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

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Ferreira, Leticia 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 ; Prudencio, Miguel ; Quick, Matthias ; Cravo, Pedro V. ; Lee, Marcus C. S. ; Fidock, David A. ; Costa, Fabio Trindade Maranhao

• Tipo de documento: Artigo Científico
• Fonte: PLOS PATHOGENS; v. 20, n. 10, p. 25-pg., 2024-10-01.

Resumo

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. (AU)

• Processo FAPESP: 18/24878-9 - Pesquisa de compostos bloqueadores da transmissão de Plasmodium usando novos modelos experimentais
• Beneficiário: Juliana Calit Paim
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 19/02171-3 - Investigação da atividade antimalárica e de alvos moleculares de compostos naturais identificados por quimioinformática contra Plasmodium vivax
• Beneficiário: Letícia Tiburcio Ferreira
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 21/06769-0 - Descoberta de alvos vacinais e compostos contra transmissão da Malária
• Beneficiário: Daniel Youssef Bargieri
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores - Fase 2
• Processo FAPESP: 21/13809-9 - Investigação da atividade antimalárica e alvos moleculares de compostos naturais identificados por quimioinformática e análise genética de parasitas Plasmodium falciparum
• Beneficiário: Letícia Tiburcio Ferreira
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado
• Processo FAPESP: 17/18611-7 - Desenvolvimento de novas ferramentas para busca e validação de alvos moleculares para terapia contra Plasmodium vivax
• Beneficiário: Fabio Trindade Maranhão Costa
• Modalidade de apoio: Auxílio à Pesquisa - Temático