Discovery of Highly Potent and Selective Matrix Metalloproteinase‑7 Inhibitors by Hybridizing the S1′ Subsite Binder with Short Peptides

Matrix metalloproteinase-7 (MMP-7) has emerged as a protein
playing
important roles in both physiological and pathophysiological processes.
Despite the growing interest in MMP-7 as a potential therapeutic target
for diseases including cancer and fibrosis, potent and selective MMP-7
inhibitors have yet to be identified. Compound 1, previously
reported by Edman and co-workers, binds to the S1′ subsite
of MMP-7, exhibiting moderate inhibitory activity and selectivity.
To achieve both higher inhibitory activity and selectivity, we conceived
hybridizing 1 with short peptides. The initially designed
compound 6, which was a hybrid molecule between 1 and a tripeptide (Ala-Leu-Met) derived from an MMP-2-inhibitory
peptide (APP-IP), showed enhanced MMP-7-inhibitory activity. Subsequent
optimization of the peptide moiety led to the development of compound 18 with remarkable potency for MMP-7 and selectivity over
other MMP subtypes.

基质金属蛋白酶-7（Matrix metalloproteinase-7, MMP-7）作为一类蛋白质，已被证实可在生理及病理生理过程中发挥重要作用。
尽管针对癌症、纤维化等多种疾病，MMP-7作为潜在治疗靶点的研究热度与日俱增，但目前仍未发现兼具强效性与选择性的MMP-7抑制剂。
此前埃德曼（Edman）及其同事曾报道过化合物1，该化合物可结合至MMP-7的S1'亚位点（S1′ subsite），并展现出中等强度的抑制活性与选择性。
为同时获得更高的抑制活性与选择性，我们提出将化合物1与短肽进行杂合的设计策略。
最初设计得到的化合物6，是化合物1与源自MMP-2抑制肽（MMP-2-inhibitory peptide, APP-IP）的三肽（丙氨酸-亮氨酸-甲硫氨酸，Ala-Leu-Met）的杂合分子，其对MMP-7的抑制活性得到了增强。
后续通过对肽段部分的优化，我们成功开发出化合物18，该化合物对MMP-7具有显著的抑制效力，且相较于其他基质金属蛋白酶亚型表现出良好的选择性。