Biomimetic Macrocyclic Inhibitors of Human Cathepsin D: Structure–Activity Relationship and Binding Mode Analysis

0522693 - ÚOCHB 2021 RIV US eng J - Journal Article
Houštecká, Radka - Hadzima, Martin - Fanfrlík, Jindřich - Brynda, Jiří - Pallová, Lenka - Hánová, Iva - Mertlíková-Kaiserová, Helena - Lepšík, Martin - Horn, Martin - Smrčina, M. - Majer, Pavel - Mareš, Michael
Biomimetic Macrocyclic Inhibitors of Human Cathepsin D: Structure–Activity Relationship and Binding Mode Analysis.
Journal of Medicinal Chemistry. Roč. 63, č. 4 (2020), s. 1576-1596. ISSN 0022-2623. E-ISSN 1520-4804
R&D Projects: GA MŠMT(CZ) EF16_019/0000729; GA ČR GA15-18929S; GA MŠMT LO1302
Institutional support: RVO:61388963
Keywords : inhibitor * macrocycle * protease
OECD category: Biochemistry and molecular biology
Impact factor: 7.446, year: 2020
Method of publishing: Limited access
https://pubs.acs.org/doi/10.1021/acs.jmedchem.9b01351

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.
Permanent Link: http://hdl.handle.net/11104/0307144