title: Discovery of trypanocidal compounds by whole cell HTS of Trypanosoma brucei.
abstract: Chemotherapy against human African trypanosomiasis relies on four drugs that cause frequent and occasionally severe side-effects. Because human African trypanosomiasis is a disease of poor people in Africa, the traditional market-driven pathways to drug development are not available. One potentially rapid and cost-effective approach to identifying and developing new trypanocidal drugs would be high throughput-screening of existing drugs already approved for other uses, as well as clinical candidates in late development. We have developed an ATP-bioluminescence assay that could be used to rapidly and efficiently screen compound libraries against trypanosomes in a high throughput-screening format to validate this notion. We screened a collection of 2160 FDA-approved drugs, bioactive compounds and natural products to identify hits that were cytotoxic to cultured Trypanosoma brucei at a concentration of 1 mum or less. This meant that any hit identified would be effective at a concentration readily achievable by standard drug dosing in humans. From the screen, 35 hits from seven different drug categories were identified. These included the two approved trypanocidal drugs, suramin and pentamidine, several other drugs suspected but never validated as trypanocidal, and 17 novel trypanocidal drugs.
authors.affiliation: Department of Pathology and the Sandler Center for Basic Research in Parasitic Diseases, University of California, QB3 1700 4th St, San Francisco, CA 94158, USA.
authors.forename: Zachary B
authors.initials: ZB
authors.lastname: Mackey
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Baca
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Mallari
authors.forename: Beth
authors.initials: B
authors.lastname: Apsel
authors.forename: Anang
authors.initials: A
authors.lastname: Shelat
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Hansell
authors.forename: Peter K
authors.initials: PK
authors.lastname: Chiang
authors.forename: Brian
authors.initials: B
authors.lastname: Wolff
authors.forename: Kiplin R
authors.initials: KR
authors.lastname: Guy
authors.forename: Janice
authors.initials: J
authors.lastname: Williams
authors.forename: James H
authors.initials: JH
authors.lastname: McKerrow
mesh_terms: D000818:Animals; D003978:Diazomethane / Q000031:analogs & derivatives; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D008163:Luminescent Measurements / Q000379:methods; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests / Q000379:methods*; D014344:Trypanocidal Agents / Q000737:chemistry / Q000191:economics / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000378:metabolism
chemical_list: D014344:Trypanocidal Agents; C024918:benzyloxycarbonylphenylalanylalanine diazomethyl ketone; D003978:Diazomethane