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

被引：31

作者：

Chittum, John E. ^{[1
,2
]}

Sankaranarayanan, Nehru Viji ^{[1
,2
]}

O'Hara, Connor P. ^{[1
,2
]}

Desai, Umesh R. ^{[1
,2
]}

机构：

[1] Virginia Commonwealth Univ, Sch Pharm, Dept Med Chem, Richmond, VA 23298 USA

[2] Virginia Commonwealth Univ, Inst Struct Biol Drug Discovery & Dev, Richmond, VA 23219 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2021年 / 12卷 / 11期

关键词：

Spike protein; glycosaminoglycans; 3-O-sulfation; microarray; molecular docking; pharmacophore modeling; CHEMOENZYMATIC SYNTHESIS; HIGH SPECIFICITY; PROTEOGLYCANS; BINDING; LIBRARY; VIRUS;

D O I：

10.1021/acsmedchemlett.1c00343

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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- GIcNS6S and GIcNS3S 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-O-sulfated GIcN 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.

引用

页码：1710 / 1717

页数：8

共 51 条

[31] Toward a robust computational screening strategy for identifying glycosaminoglycan sequences that display high specificity for target proteins [J].