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肝素酶抑制机制研究：肝素硫酸盐类似物 PG545 及其三种结构类似物的作用。

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

机构信息

Progen Pharmaceuticals, Darra, QLD 4076, Australia.

出版信息

FEBS Open Bio. 2013 Aug 2;3:346-51. doi: 10.1016/j.fob.2013.07.007. eCollection 2013.

DOI:10.1016/j.fob.2013.07.007
PMID:24251094
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3821029/
Abstract

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.

摘要

四糖肝素硫酸盐（HS）类似物 PG545 是一种临床抗癌候选药物，是 HS 降解酶肝素酶的抑制剂。研究了 PG545 和三种结构类似物对肝素酶抑制的动力学，以了解它们的抑制模式。PG545 的胆甾醇糖苷配基显著增加了对肝素酶的亲和力，并且还改变了抑制模式。对于四糖，胆甾醇糖苷配基的添加将竞争性抑制改变为抛物线竞争。对于三糖，部分竞争性抑制改变为抛物线竞争。提出了一个示意性模型来解释这些发现。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc02/3821029/81d3eb4802c5/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc02/3821029/7c575a34176b/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc02/3821029/a8d3c8956718/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc02/3821029/57e0753e8174/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc02/3821029/2e600fe69a15/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc02/3821029/293a75ce633d/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc02/3821029/81d3eb4802c5/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc02/3821029/7c575a34176b/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc02/3821029/a8d3c8956718/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc02/3821029/57e0753e8174/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc02/3821029/2e600fe69a15/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc02/3821029/293a75ce633d/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc02/3821029/81d3eb4802c5/gr5.jpg

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