Institute of Organic Chemistry and Biochemistry , Czech Academy of Sciences , Flemingovo nám. 2 , 16610 Praha 6 , Czech Republic.
First Faculty of Medicine , Charles University , Kateřinská 32 , 12108 Praha 2 , Czech Republic.
J Med Chem. 2020 Feb 27;63(4):1576-1596. doi: 10.1021/acs.jmedchem.9b01351. Epub 2020 Feb 13.
Human cathepsin D (CatD), a pepsin-family aspartic protease, plays an important role in tumor progression and metastasis. Here, we report the development of biomimetic inhibitors of CatD as novel tools for regulation of this therapeutic target. We designed a macrocyclic scaffold to mimic the spatial conformation of the minimal pseudo-dipeptide binding motif of pepstatin A, a microbial oligopeptide inhibitor, in the CatD active site. A library of more than 30 macrocyclic peptidomimetic inhibitors was employed for scaffold optimization, mapping of subsite interactions, and profiling of inhibitor selectivity. Furthermore, we solved high-resolution crystal structures of three macrocyclic inhibitors with low nanomolar or subnanomolar potency in complex with CatD and determined their binding mode using quantum chemical calculations. The study provides a new structural template and functional profile that can be exploited for design of potential chemotherapeutics that specifically inhibit CatD and related aspartic proteases.
人组织蛋白酶 D（CatD）是一种胃蛋白酶家族天冬氨酸蛋白酶，在肿瘤的进展和转移中发挥重要作用。在这里，我们报告了 CatD 仿生抑制剂的开发，作为调控这一治疗靶点的新型工具。我们设计了一个大环支架来模拟 Pepstatin A 的最小拟肽结合基序在 CatD 活性位点中的空间构象，Pepstatin A 是一种微生物寡肽抑制剂。我们使用了一个包含 30 多种大环肽模拟抑制剂的文库，对支架进行优化，对亚位点相互作用进行作图，并对抑制剂的选择性进行分析。此外，我们还解析了与 CatD 以低纳摩尔或亚纳摩尔效力结合的三种大环抑制剂的高分辨率晶体结构，并使用量子化学计算确定了它们的结合模式。这项研究提供了一个新的结构模板和功能谱，可以用于设计专门抑制 CatD 和相关天冬氨酸蛋白酶的潜在化疗药物。
