INHIBITION OF POLY(ADP-RIBOSE) POLYMERASE INTERFERES WITH Trypanosoma cruzi INFECTION AND PROLIFERATION

VILCHEZ LARREA S C; SCHLESINGER M; KEVORKIAN L; FLAWIA M M; FERNANDEZ VILLAMIL SH

Mendoza

Congreso; 48th Annual Meeting Argentine Society for Biochemistry and Molecular Biology; 2012

Sociedad Argentina de Investigacion en Bioquimica y Biologia Molecular

Poly(ADP-ribosylation) is a covalent modification of proteins catalyzed by poly(ADP-ribose) polymerases (PARPs). Poly (ADPribose) (PAR) metabolism plays a role in a wide range of biological processes such as DNA damage repair, chromatin modification, transcription and cell death. In humans, 17 different genes have been identified that encode members of the PARP superfamily, in contrast, there is only one PARPpresent in (TcPARP). PARP enzyme appears to play a role in DNA repair mechanisms and may also be involved in controlling the differentphases of cell growth. Here we describe the identification of potent inhibitors for PARP with a fluorescence-based activity assay. The inhibitors were also tested on epimastigotes,showing that they reduced PAR formation in vivo. The best inhibitor, Olaparib, reduced growth rate by 50% at 25 nanomolar. PARP inhibition also decreases drastically the amount ofintracellular amastigotes (the replicative form of the parasite). Knocking down human PARP-1 decreases both the amount of amastigotes and trypomastigotes in cell culture, indicating that theeffect would be mainly due to inhibition of human PARP-1. The result suggests that the inhibition of PARPcould be a potential way to interfere with infection.