Inhibiting Matrix Metalloproteinase‑2 Activation by Perturbing Protein–Protein Interactions Using a Cyclic Peptide

We
report on a cyclic peptide that inhibits matrix metalloproteinase-2
(MMP2) activation with a low-nM-level potency. This inhibitor specifically
binds to the D570-A583 epitope on proMMP2 and
interferes with the protein–protein interaction (PPI) between
proMMP2 and tissue inhibitor of metalloproteinases-2 (TIMP2), thereby
preventing the TIMP2-assisted proMMP2 activation process. We developed
this cyclic peptide inhibitor through an epitope-targeted library
screening process and validated its binding to proMMP2. Using a human
melanoma cell line, we demonstrated the cyclic peptide’s ability
to modulate cellular MMP2 activities and inhibit cell migration. These
results provide the first successful example of targeting the PPI
between proMMP2 and TIMP2, confirming the feasibility of an MMP2 inhibition
strategy that has been sought after for 2 decades.