RESUMO
There is an urgent need for new drugs to treat malaria, with broad therapeutic potential and novel modes of action, to widen the scope of treatment and to overcome emerging drug resistance. Here we describe the discovery of DDD107498, a compound with a potent and novel spectrum of antimalarial activity against multiple life-cycle stages of the Plasmodium parasite, with good pharmacokinetic properties and an acceptable safety profile. DDD107498 demonstrates potential to address a variety of clinical needs, including single-dose treatment, transmission blocking and chemoprotection. DDD107498 was developed from a screening programme against blood-stage malaria parasites; its molecular target has been identified as translation elongation factor 2 (eEF2), which is responsible for the GTP-dependent translocation of the ribosome along messenger RNA, and is essential for protein synthesis. This discovery of eEF2 as a viable antimalarial drug target opens up new possibilities for drug discovery.
Assuntos
Antimaláricos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Malária/parasitologia , Plasmodium/efeitos dos fármacos , Plasmodium/metabolismo , Biossíntese de Proteínas/efeitos dos fármacos , Quinolinas/farmacologia , Animais , Antimaláricos/administração & dosagem , Antimaláricos/efeitos adversos , Antimaláricos/farmacocinética , Descoberta de Drogas , Feminino , Estágios do Ciclo de Vida/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/parasitologia , Malária/tratamento farmacológico , Masculino , Modelos Moleculares , Fator 2 de Elongação de Peptídeos/antagonistas & inibidores , Fator 2 de Elongação de Peptídeos/metabolismo , Plasmodium/genética , Plasmodium/crescimento & desenvolvimento , Plasmodium berghei/efeitos dos fármacos , Plasmodium berghei/fisiologia , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/metabolismo , Plasmodium vivax/efeitos dos fármacos , Plasmodium vivax/metabolismo , Quinolinas/administração & dosagem , Quinolinas/química , Quinolinas/farmacocinéticaRESUMO
Emerging resistance to first-line antimalarial combination therapies threatens malaria treatment and the global elimination campaign. Improved therapeutic strategies are required to protect existing drugs and enhance treatment efficacy. We report that the piperazine-containing compound ACT-451840 exhibits single-digit nanomolar inhibition of the Plasmodium falciparum asexual blood stages and transmissible gametocyte forms. Genome sequence analyses of in vitro-derived ACT-451840-resistant parasites revealed single nucleotide polymorphisms in pfmdr1, which encodes a digestive vacuole membrane-bound ATP-binding cassette transporter known to alter P. falciparum susceptibility to multiple first-line antimalarials. CRISPR-Cas9 based gene editing confirmed that PfMDR1 point mutations mediated ACT-451840 resistance. Resistant parasites demonstrated increased susceptibility to the clinical drugs lumefantrine, mefloquine, quinine and amodiaquine. Stage V gametocytes harboring Cas9-introduced pfmdr1 mutations also acquired ACT-451840 resistance. These findings reveal that PfMDR1 mutations can impart resistance to compounds active against asexual blood stages and mature gametocytes. Exploiting PfMDR1 resistance mechanisms provides new opportunities for developing disease-relieving and transmission-blocking antimalarials.