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Inhibiting Matrix Metalloproteinase-2 Activation by Perturbing Protein-Protein Interactions Using a Cyclic Peptide.

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 2 decades.

SUBMITTER: Sarkar P

PROVIDER: S-EPMC7437931 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Inhibiting Matrix Metalloproteinase-2 Activation by Perturbing Protein-Protein Interactions Using a Cyclic Peptide.

Sarkar Priyanka P Li Zhonghan Z Ren Wendan W Wang Siwen S Shao Shiqun S Sun Jianan J Ren Xiaodong X Perkins Nicole G NG Guo Zhili Z Chang Chia-En A CA Song Jikui J Xue Min M

Journal of medicinal chemistry 20200618 13

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 D<sub>570</sub>-A<sub>583</sub> 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 ...[more]

PMID: 32491863

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Project description:IntroductionMatrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) are critical components of the extracellular matrix (ECM) in colorectal cancer (CRC). We aimed to evaluate the prognostic value of MMP-2 and MMP-9 in patients with CRC.MethodsWe performed a meta-analysis of cohort studies with available data on the effect of MMP-2 and MMP-9 expression on both disease-free survival (DFS) and overall survival (OS) by the risk ratios (RRs) with their 95% confidence intervals (CIs). Studies were subgrouped based on the different tissue types, including cancer tissue and normal tissue, and the subgroup effect of MMP expression in different tissues was analyzed through meta-regression. To ensure the quality and reduce the risk of bias, the Newcastle‒Ottawa Scale (NOS) was used to assess the included studies. A sensitivity analysis was randomly performed to assess the potential impact of each study on our results.ResultsEighteen trials were selected (Table 1) and included a total of 3944 patients. According to our primary meta-analysis, the expression of MMP-2 was significantly associated with a decrease in OS (RR = 1.75, 95% CI = 1.34 to 2.29, P < 0.001) and DFS (RR = 2.62, 95% CI = 1.25 to 5.49, P < 0.001), and the expression of MMP-9 was not significantly associated with a decrease in OS (RR = 1.48, 95% CI = 0.97 to 2.24, P = 0.069) or DFS (RR = 1.60, 95% CI = 0.87 to 2.94, P = 0.133). According to the subgroup analysis of MMPs in different tissues, high MMP-2 expression in cancer tissue (RR = 1.90, 95% CI = 1.29 to 2.79) and normal tissue (RR = 1.59, 95% CI = 1.17 to 2.17) were significant indicators of poor OS. High MMP-2 expression in cancer tissue was significant indicator of poor DFS (RR = 2.12, 95% CI = 1.09 to 4.11). MMP-9 expression was also associated with poor OS (RR = 1.40, 95% CI = 0.85 to 2.29), but the difference in OS between the high and low expression groups was not statistically significant.ConclusionsHigh MMP-2 expression, especially in cancer tissue, is significantly associated with both poor DFS and poor OS in patients with CRC. High MMP-9 expression tended to indicate a poor prognosis of CRC but the correlation was not significant.

Dataset Information

Inhibiting Matrix Metalloproteinase-2 Activation by Perturbing Protein-Protein Interactions Using a Cyclic Peptide.

Publications

Inhibiting Matrix Metalloproteinase-2 Activation by Perturbing Protein-Protein Interactions Using a Cyclic Peptide.

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