Discovery of nostatin A, an azole-containing proteusin with prominent cytostatic and pro-apoptotic activity.

Autor:	Delawská K; Centre Algatech, Institute of Microbiology, Czech Academy of Sciences, Novohradká 237, Centre Algatech, Institute of Microbiology, Czech Academy of Sciences, 379 01 Třeboň, Czech Republic. hrouzek@alga.cz.; Department of Medical Biology, Faculty of Science, University of South Bohemia, Branišovská 1645/31a, 370 05 České Budějovice, Czech Republic., Hájek J; Centre Algatech, Institute of Microbiology, Czech Academy of Sciences, Novohradká 237, Centre Algatech, Institute of Microbiology, Czech Academy of Sciences, 379 01 Třeboň, Czech Republic. hrouzek@alga.cz., Voráčová K; Centre Algatech, Institute of Microbiology, Czech Academy of Sciences, Novohradká 237, Centre Algatech, Institute of Microbiology, Czech Academy of Sciences, 379 01 Třeboň, Czech Republic. hrouzek@alga.cz., Kuzma M; Laboratory of Molecular Structure Characterization, Institute of Microbiology, Czech Academy of Sciences, Vídeňská 1083, 142 00 Praha 4, Czech Republic., Mareš J; Centre Algatech, Institute of Microbiology, Czech Academy of Sciences, Novohradká 237, Centre Algatech, Institute of Microbiology, Czech Academy of Sciences, 379 01 Třeboň, Czech Republic. hrouzek@alga.cz.; Institute of Hydrobiology, Biology Centre of the Czech Academy of Sciences, Na Sádkách 702/7, 370 05 České Budějovice, Czech Republic., Vicková K; Centre Algatech, Institute of Microbiology, Czech Academy of Sciences, Novohradká 237, Centre Algatech, Institute of Microbiology, Czech Academy of Sciences, 379 01 Třeboň, Czech Republic. hrouzek@alga.cz., Kádek A; Laboratory of Structural Biology and Cell Signaling, Institute of Microbiology, Czech Academy of Sciences, Vídeňská 1083, 142 00 Praha 4, Czech Republic., Tučková D; Centre Algatech, Institute of Microbiology, Czech Academy of Sciences, Novohradká 237, Centre Algatech, Institute of Microbiology, Czech Academy of Sciences, 379 01 Třeboň, Czech Republic. hrouzek@alga.cz.; Department of Medical Biology, Faculty of Science, University of South Bohemia, Branišovská 1645/31a, 370 05 České Budějovice, Czech Republic., Gallob F; CeMM - Research Center for Molecular Medicine, Austrian Academy of Sciences, Lazarettgasse 14, 1090 Wien, Austria., Divoká P; Centre Algatech, Institute of Microbiology, Czech Academy of Sciences, Novohradká 237, Centre Algatech, Institute of Microbiology, Czech Academy of Sciences, 379 01 Třeboň, Czech Republic. hrouzek@alga.cz.; Department of Medical Biology, Faculty of Science, University of South Bohemia, Branišovská 1645/31a, 370 05 České Budějovice, Czech Republic., Moos M; Institute of Entomology, Laboratory of Analytical Biochemistry and Metabolomics, Biology Centre of the Czech Academy of Sciences, Branišovská 1160/31, 370 05, České Budějovice, Czech Republic., Opekar S; Institute of Entomology, Laboratory of Analytical Biochemistry and Metabolomics, Biology Centre of the Czech Academy of Sciences, Branišovská 1160/31, 370 05, České Budějovice, Czech Republic., Koch L; Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Str. 2+4, 14195 Berlin, Germany.; Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Hoher Weg 8, 06120 Halle, (Saale), Germany., Saurav K; Centre Algatech, Institute of Microbiology, Czech Academy of Sciences, Novohradká 237, Centre Algatech, Institute of Microbiology, Czech Academy of Sciences, 379 01 Třeboň, Czech Republic. hrouzek@alga.cz., Sedlák D; Institute of Molecular Genetics, Czech Academy of Sciences, Vídeňská 1083, 142 20 Praha., Novák P; Laboratory of Structural Biology and Cell