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Re-emerging Aspartic Protease Targets: Examining Cryptococcus neoformans Major Aspartyl Peptidase 1 as a Target for Antifungal Drug Discovery

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, ORCID}
Source Title	Journal of Medicinal Chemistry. - : American Chemical Society - ISSN 0022-2623 Roč. 64, č. 10 (2021), s. 6706-6719
Number 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