A novel 4-aminoquinoline chemotype with multistage antimalarial activity and lack of cross-resistance with PfCRT and PfMDR1 mutants.

Autor: Ferreira, Letícia Tiburcio, Cassiano, Gustavo Capatti, Alvarez, Luis Carlos Salazar, Okombo, John, Calit, Juliana, Fontinha, Diana, Gil-Iturbe, Eva, Coyle, Rachael, Andrade, Carolina Horta, Sunnerhagen, Per, Bargieri, Daniel Youssef, Prudêncio, Miguel, Quick, Matthias, Cravo, Pedro V., Lee, Marcus C. S., Fidock, David A., Costa, Fabio Trindade Maranhão
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Zdroj: PLoS Pathogens; 10/29/2024, Vol. 20 Issue 10, p1-25, 25p
Abstrakt: Artemisinin-based combination therapy (ACT) is the mainstay of effective treatment of Plasmodium falciparum malaria. However, the long-term utility of ACTs is imperiled by widespread partial artemisinin resistance in Southeast Asia and its recent emergence in parts of East Africa. This underscores the need to identify chemotypes with new modes of action (MoAs) to circumvent resistance to ACTs. In this study, we characterized the asexual blood stage antiplasmodial activity and resistance mechanisms of LDT-623, a 4-aminoquinoline (4-AQ). We also detected LDT-623 activity against multiple stages (liver schizonts, stage IV-V gametocytes, and ookinetes) of Plasmodium's life cycle, a feature unlike other 4-AQs such as chloroquine (CQ) and piperaquine (PPQ). Using heme fractionation profiling and drug uptake studies in PfCRT-containing proteoliposomes, we observed inhibition of hemozoin formation and PfCRT-mediated transport, which constitute characteristic features of 4-AQs' MoA. We also found minimal cross-resistance to LDT-623 in a panel of mutant pfcrt or pfmdr1 lines, but not the PfCRT F145I mutant that is highly resistant to PPQ resistance yet is very unfit. No P. falciparum parasites were recovered in an in vitro resistance selection study, suggesting a high barrier for resistance to emerge. Finally, a competitive growth assay comprising >50 barcoded parasite lines with mutated resistance mediators or major drug targets found no evidence of cross-resistance. Our findings support further exploration of this promising 4-AQ. Author summary: The emergence of artemisinin-resistant malaria parasites, first in Southeast Asia and more recently East Africa, highlights the urgency to identify and optimize chemotypes with antimalarial activity that are not compromised by known resistance mechanisms in clinical settings. Using a computer-aided drug discovery approach, we previously identified a 4-AQ (LDT-611) that was active against P. falciparum asexual blood-stage (ABS) parasites. Herein, we report the multistage antimalarial activity of a structural analog, a side-chain-modified 4-AQ (LDT-623). This analog shares 4-AQ characteristics, such as PfCRT-mediated transport, as well as inhibition of hemozoin formation, that occurs in the parasite digestive vacuole. Cross-resistance profiling showed that this compound was not compromised by known mutations in the digestive vacuole transporters PfCRT or PfMDR1 or by other gene products that govern resistance to antimalarials under development. Efforts to evolve resistance to LDT-623 in vitro yielded parasite populations lacking noticeable phenotypic changes. In conclusion, we report a 4-AQ whose MoA is likely to differ from licensed antimalarials within this chemical class, paving the way for further studies on this chemotype as a therapeutic avenue to treat multidrug-resistant malaria. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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