Author: So Young Kim; Weihua Jin; Amika Sood; David W. Montgomery; Oliver C. Grant; Mark M. Fuster; Li Fu; Jonathan S. Dordick; Robert J. Woods; Fuming Zhang; Robert J. Linhardt
Title: Glycosaminoglycan binding motif at S1/S2 proteolytic cleavage site on spike glycoprotein may facilitate novel coronavirus (SARS-CoV-2) host cell entry Document date: 2020_4_15
ID: fs8dn7ir_31
Snippet: In conclusion, we have discovered that GAGs can facilitate host cell entry of SARS-CoV-2 by binding to SGP in the current work. SPR studies demonstrate that both monomeric and trimeric SARS-CoV-2 SGP bind HP with remarkably high affinity and it prefers long, heavily sulfated (TriS rich) structures. Additionally, we reported low IC50 of HP and derivatives against HP and SARS-CoV-2 SGP interactions suggesting therapeutic potential of HP as COVID-19.....
Document: In conclusion, we have discovered that GAGs can facilitate host cell entry of SARS-CoV-2 by binding to SGP in the current work. SPR studies demonstrate that both monomeric and trimeric SARS-CoV-2 SGP bind HP with remarkably high affinity and it prefers long, heavily sulfated (TriS rich) structures. Additionally, we reported low IC50 of HP and derivatives against HP and SARS-CoV-2 SGP interactions suggesting therapeutic potential of HP as COVID-19 competitive inhibitors. Lastly, unbiased computational ligand docking indicated that a TriS HS oligosaccharide preferably interacts with GAG-binding motifs at the S1/S2 junction and within receptor binding domain and hinted at mechanism of binding. This study adds to our current understanding of SARS-CoV-2 pathogenesis and serves a foundation for designing glycoconjugate vaccines and therapeutics to successfully contain and eliminate COVID-19. [31] . The 6-O-desulfated HP derivative, 6-DeS HP, Mw = 13 kDa, was generously provided by Prof. Lianchun Wang (University of South Florida). Nonanticoagulant low molecular weight HP (NACH) was synthesized from dalteparin, a nitrous acid depolymerization product of porcine intestinal HP, followed by periodate oxidation as described in our previous work [26] . TriS HS (NS2S6S) was synthesized from N-sulfo heparosan with subsequent modification with C5-epimerase and 2-O-and 6-O-sulfotransferases (2OST and 6OST1/6OST3) [32] . HP oligosaccharides included tetrasaccharide (dp4), hexasaccharide (dp6), octasaccharide (dp8), decasaccharide (dp10), dodecasaccharide (dp12), tetradecasaccharide (dp14), hexadecasaccharide (dp16) and octadecasaccharide (dp18) and were prepared from porcine intestinal HP controlled partial heparin lyase 1 treatment followed by size fractionation.
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