title: Glucose-6-phosphate dehydrogenase is the target for the trypanocidal action of human steroids.
abstract: 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 K(i)' 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 K(i)' 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.
authors.affiliation: Research Unit for Tropical Diseases, de Duve Institute, TROP 74.39, Avenue Hippocrate 74, B-1200 Brussels, Belgium. shree.chemistry@gmail.com
authors.forename: Shreedhara
authors.initials: S
authors.lastname: Gupta
authors.forename: Artur T
authors.initials: AT
authors.lastname: Cordeiro
authors.forename: Paul A M
authors.initials: PA
authors.lastname: Michels
mesh_terms: D000738:Androsterone / Q000494:pharmacology / Q000627:therapeutic use; D002460:Cell Line; D014355:Chagas Disease / Q000188:drug therapy / Q000201:enzymology; D003687:Dehydroepiandrosterone / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005954:Glucosephosphate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007894:Leishmania mexicana / Q000201:enzymology*; D007896:Leishmaniasis / Q000188:drug therapy / Q000201:enzymology / Q000469:parasitology; D030781:Organisms, Genetically Modified; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism*; D013045:Species Specificity; D014344:Trypanocidal Agents / Q000494:pharmacology / Q000627:therapeutic use; D014346:Trypanosoma brucei brucei / Q000166:cytology / Q000201:enzymology; D014349:Trypanosoma cruzi / Q000166:cytology / Q000201:enzymology; D014353:Trypanosomiasis, African / Q000188:drug therapy / Q000201:enzymology
chemical_list: D015800:Protozoan Proteins; D014344:Trypanocidal Agents; D003687:Dehydroepiandrosterone; D000738:Androsterone; D005954:Glucosephosphate Dehydrogenase