RESUMEN
Malaria caused by Plasmodium falciparum is a disease that is responsible for 880,000 deaths per year worldwide. Vaccine development has proved difficult and resistance has emerged for most antimalarial drugs. To discover new antimalarial chemotypes, we have used a phenotypic forward chemical genetic approach to assay 309,474 chemicals. Here we disclose structures and biological activity of the entire library-many of which showed potent in vitro activity against drug-resistant P. falciparum strains-and detailed profiling of 172 representative candidates. A reverse chemical genetic study identified 19 new inhibitors of 4 validated drug targets and 15 novel binders among 61 malarial proteins. Phylochemogenetic profiling in several organisms revealed similarities between Toxoplasma gondii and mammalian cell lines and dissimilarities between P. falciparum and related protozoans. One exemplar compound displayed efficacy in a murine model. Our findings provide the scientific community with new starting points for malaria drug discovery.
Asunto(s)
Antimaláricos/análisis , Antimaláricos/farmacología , Descubrimiento de Drogas , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/genética , Animales , Antimaláricos/aislamiento & purificación , Línea Celular , Evaluación Preclínica de Medicamentos , Resistencia a Medicamentos/efectos de los fármacos , Quimioterapia Combinada , Eritrocitos/efectos de los fármacos , Eritrocitos/parasitología , Humanos , Malaria Falciparum/tratamiento farmacológico , Malaria Falciparum/parasitología , Ratones , Fenotipo , Filogenia , Plasmodium falciparum/metabolismo , Reproducibilidad de los Resultados , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacologíaRESUMEN
The Medicines for Malaria Venture (MMV) is committed to discovering, developing and delivering new drugs for malaria. Founded in 1999 as a nonprofit organization bringing private sector management methods to bear on a global public health problem, MMV is today recognized as a leader among the public-private partnerships working on diseases for the developing world. Together with its many partners, MMV manages the world's largest malaria research and development portfolio, covering the innovation spectrum from basic drug discovery to late-stage development.