Matrix metalloproteinase inhibition by heterotrimeric triple-helical Peptide transition state analogues

Chembiochem : a European Journal of Chemical Biology
Manishabrata BhowmickGregg B Fields

Abstract

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 Ki values spanning 100-400 nM. 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.

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Citations

Apr 11, 2017·Journal of Medicinal Chemistry·Manishabrata BhowmickGregg B Fields
Jun 22, 2017·Biochimica Et Biophysica Acta. Molecular Cell Research·Maxim LevinIrit Sagi
Nov 28, 2017·Current Medicinal Chemistry·Anne C ConibearClaudia Bello
Jun 7, 2017·Journal of Cellular Biochemistry·Evette S RadiskyDerek C Radisky
Dec 5, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Anna M KnapinskaGregg B Fields
May 30, 2020·Cells·Maryam Raeeszadeh-SarmazdehBrianne G Hritz

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