title: New strategies for targeting matrix metalloproteinases.
abstract: The development of matrix metalloproteinase (MMP) inhibitors has often been frustrated by a lack of specificity and subsequent off-target effects. More recently, inhibitor design has considered secondary binding sites (exosites) to improve specificity. Small molecules and peptides have been developed that bind exosites in the catalytic (CAT) domain of MMP-13, the CAT or hemopexin-like (HPX) domain of MT1-MMP, and the collagen binding domain (CBD) of MMP-2 and MMP-9. Antibody-based approaches have resulted in selective inhibitors for MMP-9 and MT1-MMP that target CAT domain exosites. Triple-helical "mini-proteins" have taken advantage of collagen binding exosites, producing a family of novel probes. A variety of non-traditional approaches that incorporate exosite binding into the design process has yielded inhibitors with desirable selectivities within the MMP family.
authors.affiliation: Florida Atlantic University, Department of Chemistry & Biochemistry, 5353 Parkside Drive, Building MC17, Jupiter, FL 33458, United States; The Scripps Research Institute/Scripps Florida, Department of Chemistry, 130 Scripps Way, Jupiter, FL 33458, United States; Torrey Pines Institute for Molecular Studies, Department of Chemistry, 11350 SW Village Parkway, Port St. Lucie, FL 34987, United States; Torrey Pines Institute for Molecular Studies, Department of Biology, 11350 SW Village Parkway, Port St. Lucie, FL 34987, United States. Electronic address: fieldsg@fau.edu.
authors.forename: Gregg B
authors.initials: GB
authors.lastname: Fields
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008297:Male; D020782:Matrix Metalloproteinases / Q000737:chemistry* / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D054852:Small Molecule Libraries / Q000494:pharmacology; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; D010455:Peptides; D054852:Small Molecule Libraries; D020782:Matrix Metalloproteinases
keywords: Collagen; Exosite; Inhibitor; Matrix metalloproteinase (MMP); Triple-helical peptide