Proteasome inhibition for treatment of leishmaniasis, Chagas disease and sleeping sickness

Abstract

Chagas disease, leishmaniasis, and sleeping sickness affect 20 million people worldwide and lead to more than 50,000 deaths annually1. 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 drug(s) modulating the activity of a conserved parasite target2. 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.

Optimization of physicochemical properties for 4-anilinoquinazoline inhibitors of trypanosome proliferation

“…Interestingly, other researchers have also denoted the ability of oxazole compounds to show activity against related kinetoplastids T. brucei, T. cruzi , and leishmaniasis [35]. Nearly all of the linker replacements showed activity towards P. falciparum D6 with the pyrimidines 17 and 18 (EC 50 = 0.93 and 0.069 μM, respectively), amide 21 (0.53 μM), and 1,2,4-triazole 26 (0.21 μM) being the most potent analogs from all the compounds screened against P. falciparum D6.…”

Chagas disease research and development: Is there light at the end of the tunnel?

“…Efforts are being made to, on the one hand, standardize assays, models and screening cascades across the different investigators in the field, while on the other hand identifying and validating novel targets using new tools such as Bioluminescence Imaging (BLI), whole genome sequencing, and -omics. Knowing the target of a potential drug candidate issued from phenotypic screening could allow for better study design in vivo with a particular treatment regimen but also improved access to new chemical entities through target-based screens [64], [65]. Altogether, these new developments should lead to new potential candidates to move forward into clinical trials.…”

Drug candidate and target for leishmaniasis

“…A study 10 in 2016 identified the triazolopyrimidine molecule GNF6702 as having potent activity against Leishmania. It acts by inhibiting the cell's proteasomal protein-degradation machinery.…”