Mechanisms of heparanase inhibition by the heparan sulfate mimetic PG545 and three structural analogues
Mechanisms of heparanase inhibition by the heparan sulfate mimetic PG545 and three structural analogues
复制标题
DOI：
10.1016/j.fob.2013.07.007
复制
发表时间：
2013-01-01
期刊：
影响因子：
2.6
通讯作者：
Bytheway, Ian
中科院分区：
文献类型：
--
作者：
Hammond, Edward;Handley, Paul;Bytheway, Ian
四糖硫酸乙酰肝素（HS）模拟物PG 545是HS降解酶乙酰肝素酶的抑制剂，是一种临床抗癌候选物。研究了PG 545和三种结构类似物对乙酰肝素酶的抑制动力学，以了解其抑制模式。PG545的胆甾烷醇苷元显著增加了对乙酰肝素酶的亲和力，并且还改变了抑制模式。对于四糖，通过加入胆甾烷醇糖苷配基将竞争性抑制修改为抛物线竞争。对于三聚氰胺，部分竞争性抑制被修改为抛物线竞争。一个示意性的模型来解释这些发现。(C)2013作者由Elsevier B.V.代表欧洲生物化学学会联合会出版。All rights reserved.
The tetrasaccharide heparan sulfate (HS) mimetic PG545, a clinical anti-cancer candidate, is an inhibitor of the HS-degrading enzyme heparanase. The kinetics of heparanase inhibition by PG545 and three structural analogues were investigated to understand their modes of inhibition. The cholestanol aglycon of PG545 significantly increased affinity for heparanase and also modified the inhibition mode. For the tetrasaccharides, competitive inhibition was modified to parabolic competition by the addition of the cholestanol aglycon. For the trisaccharides, partial competitive inhibition was modified to parabolic competition. A schematic model to explain these findings is presented. (C) 2013 The Authors. Published by Elsevier B.V. on behalf of Federation of European Biochemical Societies. All rights reserved.