Inhibiting Matrix Metalloproteinase-2 Activation by Perturbing Protein-Protein Interactions Using a Cyclic Peptide.,Journal of Medicinal Chemistry

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Inhibiting Matrix Metalloproteinase-2 Activation by Perturbing Protein-Protein Interactions Using a Cyclic Peptide.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-06-03 , DOI: 10.1021/acs.jmedchem.0c00180
Priyanka Sarkar ₁ , Zhonghan Li ₁ , Wendan Ren ₂ , Siwen Wang ₁ , Shiqun Shao ₁ , Jianan Sun ₁ , Xiaodong Ren ₃ , Nicole G Perkins ₁ , Zhili Guo ₁ , Chia-En A Chang ₁ , Jikui Song ₂ , Min Xue ₁

Affiliation

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.

中文翻译：

通过使用环肽干扰蛋白质-蛋白质相互作用来抑制基质金属蛋白酶2活化。

我们报告了一种环状肽，可抑制基质金属蛋白酶2（MMP2）具有低nM级效力。该抑制剂与D ₅₇₀ -A ₅₈₃特异性结合proMMP2上的抗原决定簇，并干扰proMMP2和金属蛋白酶2组织抑制剂（TIMP2）之间的蛋白质相互作用（PPI），从而防止了TIMP2辅助的proMMP2激活过程。我们通过针对表位的文库筛选过程开发了这种环肽抑制剂，并验证了其与proMMP2的结合。使用人类黑素瘤细胞系，我们证明了环肽调节细胞MMP2活性并抑制细胞迁移的能力。这些结果提供了靶向proMMP2和TIMP2之间的PPI的第一个成功实例，证实了寻求了20年的MMP2抑制策略的可行性。

更新日期：2020-07-09

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