RESUMEN
Toxoplasmosis is a disease of prominent health concern that is caused by the protozoan parasite Toxoplasma gondii. Proliferation of T. gondii is dependent on its ability to invade host cells, which is mediated in part by calcium-dependent protein kinase 1 (CDPK1). We have developed ATP competitive inhibitors of TgCDPK1 that block invasion of parasites into host cells, preventing their proliferation. The presence of a unique glycine gatekeeper residue in TgCDPK1 permits selective inhibition of the parasite enzyme over human kinases. These potent TgCDPK1 inhibitors do not inhibit the growth of human cell lines and represent promising candidates as toxoplasmosis therapeutics.
Asunto(s)
Coccidiostáticos/síntesis química , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Quinasas/metabolismo , Proteínas Protozoarias/antagonistas & inhibidores , Pirazoles/síntesis química , Pirimidinas/síntesis química , Toxoplasma/efectos de los fármacos , Línea Celular , Proliferación Celular/efectos de los fármacos , Coccidiostáticos/química , Coccidiostáticos/farmacología , Cristalografía por Rayos X , Resistencia a Medicamentos , Pruebas de Enzimas , Humanos , Modelos Moleculares , Estructura Molecular , Naftalenos/síntesis química , Naftalenos/química , Naftalenos/farmacología , Piperidinas/síntesis química , Piperidinas/química , Piperidinas/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Protozoarias/metabolismo , Pirazoles/química , Pirazoles/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Relación Estructura-Actividad , Toxoplasma/enzimologíaRESUMEN
Effective control and eradication of malaria will require new tools to prevent transmission. Current antimalarial therapies targeting the asexual stage of Plasmodium do not prevent transmission of circulating gametocytes from infected humans to mosquitoes. Here, we describe a new class of transmission-blocking compounds, bumped kinase inhibitors (BKIs), which inhibit microgametocyte exflagellation. Oocyst formation and sporozoite production, necessary for transmission to mammals, were inhibited in mosquitoes fed on either BKI-1-treated human blood or mice treated with BKI-1. BKIs are hypothesized to act via inhibition of Plasmodium calcium-dependent protein kinase 4 and predicted to have little activity against mammalian kinases. Our data show that BKIs do not inhibit proliferation of mammalian cell lines and are well tolerated in mice. Used in combination with drugs active against asexual stages of Plasmodium, BKIs could prove an important tool for malaria control and eradication.