":1266},"obj":"Sentence"},{"id":"T193","span":{"begin":1267,"end":1373},"obj":"Sentence"},{"id":"T194","span":{"begin":1374,"end":1508},"obj":"Sentence"},{"id":"T195","span":{"begin":1509,"end":1618},"obj":"Sentence"},{"id":"T196","span":{"begin":1619,"end":1787},"obj":"Sentence"},{"id":"T197","span":{"begin":1788,"end":1924},"obj":"Sentence"},{"id":"T198","span":{"begin":1925,"end":1983},"obj":"Sentence"},{"id":"T199","span":{"begin":1984,"end":2090},"obj":"Sentence"},{"id":"T200","span":{"begin":2091,"end":2363},"obj":"Sentence"},{"id":"T201","span":{"begin":2364,"end":2799},"obj":"Sentence"}],"namespaces":[{"prefix":"_base","uri":"http://pubannotation.org/ontology/tao.owl#"}],"text":"3.7 Molecular mechanism of CLQ and CLQ-OH antiviral effect: preventing SARS-CoV-2 S protein access to cell surface gangliosides\nWith the aim of establishing whether CLQ and CLQ-OH could prevent the attachment of SARS-CoV-2 to plasma membrane gangliosides, the initial NTD–GM1 complex was superposed with a drug–GM1 complex (Fig. 9 ). To improve clarity, the ganglioside is not presented in Fig. 9. This superposition shows that the NTD and the drug (CLQ-OH in this case) share the same spatial position when bound to GM1, so GM1 cannot bind the viral protein and the drug simultaneously. This is due to the fact that the NTD and the drugs (CLQ and CLQ-OH) bind to GM1 with a similar mechanism controlled by a dyad of functional interactions: a hydrogen bond and a geometrically perfect CH-π stacking interaction. In the case of the NTD, the hydrogen bond involves Asn-167, whereas CH-π stacking is mediated by the aromatic ring of Phe-135 Fig. 6(b). On one hand, Asn-167 establishes a network of hydrogen bonds with the GalNAc residue of GM1. On the other hand, the flat aromatic ring of Phe-135 stacks on to the cycle of the Glc residue of GM1. In the case of CLQ and CLQ-OH, it is the nitrogen-containing ring of the drug that stacks on to the Glc ring Fig. 4(c). Note that both the Phe-135 (in red) and CLQ-OH (in green) rings are located in the same position (Fig. 9). The other CLQ-OH molecule, which covers the tip of the sugar part of the ganglioside, interacts with the GalNAc ganglioside Fig. 4(b). When the NTD is bound to the ganglioside, the side chain of Asn-137 is found in this exact position (Fig. 9). Thus, once two CLQ-OH (or two CLQ) molecules are bound to a ganglioside Fig. 4(e,f), any binding of a SARS-Cov-2 S protein to the same ganglioside is totally prevented. The energy required to overcome this steric incompatibility is estimated to be several hundred kJ.mol−1, which is far too high to occur.\nFig. 9 Mechanism of action of hydroxychloroquine (CLQ-OH). The N-terminal domain (NTD) bound to GM1 was superposed onto GM1 in interaction with two CLQ-OH molecules. The models only show the NTD and both CLQ-OH molecules (not GM1, to improve clarity). (a,b) The aromatic ring of F-135 (in red), which stacks onto the glucose cycle of GM1, overlaps the aromatic CLQ-OH rings (in green) which also bind to GM1 via a CH-π stacking mechanism. The N-137 residue of the NTD interacts with the N-acetylgalactosamine residue of GM1, but this interaction cannot occur in the presence of CLQ-OH as this part of GM1 is totally masked by the drug. (c,d) Superposition of the NTD surface (in purple) with the two CLQ-OH molecules bound to GM1, illustrating the steric impossibility that prevents NTD binding to GM1 when both CLQ-OH molecules are already interacting with the ganglioside."}

PMC:7128678 / 22206-25005 JSONTXT

Annnotations TAB JSON ListView MergeView

PMC:7128678 / 22206-25005 JSON TXT