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Glycopeptide Mimetics Recapitulate High‐Mannose‐Type Oligosaccharide Binding and Function
Author(s) -
Lusvarghi Sabrina,
Ghirlando Rodolfo,
Wong ChiHuey,
Bewley Carole A.
Publication year - 2015
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201500157
Subject(s) - glycopeptide , glycan , chemistry , mannose , lectin , biochemistry , isothermal titration calorimetry , avidity , oligosaccharide , stereochemistry , glycoprotein , biology , genetics , antibody , antibiotics
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 Man 9 GlcNAc 2 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.