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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 ASEP0543118
    Document TypeJ - Journal Article
    R&D Document TypeJournal Article
    Subsidiary JČlánek ve WOS
    TitleRe-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, ORCID
    Source TitleJournal of Medicinal Chemistry - ISSN 0022-2623
    Roč. 64, č. 10 (2021), s. 6706-6719
    Number of pages14 s.
    Languageeng - English
    CountryUS - United States
    Keywordsimmunodeficiency virus HIV ; in-vitro ; virulence factors
    OECD categoryMedicinal chemistry
    R&D ProjectsEF16_019/0000729 GA MŠk - Ministry of Education, Youth and Sports (MEYS)
    Method of publishingOpen access
    Institutional supportUOCHB-X - RVO:61388963
    UT WOS000657351500014
    EID SCOPUS85107084509
    DOI10.1021/acs.jmedchem.0c02177
    AnnotationCryptococcosis 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.
    WorkplaceInstitute of Organic Chemistry and Biochemistry
    ContactMarie Odehnalová,marie.odehnalova@uochb.cas.cz Tel.: 220 183 418 ; Viktorie Chládková, viktorie.chladkova@uochb.cas.cz, Tel.: 232 002 434
    Year of Publishing2022
    Electronic addresshttps://doi.org/10.1021/acs.jmedchem.0c02177
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