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

Analytical Chemistry
Yang YangIgor A Kaltashov

Abstract

The emergence and rapid proliferation of the novel coronavirus (SARS-CoV-2) resulted in a global pandemic, with over 6,000,000 cases and nearly 400,000 deaths reported worldwide by the end of May 2020. A rush to find a cure 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 noncovalent 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 destabi...Continue Reading

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Citations

Jan 20, 2021·Journal of Proteome Research·Paige HaasRuth Hüttenhain
Feb 11, 2021·Colloids and Surfaces. A, Physicochemical and Engineering Aspects·Kazushige Yokoyama, Akane Ichiki
Mar 27, 2021·Frontiers in Molecular Biosciences·Deling ShiLianli Chi
Apr 23, 2021·Journal of the American Society for Mass Spectrometry·Iain D G Campuzano, Wendy Sandoval
May 24, 2021·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Celso A ReisVéronique Blanchard
Apr 17, 2021·Angewandte Chemie·Chuanxiong NieRainer Haag
May 18, 2021·Trends in Analytical Chemistry : TRAC·Justin H Griffin, Kevin M Downard
Dec 5, 2020·Analytical Chemistry·Tobias P WörnerAlbert J R Heck
Aug 28, 2021·Chemical Reviews·Jack L BennettWilliam A Donald
Sep 3, 2021·Chemical Reviews·Amber D Rolland, James S Prell

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Methods Mentioned

BETA
glycosylation

Software Mentioned

Maestro

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