DIFFERENT STRAINS OF Trypanosoma cruzi PRESENT DISTINCT SUSCEPTIBILITIES TO POSACONAZOLE DERIVED DRUGS

VANRELL MC, CASASSA AF , HARGROVE TY , LEPESHEVA GI , ROMANO PS

Mendoza

Congreso; XLVIII Reunión Anual de la Sociedad Argentina de Investigación Bioquímica y Biología Molecular; 2012

Sociedad Argentina de Investigacion en Bioquimica y Biologia Molecular

The use of anti-fungal azoles, which block sterol biosynthesis, against protozoan parasites has turned out to be highly successful. Inhibitors of the trypanosome sterol 14a-demethylase (CYP51) are promising candidates as anti-Chagas disease drugs. In this work we have tested VNI, a compound identified as a potent 14ademethylase inhibitor (Lepesheva , 2010). Our results, analyzing epimastigote and intracellular amastigote growth in Y strain, show that 500 nM and 1 μM VNI affects parasite replication reducing the values around 50 % respects to controls. Trypomastigotes are also affected since a significant reduction in the percentage of infected cells obtained after VNI treatment. Although these results show an important effect of VNI, similar experiments conducted in other strains revealed a stronger action of this compound. To analyze the origin of these differences, CYP51 gene fromYstrain was cloned and sequenced. Interestingly, in contrast with CYP51s from CL Brener and Tulahuen strains, Y strain has two CYP51 genes (A and B). Chemical and structural differences in these genes could explain the higher resistance of this strain to VNI. This study will serve as the basis to design new, more potent compounds, which we will test in strains and in animal models.