Chemoenzymatically prepared heparan sulfate containing rare 2-O-sulfonated glucuronic acid residues

ACS Chemical Biology
Rio S BoothelloUmesh R Desai

Abstract

The structural diversity of natural sulfated glycosaminoglycans (GAGs) presents major promise for discovery of chemical biology tools or therapeutic agents. Yet, few GAGs have been identified so far to exhibit this promise. We reasoned that a simple approach to identify such GAGs is to explore sequences containing rare residues, for example, 2-O-sulfonated glucuronic acid (GlcAp2S). Genetic algorithm-based computational docking and filtering suggested that GlcAp2S containing heparan sulfate (HS) may exhibit highly selective recognition of antithrombin, a key plasma clot regulator. HS containing only GlcAp2S and 2-N-sulfonated glucosamine residues, labeled as HS2S2S, was chemoenzymatically synthesized in just two steps and was found to preferentially bind antithrombin over heparin cofactor II, a closely related serpin. Likewise, HS2S2S directly inhibited thrombin but not factor Xa, a closely related protease. The results show that a HS containing rare GlcAp2S residues exhibits the unusual property of selective antithrombin activation and direct thrombin inhibition. More importantly, HS2S2S is also the first molecule to activate antithrombin nearly as well as the heparin pentasaccharide although being completely devoid of the cri...Continue Reading

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Citations

Jan 27, 2017·Angewandte Chemie·Nehru Viji SankarayanarayananUmesh R Desai
Sep 2, 2016·American Journal of Respiratory Cell and Molecular Biology·Shuo ZhengJudith A Voynow
Jun 27, 2017·Journal of the American Chemical Society·Chengli ZongGeert-Jan Boons
Apr 30, 2020·Computational and Structural Biotechnology Journal·Nehru Viji SankaranarayananUmesh R Desai
Jun 25, 2021·Chemical Science·Prashant JainRaghavendra Kikkeri
Apr 21, 2020·Organic Letters·Saurabh AnandRaghavendra Kikkeri

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