High-throughput screening affords novel and selective trypanothione reductase inhibitors with anti-trypanosomal activity.
Trypanothione reductase (TR), an enzyme that buffers oxidative stress in trypanosomatid parasites, was screened against commercial libraries containing approximately 134,500 compounds. After secondary screening, four chemotypes were identified as screening positives with selectivity for TR over human glutathione reductase. Thirteen compounds from these four chemotypes were purchased, and their in vitro activity against TR and Trypanosoma brucei is described.
Martyn
Derek C
DC
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
Jones
Deuan C
DC
Fairlamb
Alan H
AH
Clardy
Jon
J
D000818:Animals; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004791:Enzyme Inhibitors; D005980:Glutathione Reductase; D006801:Humans; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000737:chemistry*; D014345:Trypanosoma / Q000187:drug effects / Q000201:enzymology; D014346:Trypanosoma brucei brucei / Q000187:drug effects*
D004791:Enzyme Inhibitors; D014344:Trypanocidal Agents; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase; D005980:Glutathione Reductase