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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
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články, práce podpořená grantem
Perzistentní odkaz
https://www.medvik.cz/link/bmc20025188
- MeSH
- biomimetické materiály chemická syntéza chemie metabolismus toxicita MeSH
- Caco-2 buňky MeSH
- cyklické peptidy chemická syntéza chemie metabolismus toxicita MeSH
- enzymatické testy MeSH
- inhibitory proteas chemická syntéza chemie metabolismus toxicita MeSH
- kathepsin D antagonisté a inhibitory chemie metabolismus MeSH
- kinetika MeSH
- lidé MeSH
- molekulární struktura MeSH
- pepstatiny chemie MeSH
- vazba proteinů MeSH
- vazebná místa MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem 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.
Citace poskytuje Crossref.org
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