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Discovery of an ergosterol-signaling factor that regulates Trypanosoma brucei growth.

Haubrich, Brad A; Singha, Ujjal K; Miller, Matthew B; Nes, Craigen R; Anyatonwu, Hosanna; Lecordier, Laurence; Patkar, Presheet; Leaver, David J; Villalta, Fernando; Vanhollebeke, Benoit; Chaudhuri, Minu; Nes, W David.
J Lipid Res; 56(2): 331-41, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25424002
Ergosterol biosynthesis and homeostasis in the parasitic protozoan Trypanosoma brucei was analyzed by RNAi silencing and inhibition of sterol C24ß-methyltransferase (TbSMT) and sterol 14α-demethylase [TbSDM (TbCYP51)] to explore the functions of sterols in T. brucei growth. Inhibition of the amount or activity of these enzymes depletes ergosterol from cells at <6 fg/cell for procyclic form (PCF) cells or <0.01 fg/cell for bloodstream form (BSF) cells and reduces infectivity in a mouse model of infection. Silencing of TbSMT expression by RNAi in PCF or BSF in combination with 25-azalanosterol (AZA) inhibited parasite growth and this inhibition was restored completely by adding synergistic cholesterol (7.8 µM from lipid-depleted media) with small amounts of ergosterol (1.2 µM) to the medium. These observations are consistent with the proposed requirement for ergosterol as a signaling factor to spark cell proliferation while imported cholesterol or the endogenously formed cholesta-5,7,24-trienol act as bulk membrane components. To test the potential chemotherapeutic importance of disrupting ergosterol biosynthesis using pairs of mechanism-based inhibitors that block two enzymes in the post-squalene segment, parasites were treated with AZA and itraconazole at 1 µM each (ED50 values) resulting in parasite death. Taken together, our results demonstrate that the ergosterol pathway is a prime drug target for intervention in T. brucei infection.
Selo DaSilva