Glycopeptide mimetics recapitulate high-mannose-type oligosaccharide binding and function

Angewandte Chemie
Sabrina LusvarghiCarole A Bewley

Abstract

High-mannose-type glycans (HMTGs) decorating viral spike proteins are targets for virus neutralization. For carbohydrate-binding proteins, multivalency is important for high avidity binding and potent inhibition. To define the chemical determinants controlling multivalent interactions we designed glycopeptide HMTG mimetics with systematically varied mannose valency and spacing. Using the potent antiviral lectin griffithsin (GRFT) as a model, we identified by NMR spectroscopy, SPR, analytical ultracentrifugation, and microcalorimetry glycopeptides that fully recapitulate the specificity and kinetics of binding to Man9 GlcNAc2 Asn and a synthetic nonamannoside. We find that mannose spacing and valency dictate whether glycopeptides engage GRFT in a face-to-face or an intermolecular binding mode. Surprisingly, although face-to-face interactions are of higher affinity, intermolecular interactions are longer lived. These findings yield key insights into mechanisms involved in glycan-mediated viral inhibition.

References

Dec 23, 2004·The Journal of Biological Chemistry·Toshiyuki MoriMichael R Boyd
Oct 29, 2005·The Lancet Infectious Diseases·Jan Balzarini
Jul 17, 2007·Nature Reviews. Microbiology·Jan Balzarini
Mar 4, 2008·Proceedings of the National Academy of Sciences of the United States of America·Sheng-Kai WangChi-Huey Wong
May 12, 2009·Glycobiology·Ajit Varki
Sep 13, 2012·Journal of the American Chemical Society·Kamil Godula, Carolyn R Bertozzi

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Citations

Oct 27, 2016·Viruses·Sabrina Lusvarghi, Carole A Bewley
Dec 21, 2017·Beilstein Journal of Organic Chemistry·Christoph P SagerBeat Ernst
Jan 1, 2021·ACS Applied Materials & Interfaces·Jiayao LyuZhirong Zhong

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