Inhibiting Matrix Metalloproteinase-2 Activation by Perturbing Protein–Protein Interactions Using a Cyclic Peptide
- 18 June 2020
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 63 (13), 6979-6990
- https://doi.org/10.1021/acs.jmedchem.0c00180
Abstract
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 two decades.Keywords
Funding Information
- Division of Molecular and Cellular Biosciences (MCB-1932984)
- National Institute of Biomedical Imaging and Bioengineering (1R21EB025393)
- National Institute of General Medical Sciences (1R35GM119721)
This publication has 63 references indexed in Scilit:
- A monoclonal antibody interferes with TIMP-2 binding and incapacitates the MMP-2-activating function of multifunctional, pro-tumorigenic MMP-14/MT1–MMPOncogenesis, 2013
- Small-Molecule Anticancer Compounds Selectively Target the Hemopexin Domain of Matrix Metalloproteinase-9Cancer Research, 2011
- The tissue inhibitors of metalloproteinases (TIMPs): An ancient family with structural and functional diversityBiochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2010
- Direct inhibition of the NOTCH transcription factor complexNature, 2009
- Rapid Microwave-Assisted CNBr Cleavage of Bead-Bound PeptidesJournal of Combinatorial Chemistry, 2008
- Matrix metalloproteinases and the regulation of tissue remodellingNature Reviews Molecular Cell Biology, 2007
- Validating matrix metalloproteinases as drug targets and anti-targets for cancer therapyNature Reviews Cancer, 2006
- Development and testing of a general amber force fieldJournal of Computational Chemistry, 2004
- Fast, efficient generation of high‐quality atomic charges. AM1‐BCC model: II. Parameterization and validationJournal of Computational Chemistry, 2002
- Comparison of simple potential functions for simulating liquid waterThe Journal of Chemical Physics, 1983