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On the Selectivity of Heparan Sulfate Recognition by SARS-CoV-2 Spike Glycoprotein

Overview
Journal ACS Med Chem Lett
Publisher American Chemical Society
Specialty Chemistry
Date 2021 Nov 17
PMID 34786180
Citations 20
Authors
John E Chittum
Nehru Viji Sankaranarayanan
Connor P OHara
Umesh R Desai
Affiliations
Soon will be listed here.
Abstract

SARS-CoV-2 infects human cells through its surface spike glycoprotein (SgP), which relies on host cell surface heparan sulfate (HS) proteoglycans that facilitate interaction with the ACE2 receptor. Targeting this process could lead to inhibitors of early steps in viral entry. Screening a microarray of 24 HS oligosaccharides against recombinant S1 and receptor-binding domain (RBD) proteins led to identification of only eight sequences as potent antagonists; results that were supported by detailed dual-filter computational studies. Competitive studies using the HS microarray suggested almost equivalent importance of IdoA2S-GlcNS6S and GlcNS3S structures, which were supported by affinity studies. Exhaustive virtual screening on a library of >93 000 sequences led to a novel pharmacophore with at least two 3--sulfated GlcN residues that can engineer unique selectivity in recognizing the RBD. This work puts forward the key structural motif in HS that should lead to potent and selective HS or HS-like agents against SARS-CoV-2.

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