RESUMEN
Chagas disease, leishmaniasis and sleeping sickness affect 20 million people worldwide and lead to more than 50,000 deaths annually. The diseases are caused by infection with the kinetoplastid parasites Trypanosoma cruzi, Leishmania spp. and Trypanosoma brucei spp., respectively. These parasites have similar biology and genomic sequence, suggesting that all three diseases could be cured with drugs that modulate the activity of a conserved parasite target. However, no such molecular targets or broad spectrum drugs have been identified to date. Here we describe a selective inhibitor of the kinetoplastid proteasome (GNF6702) with unprecedented in vivo efficacy, which cleared parasites from mice in all three models of infection. GNF6702 inhibits the kinetoplastid proteasome through a non-competitive mechanism, does not inhibit the mammalian proteasome or growth of mammalian cells, and is well-tolerated in mice. Our data provide genetic and chemical validation of the parasite proteasome as a promising therapeutic target for treatment of kinetoplastid infections, and underscore the possibility of developing a single class of drugs for these neglected diseases.
Asunto(s)
Enfermedad de Chagas/tratamiento farmacológico , Kinetoplastida/efectos de los fármacos , Kinetoplastida/enzimología , Leishmaniasis/tratamiento farmacológico , Complejo de la Endopetidasa Proteasomal/efectos de los fármacos , Inhibidores de Proteasoma/farmacología , Inhibidores de Proteasoma/uso terapéutico , Pirimidinas/farmacología , Triazoles/farmacología , Tripanosomiasis Africana/tratamiento farmacológico , Animales , Enfermedad de Chagas/parasitología , Quimotripsina/antagonistas & inhibidores , Quimotripsina/metabolismo , Modelos Animales de Enfermedad , Femenino , Humanos , Concentración 50 Inhibidora , Leishmaniasis/parasitología , Ratones , Estructura Molecular , Terapia Molecular Dirigida , Inhibidores de Proteasoma/efectos adversos , Inhibidores de Proteasoma/clasificación , Pirimidinas/efectos adversos , Pirimidinas/química , Pirimidinas/uso terapéutico , Especificidad de la Especie , Triazoles/efectos adversos , Triazoles/química , Triazoles/uso terapéutico , Tripanosomiasis Africana/parasitologíaRESUMEN
Visceral leishmaniasis is responsible for up to 30,000 deaths every year. Current treatments have shortcomings that include toxicity and variable efficacy across endemic regions. Previously, we reported the discovery of GNF6702, a selective inhibitor of the kinetoplastid proteasome, which cleared parasites in murine models of leishmaniasis, Chagas disease, and human African trypanosomiasis. Here, we describe the discovery and characterization of LXE408, a structurally related kinetoplastid-selective proteasome inhibitor currently in Phase 1 human clinical trials. Furthermore, we present high-resolution cryo-EM structures of the Leishmania tarentolae proteasome in complex with LXE408, which provides a compelling explanation for the noncompetitive mode of binding of this novel class of inhibitors of the kinetoplastid proteasome.