Abstract
Poly(ADP-ribosylation) is a post-translational covalent modification of proteins catalyzed by a family of enzymes termed poly(ADP-ribose) polymerases (PARPs). In the human genome, 17 different genes have been identified that encode members of the PARP superfamily. Poly (ADP-ribose) metabolism plays a role in a wide range of biological processes. In Trypanosoma cruzi, PARP enzyme appears to play a role in DNA repair mechanisms and may also be involved in controlling the different phases of cell growth. Here we describe the identification of potent inhibitors for T. cruzi PARP with a fluorescence-based activity assay. The inhibitors were also tested on T. cruzi epimastigotes, showing that they reduced ADP-ribose polymer formation in vivo. Notably, the identified inhibitors are able to reduce the growth rate of T. cruzi epimastigotes. The best inhibitor, Olaparib, is effective at nanomolar concentrations, making it an efficient chemical tool for chacterization of ADP-ribose metabolism in T. cruzi. PARP inhibition also decreases drastically the amount of amastigotes but interestingly has no effect on the amount of trypomastigotes in the cell culture. Knocking down human PARP-1 decreases both the amount of amastigotes and trypomastigotes in cell culture, indicating that the effect would be mainly due to inhibition of human PARP-1. The result suggests that the inhibition of PARP could be a potential way to interfere with T. cruzi infection.
Highlights
The protozoan pathogen Trypanosoma cruzi is the causative agent of American Trypanosomosis or Chagas’ disease, with over 15 million people infected only in Latin America and 12,500 deaths reported each year [1]
In an effort to characterize the metabolism of T. cruzi, we found out that the protozoan parasite has an enzyme displaying similarities to human poly(ADP-ribose) polymerases (PARPs) recently renamed as diptheria toxin like ADP-ribose transferases (ARTDs) (EC 2.4.2.30) [3]
The critical role played by human PARP-1 in DNA damage signaling and repair is its most extensively studied function. hPARP-1 has received a lot of interest as a therapeutic target in the pharmaceutical industry after the discovery that the growth of transformed cancer cells deficient in BRCA1/2 can be inhibited by hPARP-1 inhibitors alone [5]
Summary
The protozoan pathogen Trypanosoma cruzi (family Trypanosomatidae, order Kinetoplastida) is the causative agent of American Trypanosomosis or Chagas’ disease, with over 15 million people infected only in Latin America and 12,500 deaths reported each year [1]. Several proteins contain the characteristic PARP domain in higher eukaryotes and currently 17 members are included in the human PARP superfamily These PARP enzymes are involved in diverse cellular processes such as signaling mechanisms in DNA damage, chromatin modification, transcription, cell death pathways, and mitosis [4]. HPARP-1 has received a lot of interest as a therapeutic target in the pharmaceutical industry after the discovery that the growth of transformed cancer cells deficient in BRCA1/2 can be inhibited by hPARP-1 inhibitors alone [5] This has accelerated the development of inhibitors and compounds from several companies have entered clinical trials in the past few years [6]
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