Nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitors as promising new leads for Chagas disease chemotherapy.

Abstract	A century after discovering that the Trypanosoma cruzi parasite is the etiological agent of Chagas disease, treatment is still plagued by limited efficacy, toxicity, and the emergence of drug resistance. The development of inhibitors of the major T. cruzi cysteine protease, cruzain, has been demonstrated to be a promising drug discovery avenue for this neglected disease. Here we establish that a nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitor substantially ameliorates symptoms of acute Chagas disease in a mouse model with no apparent toxicity. A high-resolution crystal structure confirmed the mode of inhibition and revealed key binding interactions of this novel inhibitor class. Subsequent structure-guided optimization then resulted in inhibitor analogues with improvements in potency despite minimal or no additions in molecular weight. Evaluation of the analogues in cell culture showed enhanced activity. These results suggest that nonpeptidic tetrafluorophenoxymethyl ketone cruzain inhibitors have the potential to fulfill the urgent need for improved Chagas disease chemotherapy.
Authors	Katrien Brak, Iain D Kerr, Kimberly T Barrett, Nobuhiro Fuchi, Moumita Debnath, Kenny Ang, Juan C Engel, James H McKerrow, Patricia S Doyle, Linda S Brinen, Jonathan A Ellman
Journal	Journal of medicinal chemistry (J Med Chem) Vol. 53 Issue 4 Pg. 1763-73 (Feb 25 2010) ISSN: 1520-4804 [Electronic] United States
PMID	20088534 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References	Ketones Protozoan Proteins Quinolines Triazoles Trypanocidal Agents Cysteine Endopeptidases cruzain, Trypanosoma cruzi
Topics	Animals Cattle Cells, Cultured Chagas Disease (drug therapy) Cysteine Endopeptidases Female Ketones (chemical synthesis, chemistry, pharmacology) Macrophages (drug effects, parasitology) Mice Mice, Inbred C3H Models, Molecular Parasitic Sensitivity Tests Protozoan Proteins (antagonists & inhibitors) Quinolines (chemical synthesis, chemistry, pharmacology) Stereoisomerism Structure-Activity Relationship Triazoles (chemical synthesis, chemistry, pharmacology) Trypanocidal Agents (chemical synthesis, chemistry, pharmacology) Trypanosoma cruzi (drug effects)

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