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Biomimetic Macrocyclic Inhibitors of Human Cathepsin D: Structure-Activity Relationship and Binding Mode Analysis
R. Houštecká, M. Hadzima, J. Fanfrlík, J. Brynda, L. Pallová, I. Hánová, H. Mertlíková-Kaiserová, M. Lepšík, M. Horn, M. Smrčina, P. Majer, M. Mareš,
Journal of medicinal chemistry.
2020 ;
63 (4) :
1576-1596.
[pub] 20200213
Language English Country United States
Document type Journal Article, Research Support, Non-U.S. Gov't
Persistent link
https://www.medvik.cz/link/bmc20025188
- MeSH
- Biomimetic Materials chemical synthesis chemistry metabolism toxicity MeSH
- Caco-2 Cells MeSH
- Peptides, Cyclic chemical synthesis chemistry metabolism toxicity MeSH
- Enzyme Assays MeSH
- Protease Inhibitors chemical synthesis chemistry metabolism toxicity MeSH
- Cathepsin D antagonists & inhibitors chemistry metabolism MeSH
- Kinetics MeSH
- Humans MeSH
- Molecular Structure MeSH
- Pepstatins chemistry MeSH
- Protein Binding MeSH
- Binding Sites MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
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.
References provided by Crossref.org
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