Signaling, Institute of Microbiology, Czech Academy of Sciences, Vídeňská 1083, 142 00 Praha 4, Czech Republic., Urajová P; Centre Algatech, Institute of Microbiology, Czech Academy of Sciences, Novohradká 237, Centre Algatech, Institute of Microbiology, Czech Academy of Sciences, 379 01 Třeboň, Czech Republic. hrouzek@alga.cz., Dean J; Centre Algatech, Institute of Microbiology, Czech Academy of Sciences, Novohradká 237, Centre Algatech, Institute of Microbiology, Czech Academy of Sciences, 379 01 Třeboň, Czech Republic. hrouzek@alga.cz., Gažák R; Laboratory of Antibiotic Resistance and Microbial Metabolomics, Institute of Microbiology, Czech Academy of Sciences, Vídeňská 1083, 142 00 Praha 4, Czech Republic., Niedermeyer TJH; Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Str. 2+4, 14195 Berlin, Germany.; Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Hoher Weg 8, 06120 Halle, (Saale), Germany., Kameník Z; Laboratory of Antibiotic Resistance and Microbial Metabolomics, Institute of Microbiology, Czech Academy of Sciences, Vídeňská 1083, 142 00 Praha 4, Czech Republic., Šimek P; Institute of Entomology, Laboratory of Analytical Biochemistry and Metabolomics, Biology Centre of the Czech Academy of Sciences, Branišovská 1160/31, 370 05, České Budějovice, Czech Republic., Villunger A; CeMM - Research Center for Molecular Medicine, Austrian Academy of Sciences, Lazarettgasse 14, 1090 Wien, Austria.; Institute for Developmental Immunology, Medical University of Innsbruck, Biocenter, Innsbruck, Austria., Hrouzek P; Centre Algatech, Institute of Microbiology, Czech Academy of Sciences, Novohradká 237, Centre Algatech, Institute of Microbiology, Czech Academy of Sciences, 379 01 Třeboň, Czech Republic. hrouzek@alga.cz.
Jazyk:	angličtina
Zdroj:	Organic & biomolecular chemistry [Org Biomol Chem] 2024 Nov 22. Date of Electronic Publication: 2024 Nov 22.
DOI:	10.1039/d4ob01395f
Abstrakt:	Ribosomally synthesized and post-translationally modified peptides (RiPPs) are intriguing compounds with potential pharmacological applications. While many RiPPs are known as antimicrobial agents, a limited number of RiPPs with anti-proliferative effects in cancer cells are available. Here we report the discovery of nostatin A (NosA), a highly modified RiPP belonging among nitrile hydratase-like leader peptide RiPPs (proteusins), isolated from a terrestrial cyanobacterium Nostoc sp. Its structure was established based on the core peptide sequence encoded in the biosynthetic gene cluster recovered from the producing strain and subsequent detailed nuclear magnetic resonance and high-resolution mass spectrometry analyses. NosA, composed of a 30 amino-acid peptide core, features a unique combination of moieties previously not reported in RiPPs: the simultaneous presence of oxazole/thiazole heterocycles, dehydrobutyrine/dehydroalanine residues, and a sactionine bond. NosA includes an isobutyl-modified proline residue, highly unusual in natural products. NosA inhibits proliferation of multiple cancer cell lines at low nanomolar concentration while showing no hemolysis. It induces cell cycle arrest in S-phase followed by mitochondrial apoptosis employing a mechanism different from known tubulin binding and DNA damaging compounds. NosA also inhibits Staphylococcus strains while it exhibits no effect in other tested bacteria or yeasts. Due to its novel structure and selective bioactivity, NosA represents an excellent candidate for combinatorial chemistry approaches leading to development of novel NosA-based lead compounds.
Databáze:	MEDLINE
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