About: The utility of native MS for understanding the mechanism of action of repurposed therapeutics in COVID-19: heparin as a disruptor of the SARS-CoV-2 interaction with its host cell receptor

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About: The utility of native MS for understanding the mechanism of action of repurposed therapeutics in COVID-19: heparin as a disruptor of the SARS-CoV-2 interaction with its host cell receptor Goto Sponge NotDistinct Permalink

An Entity of Type : schema:ScholarlyArticle, within Data Space : wasabi.inria.fr associated with source document(s)

Attributes	Values
type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
has title	The utility of native MS for understanding the mechanism of action of repurposed therapeutics in COVID-19: heparin as a disruptor of the SARS-CoV-2 interaction with its host cell receptor
Creator	Yang, Yang Du, Yi Kaltashov, Igor
topic	covid:47ce45e7dea869af4b1d63e964c82e46b7138b8e#this
Source	BioRxiv; Medline; WHO
abstract	The emergence and rapid proliferation of the novel coronavirus (SARS-CoV-2) resulted in a global pandemic, with over six million cases and nearly four hundred thousand deaths reported world-wide by the end of May 2020. A rush to find the cures prompted re-evaluation of a range of existing therapeutics vis-à-vis their potential role in treating COVID-19, placing a premium on analytical tools capable of supporting such efforts. Native mass spectrometry (MS) has long been a tool of choice in supporting the mechanistic studies of drug/therapeutic target interactions, but its applications remain limited in the cases that involve systems with a high level of structural heterogeneity. Both SARS-CoV-2 spike protein (S-protein), a critical element of the viral entry to the host cell, and ACE2, its docking site on the host cell surface, are extensively glycosylated, making them challenging targets for native MS. However, supplementing native MS with a gas-phase ion manipulation technique (limited charge reduction) allows meaningful information to be obtained on the non-covalent complexes formed by ACE2 and the receptor-binding domain (RBD) of the S-protein. Using this technique in combination with molecular modeling also allows the role of heparin in destabilizing the ACE2/RBD association to be studied, providing critical information for understanding the molecular mechanism of its interference with the virus docking to the host cell receptor. Both short (pentasaccharide) and relatively long (eicosasaccharide) heparin oligomers form 1:1 complexes with RBD, indicating the presence of a single binding site. This association alters the protein conformation (to maximize the contiguous patch of the positive charge on the RBD surface), resulting in a notable decrease of its ability to associate with ACE2. The destabilizing effect of heparin is more pronounced in the case of the longer chains due to the electrostatic repulsion between the low-pI ACE2 and the heparin segments not accommodated on the RBD surface. In addition to providing important mechanistic information on attenuation of the ACE2/RBD association by heparin, the study demonstrates the yet untapped potential of native MS coupled to gas-phase ion chemistry as a means of facilitating rational repurposing of the existing medicines for treating COVID-19.
has issue date	2020-06-10(xsd:dateTime)
bibo:doi	10.1101/2020.06.09.142794
bibo:pmid	32577646
has license	biorxiv
sha1sum (hex)	47ce45e7dea869af4b1d63e964c82e46b7138b8e
schema:url	https://doi.org/10.1101/2020.06.09.142794
resource representing a document's title	The utility of native MS for understanding the mechanism of action of repurposed therapeutics in COVID-19: heparin as a disruptor of the SARS-CoV-2 interaction with its host cell receptor
has PubMed identifier	32577646
schema:publication	bioRxiv
resource representing a document's body	covid:47ce45e7dea869af4b1d63e964c82e46b7138b8e#body_text
is http://vocab.deri.ie/void#inDataset of	proxy:http/ns.inria.fr/covid19/47ce45e7dea869af4b1d63e964c82e46b7138b8e
is schema:about of	named entity 'existing' named entity 'short' named entity 'ion' named entity 'heterogeneity' named entity 'SARS-CoV-2' named entity 'ACE2' named entity 'RE-EVALUATION' named entity 'FACILITATING' named entity 'MS.' named entity 'COMBINATION' named entity 'PROTEIN ' named entity 'DRUG' named entity 'ION' named entity 'END' named entity 'ASSOCIATION' named entity 'WORLDWIDE' named entity 'DOCKING' named entity 'MEDICINES' named entity 'PROMPTED' named entity 'BUT' named entity 'cases' named entity 'complexes' named entity 'COVID-19' named entity 'proliferation' named entity 'RBD' named entity 'positive' named entity 'indicating' named entity 'SARS-CoV-2' named entity 'involve' named entity 'systems' named entity 'complexes' named entity 'RBD' named entity 'emergence' named entity 'facilitating' named entity 'vis-à-vis' named entity 'cases' named entity 'RBD' named entity 'spike protein' named entity 'heparin' named entity 'ACE2' named entity 'molecular mechanism' named entity 'viral entry' named entity 'RBD' named entity 'SARS-CoV-2' named entity 'protein' named entity 'RBD' named entity 'COVID' named entity 'heparin' named entity 'mechanism of action' named entity 'host cell receptor' named entity 'ACE2' named entity 'polyanion' named entity 'PDB' named entity 'ACE2' named entity 'oligomer' named entity 'non-covalent' named entity 'heparin' named entity 'HIT' named entity 'pentasaccharide' named entity 'oligomer' named entity 'fondaparinux' named entity 'RBD' named entity 'ACE2' named entity 'positive charge' named entity 'heparin' named entity 'mass spectrum' named entity '5.6' named entity 'ACE2' named entity 'SARS-CoV-2' named entity 'virus' named entity 'force field' named entity 'ACE2' named entity 'fondaparinux' named entity 'platelet factor 4' named entity 'dimer' named entity 'ACE2' named entity 'ACE2' named entity 'coronavirus'

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