Inhibition of poly(ADP-ribose) polymerase interferes with Trypanosoma cruzi infection

SALOMÉ VILCHEZ LARREA; TEEMU HAIKARAINEN; MOHIT NARWAL; MARIANA SCHLESINGER; HARIKANTH VENKANNAGARI; MIRTHA M. FLAWIÁ; SILVIA H. FERNÁNDEZ VILLAMIL; LARI LEHTIÖ

PLOS ONE

PUBLIC LIBRARY SCIENCE

Lugar: San Francisco; Año: 2012 vol. 7 p. 1 - 9

1932-6203

Poly(ADP-ribosylation) is a post-translational covalent modification of proteinscatalyzed by a family of enzymes termed poly(ADP-ribose) polymerases (PARPs). Inthe human genome, 17 different genes have been identified that encode members ofthe PARP superfamily. Poly (ADP-ribose) metabolism plays a role in a wide range ofbiological processes. In Trypanosoma cruzi, PARP enzyme appears to play a role inDNA repair mechanisms and may also be involved in controlling the different phases ofcell growth. We describe here the identification of potent inhibitors for T. cruzi PARP.The inhibitors were also tested on T. cruzi epimastigotes, showing that they reducedthe ADP-ribose polymer formation in vivo. Notably, the identified inhibitors are able toreduce the growth rate of T. cruzi epimastigotes. The best inhibitor, Olaparib, iseffective at nanomolar concentrations, making it an efficient chemical tool forchacterization of ADP-ribose metabolism in T. cruzi. PARP inhibition also affects theproliferation of amastigotes and reduces the amount of trypomastigotes in the cellculture. The results indicates that this is mainly due to inhibition of human PARP1, butalso suggest that the inhibition of PARP could be potential way to interfere T. cruziinfection.