Authors
M Crispim3; R Girard3; C G Baptista3; P Silva2; A M Silber3; F Emery2; G H Trossini1; C C Avila1;
1 Department of Clinical and Toxicologial Analysis Faculty of Pharmaceutical Sciences - University of São Paulo, São Paulo, SP, Brazil; 2 Faculty of Pharmaceutical Sciences at Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil; 3 Laboratory of Biochemistry of Tryps - LaBTryps - Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil
Discussion
The
therapy against Trypanosoma brucei, presents several limitations in
terms of toxicity, drug administration and efficiency. Sirtuins were proposed
as interesting potential drug targets. We designed and synthetized 46 new
compounds based on known Sirtuin inhibitors and tested against T.
brucei Lister 427 procyclic forms (PCF) proliferation. The Sirtuin Inhibitor
2 (SI-2) exhibited the most promising inhibition and dose-dependent response (EC50 =
0.75 μM). We further
investigated the cell death mechanism triggered by SI-2. A sub-population of these
parasites were labeled by Annexin V but not propidium iodide, suggesting an
apoptotic-like cell death. Moreover, parasites treated with SI-2 showed an
increased production of reactive oxygen species (ROS) and intracellular calcium
levels. Concomitant with this, a mitochondrial depolarization was observed.
Taken together, these results show that SI-2 trigger programmed cell death,
making of SI-2 a promising drug candidate against T. brucei. Further
studies are being conducted to investigate in more detail the effect of SI-2.
