RESUMO
The emergence of drug resistance is a major limitation of current antimalarials. The discovery of new druggable targets and pathways including those that are critical for multiple life cycle stages of the malaria parasite is a major goal for developing next-generation antimalarial drugs. Using an integrated chemogenomics approach that combined drug resistance selection, whole-genome sequencing, and an orthogonal yeast model, we demonstrate that the cytoplasmic prolyl-tRNA (transfer RNA) synthetase (PfcPRS) of the malaria parasite Plasmodium falciparum is a biochemical and functional target of febrifugine and its synthetic derivative halofuginone. Febrifugine is the active principle of a traditional Chinese herbal remedy for malaria. We show that treatment with febrifugine derivatives activated the amino acid starvation response in both P. falciparum and a transgenic yeast strain expressing PfcPRS. We further demonstrate in the Plasmodium berghei mouse model of malaria that halofuginol, a new halofuginone analog that we developed, is active against both liver and asexual blood stages of the malaria parasite. Halofuginol, unlike halofuginone and febrifugine, is well tolerated at efficacious doses and represents a promising lead for the development of dual-stage next-generation antimalarials.
Assuntos
Aminoacil-tRNA Sintetases/antagonistas & inibidores , Antimaláricos/farmacologia , Inibidores Enzimáticos/farmacologia , Malária Falciparum/tratamento farmacológico , Piperidinas/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Proteínas de Protozoários/antagonistas & inibidores , Quinazolinas/farmacologia , Quinazolinonas/farmacologia , Aminoacil-tRNA Sintetases/metabolismo , Animais , Antimaláricos/química , Antimaláricos/toxicidade , Desenho Assistido por Computador , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Desenho de Fármacos , Resistência a Medicamentos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/toxicidade , Eritrócitos/parasitologia , Fígado/parasitologia , Malária Falciparum/sangue , Malária Falciparum/parasitologia , Camundongos , Modelos Moleculares , Estrutura Molecular , Terapia de Alvo Molecular , Piperidinas/química , Piperidinas/toxicidade , Plasmodium falciparum/enzimologia , Proteínas de Protozoários/metabolismo , Quinazolinas/química , Quinazolinas/toxicidade , Quinazolinonas/química , Quinazolinonas/toxicidade , Relação Estrutura-Atividade , Fatores de TempoRESUMO
Most malaria drug development focuses on parasite stages detected in red blood cells, even though, to achieve eradication, next-generation drugs active against both erythrocytic and exo-erythrocytic forms would be preferable. We applied a multifactorial approach to a set of >4000 commercially available compounds with previously demonstrated blood-stage activity (median inhibitory concentration < 1 micromolar) and identified chemical scaffolds with potent activity against both forms. From this screen, we identified an imidazolopiperazine scaffold series that was highly enriched among compounds active against Plasmodium liver stages. The orally bioavailable lead imidazolopiperazine confers complete causal prophylactic protection (15 milligrams/kilogram) in rodent models of malaria and shows potent in vivo blood-stage therapeutic activity. The open-source chemical tools resulting from our effort provide starting points for future drug discovery programs, as well as opportunities for researchers to investigate the biology of exo-erythrocytic forms.