Biomimetic macrocyclic inhibitors of human cathepsin D: structure-activity relationship and binding mode analysis.

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ID: 92800
2020
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Abstract
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.
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houteck2020biomimeticjournal Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Houštecká, Radka;Hadzima, Martin;Fanfrlík, Jindřich;Brynda, Jiří;Pallová, Lenka;Hánová, Iva;Mertlíková-Kaiserová, Helena;Lepšík, Martin;Horn, Martin;Smrčina, Martin;Majer, Pavel;Mares, Michael;
Journal Journal of medicinal chemistry
Year 2020
DOI
10.1021/acs.jmedchem.9b01351
URL
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