Science 355, 1416–1420 (2017)

Trypanosomes cause substantial disease in both humans and livestock, yet the few treatments available are frequently toxic or not curative. Dawidowski et al. sought to identify new drugs that kill these parasites by inhibiting transport of trypanosomal enzymes into glycosomes, essential organelles required for glucose metabolism in the parasite. The interaction of the N termini of trypanosomal peroxins PEX5 and PEX14 is required for both glycosome biogenesis and import of glycolytic enzymes from the parasite cytoplasm, and silencing PEX14 has been shown to be lethal to Trypanosoma brucei. The researchers solved the NMR structure of the PEX14 N terminus to screen in silico for pharmacophores that mimicked its interaction with the WxxxF peptide motif of PEX5. Optimization of one of the hits containing a pyrazolo-[4,3-c]pyridine scaffold led to compounds with two aromatic ring systems that are shown to bind PEX14 through hydrophobic interactions in X-ray structures. The derivatives caused mislocalization of glycosomal enzymes and were toxic against Trypanosoma species in vitro. One of the molecules was twice as potent against Trypanosoma cruzi as benznidazole, which is approved for the treatment of Chagas disease in humans. Another derivative, with improved plasma properties, restricted parasitemia in T. brucei– infected mice without causing adverse side effects, suggesting that inhibitors of PEX5–PEX14 interactions may generate clinical candidates for treating trypanosomiases.