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Re-emerging Aspartic Protease Targets: Examining Cryptococcus neoformans Major Aspartyl Peptidase 1 as a Target for Antifungal Drug Discovery
R. Kryštůfek, P. Šácha, J. Starková, J. Brynda, M. Hradilek, E. Tloušt'ová, J. Grzymska, W. Rut, MJ. Boucher, M. Drąg, P. Majer, M. Hájek, P. Řezáčová, HD. Madhani, CS. Craik, J. Konvalinka
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural, práce podpořená grantem
Grantová podpora
F32 AI152270
NIAID NIH HHS - United States
R01 AI100272
NIAID NIH HHS - United States
T32 HL007185
NHLBI NIH HHS - United States
P50 GM082250
NIGMS NIH HHS - United States
Odkazy
PubMed
34006103
DOI
10.1021/acs.jmedchem.0c02177
Knihovny.cz E-zdroje
- MeSH
- antifungální látky chemie metabolismus farmakologie MeSH
- aspartátové proteasy antagonisté a inhibitory genetika metabolismus MeSH
- Cryptococcus neoformans enzymologie MeSH
- fungální proteiny antagonisté a inhibitory genetika metabolismus MeSH
- HIV-proteasa chemie metabolismus MeSH
- HIV enzymologie MeSH
- houby účinky léků MeSH
- katalytická doména MeSH
- krystalografie rentgenová MeSH
- preklinické hodnocení léčiv MeSH
- rekombinantní proteiny biosyntéza chemie izolace a purifikace MeSH
- simulace molekulární dynamiky MeSH
- substrátová specifita MeSH
- vazebná místa MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
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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- $a Kryštůfek, Robin $u Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 2, Prague 6 16610, Czech Republic $u Department of Physical and Macromolecular Chemistry, Faculty of Science, Charles UniversityHlavova 8, Prague 2 12843, Czech Republic
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- $a 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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