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Re-emerging Aspartic Protease Targets: Examining Cryptococcus neoformans Major Aspartyl Peptidase 1 as a Target for Antifungal Drug Discovery
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SYSNO ASEP 0543118 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Re-emerging Aspartic Protease Targets: Examining Cryptococcus neoformans Major Aspartyl Peptidase 1 as a Target for Antifungal Drug Discovery Author(s) Kryštůfek, Robin (UOCHB-X) ORCID
Šácha, Pavel (UOCHB-X) RID, ORCID
Starková, Jana (UOCHB-X)
Brynda, Jiří (UOCHB-X) RID, ORCID
Hradilek, Martin (UOCHB-X) ORCID
Tloušťová, Eva (UOCHB-X) RID, ORCID
Grzymska, J. (PL)
Rut, W. (PL)
Boucher, M. J. (US)
Drag, M. (PL)
Majer, Pavel (UOCHB-X)
Hájek, Miroslav (UOCHB-X) RID, ORCID
Řezáčová, Pavlína (UOCHB-X) RID, ORCID
Madhani, H. D. (US)
Craik, C. S. (US)
Konvalinka, Jan (UOCHB-X) RID, ORCIDSource Title Journal of Medicinal Chemistry. - : American Chemical Society - ISSN 0022-2623
Roč. 64, č. 10 (2021), s. 6706-6719Number of pages 14 s. Language eng - English Country US - United States Keywords immunodeficiency virus HIV ; in-vitro ; virulence factors OECD category Medicinal chemistry R&D Projects EF16_019/0000729 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Method of publishing Open access Institutional support UOCHB-X - RVO:61388963 UT WOS 000657351500014 EID SCOPUS 85107084509 DOI 10.1021/acs.jmedchem.0c02177 Annotation Cryptococcosis is an invasive infection that accounts for 15% of AIDS-related fatalities. Still, treating cryptococcosis remains a significant challenge due to the poor availability of effective antifungal therapies and emergence of drug resistance. Interestingly, protease inhibitor components of antiretroviral therapy regimens have shown some clinical benefits in these opportunistic infections. We investigated Major aspartyl peptidase 1 (May1), a secreted Cryptococcus neoformans protease, as a possible target for the development of drugs that act against both fungal and retroviral aspartyl proteases. Here, we describe the biochemical characterization of May1, present its high-resolution X-ray structure, and provide its substrate specificity analysis. Through combinatorial screening of 11,520 compounds, we identified a potent inhibitor of May1 and HIV protease. This dual-specificity inhibitor exhibits antifungal activity in yeast culture, low cytotoxicity, and low off-target activity against host proteases and could thus serve as a lead compound for further development of May1 and HIV protease inhibitors. Workplace Institute of Organic Chemistry and Biochemistry Contact asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Viktorie Chládková, Tel.: 232 002 434 Year of Publishing 2022 Electronic address https://doi.org/10.1021/acs.jmedchem.0c02177
Number of the records: 1