Trypanosoma brucei: Effects of methoprene and other isoprenoid compounds on procyclic and bloodstream forms in vitro and in mice

Drug therapy for the treatment of African sleeping sickness is limited by toxicity and resistance and in the last 50 years only one new drug has been introduced for the treatment of the human disease. We report that the juvenile hormane analog, methoprene, and several structurally related isoprenoid compounds kill Trypanosoma brucei in culture. Of the other isoprenoids tested, juvenile hormone m and mammalian retinoid X receptor ligands were the most potent trypanocides. Both the procyclic forms and the bloodstream trypomastigotes are killed by these compounds with LD₅₀ values of 5-30 μM. Of the two methoprene stereoisomers, the EE form was the most active, suggesting that a protein target may he involved in mediating effects of these analogues against the parasite. Methoprene was not, however, able to clear trypanosomes from the blood of infected mice. Methoprene acid, the immediate downstream metabolite of methoprene, is not an effective anti-trypanosomal agent, suggesting that in the mice methoprene is converted to an inactive compound. Since methoprene and its analogues have low and well characterized toxicity in mammals these studies stress the importance of further exploring these isoprenoids as lead compounds for the treatment of African sleeping sickness.