Mechanisms of heparanase inhibition by the heparan sulfate mimetic PG545 and three structural analogues

被引：52
作者：
Hammond, Edward [1 ]
Handley, Paul [1 ]
Dredge, Keith [2 ]
Bytheway, Ian [1 ]
机构：
[1] Progen Pharmaceut, Darra, Qld 4076, Australia
[2] Univ Queensland, Ctr Integrated Preclin Drug Dev, St Lucia, Qld 4072, Australia
来源：
FEBS OPEN BIO | 2013年 / 3卷
关键词：
Heparanase; PG545; Inhibitor; Kinetics; Cancer; ANGIOGENESIS INHIBITOR; TUMOR-GROWTH; PI-88; METASTASIS; MOLECULE; BINDING; TARGET; OLIGOSACCHARIDE; SPECIFICITY; DERIVATIVES;
D O I：
10.1016/j.fob.2013.07.007
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
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.
引用
收藏
页码：346 / 351
页数：6
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