bortezomib and Leishmaniasis--Visceral

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

Topics: Animals; Antiprotozoal Agents; Dogs; Humans; Leishmania donovani; Leishmania major; Leishmaniasis, Visceral; Liver; Macaca fascicularis; Mice; Mice, Inbred BALB C; Oxazoles; Proteasome Inhibitors; Pyrimidines; Rats; Rats, Sprague-Dawley; Triazoles