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Matrix Metalloproteinase Inhibition by Heterotrimeric Triple‐Helical Peptide Transition State Analogues
Author(s) -
Bhowmick Manishabrata,
Stawikowska Roma,
TokminaRoszyk Dorota,
Fields Gregg B.
Publication year - 2015
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201402716
Subject(s) - heterotrimeric g protein , chemistry , peptide , stereochemistry , matrix metalloproteinase , biochemistry , combinatorial chemistry , biophysics , biology , g protein , receptor
Matrix metalloproteinases (MMPs) have been implicated in numerous pathologies. An overall lack of selectivity has rendered active‐site‐targeted MMP inhibitors problematic. The present study describes MMP inhibitors that function by binding both secondary binding sites (exosites) and the active site. Heterotrimeric triple‐helical peptide transition‐state analogue inhibitors (THPIs) were assembled utilizing click chemistry. Three different heterotrimers were constructed, allowing for the inhibitory phosphinate moiety to be present uniquely in the leading, middle, or trailing strand of the triple helix. All heterotrimeric constructs had sufficient thermally stability to warrant analysis as inhibitors. The heterotrimeric THPIs were effective against MMP‐13 and MT1‐MMP, with K i values spanning 100–400 n M . Unlike homotrimeric THPIs, the heterotrimeric THPIs offered complete selectivity between MT1‐MMP and MMP‐1. Exosite‐based approaches such as this provide inhibitors with desired MMP selectivities.