{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Thomas SM"],"funding":["NIAID NIH HHS"],"pagination":["32083"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC5000474"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["6"],"pubmed_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."],"journal":["Scientific reports"],"pubmed_title":["Discovery of a Carbazole-Derived Lead Drug for Human African Trypanosomiasis."],"pmcid":["PMC5000474"],"funding_grant_id":["R21 AI098998"],"pubmed_authors":["Purmal A","Mensa-Wilmot K","Thomas SM","Pollastri M"],"additional_accession":[]},"is_claimable":false,"name":"Discovery of a Carbazole-Derived Lead Drug for Human African Trypanosomiasis.","description":"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.","dates":{"release":"2016-01-01T00:00:00Z","publication":"2016 Aug","modification":"2025-04-04T11:55:38.796Z","creation":"2019-03-27T02:22:45Z"},"accession":"S-EPMC5000474","cross_references":{"pubmed":["27561392"],"doi":["10.1038/srep32083"]}}