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Chemical evaluation of fatty acid desaturases as drug targets in Trypanosoma cruzi.
MedLine Citation:
PMID:  19249306     Owner:  NLM     Status:  In-Process    
Four positional isomers of Thiastearate (TS) and Isoxyl (Thiocarlide) were assayed as fatty acid desaturase inhibitors in Trypanosoma cruzi epimastigotes. 9-TS did not exert a significant effect on growth of T. cruzi, nor on the fatty acid profile of the parasite cells. One hundred micromolars of 10-TS totally inhibited growth, with an effective concentration for 50% growth inhibition (EC(50)) of 3.0+/-0.2microM. Growth inhibition was reverted by supplementing the culture media with oleate. The fatty acid profile of treated cells revealed that conversion of stearate to oleate and palmitate to palmitoleate were drastically reduced and, as a consequence, the total level of unsaturated fatty acids decreased from 60% to 32%. Isoxyl, a known inhibitor of stearoyl-CoA Delta9 desaturase in mycobacteria, had similar effects on T. cruzi growth (EC(50) 2.0+/-0.3microM) and fatty acid content, indicating that Delta9 desaturase was the target of both drugs. 12- and 13-TS were inhibitors of growth with EC(50) values of 50+/-2 and 10+/-3microM, respectively, but oleate or linoleate were unable to revert the effect. Both drugs increased the percentage of oleate and palmitate in the cell membrane and drastically reduced the content of linoleate from 38% to 16% and 12%, respectively, which is in agreement with a specific inhibition of oleate Delta12 desaturase. The absence of corresponding enzyme activity in mammalian cells and the significant structural differences between trypanosome and mammalian Delta9 desaturases, together with our results, highlight these enzymes as promising targets for selective chemotherapeutic intervention.
Andrés Alloatti; Sebastián A Testero; Antonio D Uttaro
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-02-26
Journal Detail:
Title:  International journal for parasitology     Volume:  39     ISSN:  1879-0135     ISO Abbreviation:  Int. J. Parasitol.     Publication Date:  2009 Jul 
Date Detail:
Created Date:  2009-06-03     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0314024     Medline TA:  Int J Parasitol     Country:  England    
Other Details:
Languages:  eng     Pagination:  985-93     Citation Subset:  IM    
Instituto de Biología Molecular y Celular de Rosario (IBR), CONICET, Departamento de Microbiología, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Santa Fe, Argentina.
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