Potent anti-Trypanosoma cruzi activities of oxidosqualene cyclase inhibitors.
Trypanosoma cruzi is the protozoan agent that causes Chagas' disease, a major health problem in Latin America. Better drugs are needed to treat infected individuals. The sterol biosynthesis pathway is a potentially excellent target for drug therapy against T. cruzi. In this study, we investigated the antitrypanosomal activities of a series of compounds designed to inhibit a key enzyme in sterol biosynthesis, oxidosqualene cyclase. This enzyme converts 2,3-oxidosqualene to the tetracyclic product, lanosterol. The lead compound, N-(4E,8E)-5,9, 13-trimethyl-4,8, 12-tetradecatrien-1-ylpyridinium, is an electron-poor aromatic mimic of a monocyclized transition state or high-energy intermediate formed from oxidosqualene. This compound and 27 related compounds were tested against mammalian-stage T. cruzi, and 12 inhibited growth by 50% at concentrations below 25 nM. The lead compound was shown to cause an accumulation of oxidosqualene and decreased production of lanosterol and ergosterol, consistent with specific inhibition of the oxidosqualene cyclase. The data demonstrate potent anti-T. cruzi activity associated with inhibition of oxidosqualene cyclase.
Buckner
F S
FS
Department of Medicine, University of Washington, Seattle, Washington 98195, USA. fbuckner@u.washington.edu
Griffin
J H
JH
Wilson
A J
AJ
Van Voorhis
W C
WC
D016475:3T3 Cells; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D019751:Intramolecular Transferases / Q000037:antagonists & inhibitors*; D007654:Ketoconazole / Q000494:pharmacology; D051379:Mice; D021261:Parasitic Sensitivity Tests; D013185:Squalene / Q000031:analogs & derivatives / Q000494:pharmacology*; D013261:Sterols / Q000096:biosynthesis; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000201:enzymology
C002821:2,3-oxidosqualene; D000935:Antifungal Agents; D013261:Sterols; D013185:Squalene; D019751:Intramolecular Transferases; C021924:lanosterol synthase; D007654:Ketoconazole