Mechanisms of Heparanase Inhibition by the Heparan Sulfate Mimetic PG545 and Three Structural Analogues

Overview

Journal FEBS Open Bio

Specialty Biology

Date 2013 Nov 20

PMID 24251094

Citations 19

Authors

Edward Hammond

Paul Handley

Keith Dredge

Ian Bytheway

Affiliations

Soon will be listed here.

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.

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