New strategies for targeting matrix metalloproteinases

Matrix Biol. May-Jul 2015;44-46:239-46. doi: 10.1016/j.matbio.2015.01.002. Epub 2015 Jan 14.


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.

Keywords: Collagen; Exosite; Inhibitor; Matrix metalloproteinase (MMP); Triple-helical peptide.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Binding Sites / drug effects
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Male
  • Matrix Metalloproteinases / chemistry*
  • Matrix Metalloproteinases / metabolism*
  • Peptides / pharmacology
  • Small Molecule Libraries / pharmacology
  • Substrate Specificity


  • Enzyme Inhibitors
  • Peptides
  • Small Molecule Libraries
  • Matrix Metalloproteinases