title: Discovery of a Carbazole-Derived Lead Drug for Human African Trypanosomiasis.
abstract: The protozoan parasite Trypanosoma brucei causes the fatal illness human African trypanosomiasis (HAT). Standard of care medications currently used to treat HAT have severe limitations, and there is a need to find new chemical entities that are active against infections of T. brucei. Following a "drug repurposing" approach, we tested anti-trypanosomal effects of carbazole-derived compounds called "Curaxins". In vitro screening of 26 compounds revealed 22 with nanomolar potency against axenically cultured bloodstream trypanosomes. In a murine model of HAT, oral administration of compound 1 cured the disease. These studies established 1 as a lead for development of drugs against HAT. Pharmacological time-course studies revealed the primary effect of 1 to be concurrent inhibition of mitosis coupled with aberrant licensing of S-phase entry. Consequently, polyploid trypanosomes containing 8C equivalent of DNA per nucleus and three or four kinetoplasts were produced. These effects of 1 on the trypanosome are reminiscent of "mitotic slippage" or endoreplication observed in some other eukaryotes.
authors: Department of Cellular Biology, Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, Georgia 30602, USA.
authors: Sarah M
authors: SM
authors: Thomas
authors: Cleveland BioLabs, Inc., Buffalo, New York 14203, USA.
authors: Andrei
authors: A
authors: Purmal
authors: Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, USA.
authors: Michael
authors: M
authors: Pollastri
authors: Department of Cellular Biology, Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, Georgia 30602, USA.
authors: Kojo
authors: K
authors: Mensa-Wilmot
mesh_terms: D002227:Carbazoles / Q000737:chemistry / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000378:metabolism*; D014353:Trypanosomiasis, African / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D002227:Carbazoles; D014344:Trypanocidal Agents; C041514:carbazole