Abstract
The pathway for unsaturated fatty acid biosynthesis is essential in trypanosomatid parasites and has been a key target in our work on the discovery and analysis of several inhibitory compounds. Here, we show the effect of novel inhibitors of stearoyl-CoA desaturase (SCD) and oleate desaturase (OD), alone and in combination, on the growth rate of parasite cultures. GS-456332, an inhibitor of human Δ9 desaturase, efficiently inhibited growth of both Trypanosoma cruzi epimastigotes and Trypanosoma brucei bloodstream form cells, with EC50 values of 136.9 ± 24.2 and 9.4 ± 3.1 nM, respectively. This effect was specific for SCD. Stearolic acid (9-octadecynoic acid) was also able to arrest T. cruzi and T. brucei growth by specific inhibition of their OD, with EC50 values of 1.0 ± 0.2 μM and 0.1 ± 0.01 μM, respectively. When these compounds were administered simultaneously, a clearly synergistic effect was observed for both Trypanosoma species, with EC50 values in the low nanomolar range. These results demonstrate the feasibility of using combinations of drugs, inhibiting different enzymes on the same metabolic pathway, for the development of more efficient chemotherapeutic strategies against neglected diseases caused by these parasites.
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Acknowledgments
We wish to thank Dr. Paul A. M. Michels for comments and suggestions on the manuscript and Dr. Roberto Docampo for suggestions on synergy assays. We also wish to thank Bunge y Born Foundation for its support through the Mariano Levin Fellowship. ADU and KEJT are members of the Carrera del Investigador Científico, CONICET, Argentina. AA is a fellow from Bunge y Born Foundation, Argentina.
Funding
This work was supported by FONCyT, through Grant PICT 2007, No. 00654.
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Alloatti, A., Tripodi, K.E.J. & Uttaro, A.D. Synergistic effect of inhibitors of fatty acid desaturases on Trypanosoma parasites. Parasitol Res 112, 3289–3294 (2013). https://doi.org/10.1007/s00436-013-3508-y
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DOI: https://doi.org/10.1007/s00436-013-3508-y