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

[Image: see text] 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 inhibito...

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Autores principales: Kryštůfek, Robin, Šácha, Pavel, Starková, Jana, Brynda, Jiří, Hradilek, Martin, Tloušt’ová, Eva, Grzymska, Justyna, Rut, Wioletta, Boucher, Michael J., Drąg, Marcin, Majer, Pavel, Hájek, Miroslav, Řezáčová, Pavlína, Madhani, Hiten D., Craik, Charles S., Konvalinka, Jan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2021
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165695/
https://www.ncbi.nlm.nih.gov/pubmed/34006103
http://dx.doi.org/10.1021/acs.jmedchem.0c02177
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author Kryštůfek, Robin
Šácha, Pavel
Starková, Jana
Brynda, Jiří
Hradilek, Martin
Tloušt’ová, Eva
Grzymska, Justyna
Rut, Wioletta
Boucher, Michael J.
Drąg, Marcin
Majer, Pavel
Hájek, Miroslav
Řezáčová, Pavlína
Madhani, Hiten D.
Craik, Charles S.
Konvalinka, Jan
author_facet Kryštůfek, Robin
Šácha, Pavel
Starková, Jana
Brynda, Jiří
Hradilek, Martin
Tloušt’ová, Eva
Grzymska, Justyna
Rut, Wioletta
Boucher, Michael J.
Drąg, Marcin
Majer, Pavel
Hájek, Miroslav
Řezáčová, Pavlína
Madhani, Hiten D.
Craik, Charles S.
Konvalinka, Jan
author_sort Kryštůfek, Robin
collection PubMed
description [Image: see text] 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.
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spelling pubmed-81656952021-06-01 Re-emerging Aspartic Protease Targets: Examining Cryptococcus neoformans Major Aspartyl Peptidase 1 as a Target for Antifungal Drug Discovery Kryštůfek, Robin Šácha, Pavel Starková, Jana Brynda, Jiří Hradilek, Martin Tloušt’ová, Eva Grzymska, Justyna Rut, Wioletta Boucher, Michael J. Drąg, Marcin Majer, Pavel Hájek, Miroslav Řezáčová, Pavlína Madhani, Hiten D. Craik, Charles S. Konvalinka, Jan J Med Chem [Image: see text] 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. American Chemical Society 2021-05-18 2021-05-27 /pmc/articles/PMC8165695/ /pubmed/34006103 http://dx.doi.org/10.1021/acs.jmedchem.0c02177 Text en © 2021 The Authors. Published by American Chemical Society Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Kryštůfek, Robin
Šácha, Pavel
Starková, Jana
Brynda, Jiří
Hradilek, Martin
Tloušt’ová, Eva
Grzymska, Justyna
Rut, Wioletta
Boucher, Michael J.
Drąg, Marcin
Majer, Pavel
Hájek, Miroslav
Řezáčová, Pavlína
Madhani, Hiten D.
Craik, Charles S.
Konvalinka, Jan
Re-emerging Aspartic Protease Targets: Examining Cryptococcus neoformans Major Aspartyl Peptidase 1 as a Target for Antifungal Drug Discovery
title Re-emerging Aspartic Protease Targets: Examining Cryptococcus neoformans Major Aspartyl Peptidase 1 as a Target for Antifungal Drug Discovery
title_full Re-emerging Aspartic Protease Targets: Examining Cryptococcus neoformans Major Aspartyl Peptidase 1 as a Target for Antifungal Drug Discovery
title_fullStr Re-emerging Aspartic Protease Targets: Examining Cryptococcus neoformans Major Aspartyl Peptidase 1 as a Target for Antifungal Drug Discovery
title_full_unstemmed Re-emerging Aspartic Protease Targets: Examining Cryptococcus neoformans Major Aspartyl Peptidase 1 as a Target for Antifungal Drug Discovery
title_short Re-emerging Aspartic Protease Targets: Examining Cryptococcus neoformans Major Aspartyl Peptidase 1 as a Target for Antifungal Drug Discovery
title_sort re-emerging aspartic protease targets: examining cryptococcus neoformans major aspartyl peptidase 1 as a target for antifungal drug discovery
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165695/
https://www.ncbi.nlm.nih.gov/pubmed/34006103
http://dx.doi.org/10.1021/acs.jmedchem.0c02177
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