New strategies for targeting matrix metalloproteinases

•Matrix metalloproteinase (MMP) inhibitor design has considered secondary binding sites (exosites) to improve specificity.•Small molecules and peptides have been developed that bind exosites in MMP-2, MMP-9, MMP-13, and MT1-MMP.•Antibody-based approaches have resulted in selective inhibitors for MMP-9 and MT1-MMP.•Biomolecules designed for specific exosite targeting have provided selective MMP probes.

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.