Characterization of heparin and severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) spike glycoprotein binding interactions

被引：235

作者：

Kim, So Young ^{[1
,2
]}

Jin, Weihua ^{[6
]}

Sood, Amika ^{[4
]}

Montgomery, David W. ^{[5
]}

Grant, Oliver C. ^{[5
]}

Fuster, Mark M. ^{[1
,2
,3
]}

Fu, Li ^{[6
]}

Dordick, Jonathan S. ^{[7
]}

Woods, Robert J. ^{[5
]}

Zhang, Fuming ^{[7
]}

Linhardt, Robert J. ^{[6
,7
,8
,9
]}

机构：

[1] Univ Calif San Diego, Div Pulm & Crit Care, Dept Med, La Jolla, CA 92093 USA

[2] VA San Diego Healthcare Syst, Med & Res Sect, La Jolla, CA USA

[3] Univ Calif San Diego, Glycobiol Res & Training Ctr, La Jolla, CA 92093 USA

[4] Duke Univ, Dept Biostat & Bioinformat, Durham, NC USA

[5] Univ Georgia, Complex Carbohydrate Res Ctr, Athens, GA 30602 USA

[6] Rensselaer Polytech Inst, Dept Chem & Chem Biol, Troy, NY 12180 USA

[7] Rensselaer Polytech Inst, Ctr Biotechnol & Interdisciplinary Studies, Dept Chem & Biol Engn, Troy, NY USA

[8] Rensselaer Polytech Inst, Ctr Biotechnol & Interdisciplinary Studies, Dept Biol Sci, Troy, NY USA

[9] Rensselaer Polytech Inst, Ctr Biotechnol & Interdisciplinary Studies, Biomed Engn, Troy, NY USA

来源：

ANTIVIRAL RESEARCH | 2020年 / 181卷

基金：

美国国家卫生研究院;

关键词：

SARS-CoV-2; COVID-19; Glycosaminoglycans; Heparin; Spike glycoprotein; Binding interactions; SARS-CORONAVIRUS; FURIN CLEAVAGE; PROTEIN; ENTRY; RECEPTOR; SULFATE; CELLS;

D O I：

10.1016/j.antiviral.2020.104873

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) has resulted in a pandemic and continues to spread around the globe at an unprecedented rate. To date, no effective therapeutic is available to fight its associated disease, COVID-19. Our discovery of a novel insertion of glycosaminoglycan (GAG)-binding motif at S1/S2 proteolytic cleavage site (681-686 (PRRARS)) and two other GAG-binding-like motifs within SARS-CoV-2 spike glycoprotein (SGP) led us to hypothesize that host cell surface GAGs may interact SARS-CoV-2 SGPs to facilitate host cell entry. Using a surface plasmon resonance direct binding assay, we found that both monomeric and trimeric SARS-CoV-2 SGP bind more tightly to immobilized heparin (KD 1/4 40 pM and 73 pM, respectively) than the SARS-CoV and MERS-CoV SGPs (500 nM and 1 nM, respectively). In competitive binding studies, the IC50 of heparin, tri-sulfated non-anticoagulant heparan sulfate, and non-anticoagulant low molecular weight heparin against SARS-CoV-2 SGP binding to immobilized heparin were 0.056 mu M, 0.12 mu M, and 26.4 mu M, respectively. Finally, unbiased computational ligand docking indicates that heparan sulfate interacts with the GAG-binding motif at the S1/S2 site on each monomer interface in the trimeric SARS-CoV-2 SGP, and at another site (453-459 (YRLFRKS)) when the receptor-binding domain is in an open conformation. The current study serves a foundation to further investigate biological roles of GAGs in SARS-CoV-2 pathogenesis. Furthermore, our findings may provide additional basis for further heparin-based interventions for COVID-19 patients exhibiting thrombotic complications.

引用

页数：9