Enzyme Engineering
Open Access

Abstract

Highly Efficient and Controllable Method for Sulfation of Complex Carbohydrates

Chih-Wei Chang

Body Sulfated glycosaminoglycans (GAGs) are important biological molecules, a number of which, for example heparin, Fondaparinux Sodium (ARIXTRA®) and Pentosan Polysulfate Sodium (ELMIRON®), have been in clinical use for decades. A key step in the preparation of homogeneous sulfated carbohydrates is efficient, reproducible and scalable chemical O- and N-sulfation method. A significant difficulty that arises during attempts to sulfate polyfunctional substrates using conventional approaches is incomplete conversion and unpredictable outcome. In this presentation we describe a new chemical sulfation method [1] successfully applied to O- and N-sulfation of a wide range of substrates for synthesis of a library of discrete homogeneous heparan sulfate fragments ranging from mono to octa-saccharides which has been exploited to uncover the specific binding interactions of pure GAG fragments with proteins and in metalloorganic complexes [2,3,4]. In the meantime we exploited this new method to acquire a library of densely sulfated GAG mimetics as potent inhibitors of EV71 infection [5]. We also successfully extended this new protocol to sulfate a polyol substrate on a scale of 232 grams in the academic lab and transferred the technology to GMP production (7 kg scale) of a lead drug candidate currently in a human clinical trial for therapeutic development against sepsis.

Published Date: 2020-09-18;