Glucose-6-phosphate dehydrogenase is the target for the trypanocidal action of human steroids

Steroids such as dehydroepiandrosterone (DHEA) and epiandrosterone (EA) exert multiple effects in mammals including the inhibition of glucose-6-phosphate dehydrogenase (G6PDH). Initially, the inhibition was considered specific for the mammalian enzyme. The beneficial effect of these steroids on infections by protists and nematodes was attributed to stimulation of the immune system. However, we showed previously that DHEA and EA also inhibit Trypanosoma brucei and T. cruzi G6PDH, with low micromolar Ki’ values, but not the enzyme from Leishmania species, and kill in vitro cultured trypanosomes. We report here that, contrary to wild-type trypanosomes, mutant bloodstream-form T. brucei cells expressing L. mexicana G6PDH are not susceptible to the steroids, proving that G6PDH is the in situ target. Moreover, bromo-derivatives of the steroids show 50–100 fold lower Ki’ values for the enzyme and display an increased potency to kill the parasites. Therefore, the compounds offer promise for use in development of parasite-selective drugs.

Figure optionsDownload high-quality image (141 K)Download as PowerPoint slideResearch highlights▶ Glucose-6-phosphate dehydrogenase (G6PDH) is a validated drug target of T. brucei. ▶ The human steroids DHEA and EA inhibit Trypanosoma but not Leishmania G6PDH. ▶ DHEA and EA bromidation increases the Ki for T. brucei G6PDH inhibition 50–100 fold. ▶ The steroids kill cultured bloodstream-form T. brucei, not Leishmania promastigotes. ▶ Expression of L. mexicana G6PDH rescues T. brucei from killing by DHEA and EA.