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【启智讲坛第二十一讲】Design and discovery of enzyme inhibitors as potential therapies for diabetes

主要完成人: 发表日期:2016-04-08 点击数:593

报告题目:Design and discovery of enzyme inhibitors as potential therapies for diabetes

主 讲  人:Stephen G. Withers
             
   加拿大不列颠哥伦比亚大学Khorana讲席教授

上海交通大学顾问教授

英国皇家学会院士

加拿大皇家学会院士

报告时间:414日(星期四) 9:30
报告地点:闵行校区生物药学楼树华多功能厅(800号)

联 系  人:杨广宇 yanggy@sjtu.edu.cn

 

主讲人简介:

Stephen G. Withers教授主要从事糖类代谢酶的作用机制、糖类合成酶分子改造、糖代谢酶小分子药物设计研究,在糖化学生物领域有着卓越成就和重大影响。1992年获加拿大皇家学会卢瑟福奖,2002年获国际碳水化合物组织惠斯勒奖,2012年获英国皇家学会百年奖。

Professor Stephen G. Withers holds the Khorana Chair of Biological Chemistry at the University of British Columbia, the Fellow of the Royal Society of UK and the Fellow of the Royal Society of Canada. His research group focused on catalytic mechanism of glycosidase, molecular modification of glycosynthase, and small molecular drug design towards virus, parasites, diabetes and self-immunity. He has published more than 400 papers in Nature, Science, PNAS, Nature Chemical Biology, Angew. Chem., J. Am. Chem. Soc, etc. (H index = 83).

 

演讲摘要:

Carbohydrates play important roles in biological systems, not only in the form of energy storage materials such as starch, but also as “recognition elements” on cell surfaces. The degradation of such sugar structures is achieved using enzymes known as glycoside hydrolases (glycosidases). Specific enzyme inhibitors are not only useful tools for understanding enzyme mechanisms, but also can play important roles as therapeutics if inhibition suppresses unwanted reactions. I shall illustrate this with two recent examples of potent inhibitors of human amylase that we have identified as potential therapeutics for controlling blood glucose levels.

High-throughput screening of natural product extract libraries from terrestrial and marine sources, in conjunction with my colleague Ray Andersen, has yielded two new classes of potent Montbretin A (Ki = 8 nM) and Helianthamide (Ki = 10 pM) inhibitors of the human starch-digesting enzyme α-amylase. Importantly, good control of blood glucose levels is seen in diabetic rats given Montbretin A in their drinking water. Structural studies with these inhibitors reveal a new paradigm for glycosidase inhibition that we are currently exploiting and exploring.

 

1. Williams, L. et al (2015) Nature Chem. Biol. 11, 691-696.

2. Tysoe et al (2016) ACS Central Science, 2, 154-161.

3. Yuen V et al (2016) Mol. Cell. Biochem. 411, 473-381