title: Matrix metalloproteinase inhibition by heterotrimeric triple-helical Peptide transition state analogues.
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.
authors.affiliation: Departments of Chemistry and Biology, Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987 (USA); Organix Inc. 240 Salem Street, Woburn, MA 01801 (USA).
authors.forename: Manishabrata
authors.initials: M
authors.lastname: Bhowmick
authors.forename: Roma
authors.initials: R
authors.lastname: Stawikowska
authors.forename: Dorota
authors.initials: D
authors.lastname: Tokmina-Roszyk
authors.forename: Gregg B
authors.initials: GB
authors.lastname: Fields
mesh_terms: D000595:Amino Acid Sequence; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D055503:Protein Multimerization; D017433:Protein Structure, Secondary
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D010455:Peptides; D020782:Matrix Metalloproteinases
keywords: click chemistry; collagen; heterotrimers; matrix metalloproteinase; transition-state analogue