Open AccessMechanisms of heparanase inhibition by the heparan sulfate mimetic PG545 and three structural analogues
Author(s) -
Hammond Edward,
Handley Paul,
Dredge Keith,
Bytheway Ian
Publication year - 2013
Publication title -
febs open bio
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.718
H-Index - 31
ISSN - 2211-5463
DOI - 10.1016/j.fob.2013.07.007
Subject(s) - heparanase , heparan sulfate , chemistry , non competitive inhibition , tetrasaccharide , biochemistry , enzyme , stereochemistry , glycosaminoglycan , polysaccharide
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.