Drugs combining antifungal and antiretroviral activities
Cryptococcosis, caused by Cryptococcus neoformans, is a systemic mycosis, which can be life-threatening especially in immunosuppressed patients suffering from HIV infection. Poor availability of antifungal drugs and drug resistance complicate the successful treatment. A possible target for drugs combining antifungal and antiretroviral activities might be secreted protease Major aspartyl peptidase 1, or May1.
The group of Jan Konvalinka from IOCB Prague and Charles University in collaboration with colleagues from the Institute of Molecular Genetics of the CAS, University of Wroclaw, and University of California San Francisco described the biochemical properties of May1 and characterized its structure using X-ray analysis. The scientists applied a combinatorial screening to identify a peptidomimetic inhibitor blocking May1 together with the HIV-1 protease.
The lead structure shows favorable cytotoxicity and low off-target activity thus can serve as a scaffold for novel inhibitor development. The research was published in the Journal of Medicinal Chemistry with undergraduate student of Charles University Robin Kryštůfek as the first author.
Read the paper:
- Kryštůfek, R.; Šácha, P.; Starková, J.; Brynda, J.; Hradilek, M.; Tloušt’ová, E.; Grzymska, J.; Rut, W.; Boucher, M. J.; Drąg, M.; Majer, P.; Hájek, M.; Řezáčová, P.; Madhani, H. D.; Craik, C. S.; Konvalinka, J. Re-emerging Aspartic Protease Targets: Examining Cryptococcus neoformans Major Aspartyl Peptidase 1 as a Target for Antifungal Drug Discovery. Journal of Medicinal Chemistry 2021. https://pubs.acs.org/doi/10.1021/acs.jmedchem.0c02177