Development of Potent and Highly Selective Epoxyketone-Based Plasmodium Proteasome Inhibitors

0570610 - ÚOCHB 2024 RIV DE eng J - Článek v odborném periodiku
Almaliti, J. - Fajtová, Pavla - Calla, J. - LaMonte, G. M. - Feng, M. - Rocamora, F. - Ottilie, S. - Glukhov, E. - Bouřa, Evžen - Suhandynata, R. T. - Momper, J. D. - Gilson, M. K. - Winzeler, E. A. - Gerwick, W. H. - O'Donoghue, A. J.
Development of Potent and Highly Selective Epoxyketone-Based Plasmodium Proteasome Inhibitors.
Chemistry - A European Journal. Roč. 29, č. 20 (2023), č. článku e202203958. ISSN 0947-6539. E-ISSN 1521-3765
GRANT EU: European Commission(XE) 846688 - ProTeCT
Institucionální podpora: RVO:61388963
Klíčová slova: epoxyketone * inhibition * malaria * plasmodium * proteasome
Obor OECD: Biochemistry and molecular biology
Impakt faktor: 4.3, rok: 2022
Způsob publikování: Open access
https://doi.org/10.1002/chem.202203958

Here, we present remarkable epoxyketone-based proteasome inhibitors with low nanomolar in vitro potency for blood-stage Plasmodium falciparum and low cytotoxicity for human cells. Our best compound has more than 2,000-fold greater selectivity for erythrocytic-stage P. falciparum over HepG2 and H460 cells, which is largely driven by the accommodation of the parasite proteasome for a D-amino acid in the P3 position and the preference for a difluorobenzyl group in the P1 position. We isolated the proteasome from P. falciparum cell extracts and determined that the best compound is 171-fold more potent at inhibiting the β5 subunit of P. falciparum proteasome when compared to the same subunit of the human constitutive proteasome. These compounds also significantly reduce parasitemia in a P. berghei mouse infection model and prolong survival of animals by an average of 6 days. The current epoxyketone inhibitors are ideal starting compounds for orally bioavailable anti-malarial drugs.
Trvalý link: https://hdl.handle.net/11104/0341912