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 metalloprotein...

Full description

Saved in:
Bibliographic Details
Published inJournal of medicinal chemistry Vol. 63; no. 13; pp. 6979 - 6990
Main Authors Sarkar, Priyanka, Li, Zhonghan, Ren, Wendan, Wang, Siwen, Shao, Shiqun, Sun, Jianan, Ren, Xiaodong, Perkins, Nicole G, Guo, Zhili, Chang, Chia-En A, Song, Jikui, Xue, Min
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 09.07.2020
Amer Chemical Soc
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
COMPLEX-FORMATION
DOMAIN
INVASION
MMP-2
THERAPEUTIC AGENTS
TISSUE INHIBITORS
CELL-SURFACE
TARGETS
BINDING
CANCER-THERAPY
Online AccessGet full text

Cover

More Information
Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.0c00180