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
Model studies for the syntheses of phosphonate analogs of sphingomyelin and ceramide 1-phosphate are described. The pentacovalent oxaphospholene 3b (derived from methyl vinyl ketone and triethyl phosphite) readily condensed with dialkyl azodicarboxylates (R = Et, t-Bu, CH(2)CCl(3)) to form beta-hydrazido gamma-ketophosphonates 5 and 8 in excellent yields. Cleavage of the N-N bond in 5a (R = Et) or 5b (R = t-Bu) via standard methods was unsuccessful. Upon reduction with NaBH(4), 8 produced the oxazolidinone 9 (93%) as a diastereomeric mixture of 3:1. Treatment of 9 with Zn/HOAc/acetone at rt readily cleaved the N-N bond to form 11 (78-83%). Confirmation of stereochemical assignments in 11 (3:1, trans:cis) was accomplished via NOE experiments.