Authors

T Kalejaiye³; J Munday³; H de Koning⁵; J Siciliano de Araújo¹; M de Nazaré Correia Soeiro¹; L Maes²; R Leurs⁴;  ¹ Instituto Oswaldo Cruz, Brazil;  ² University of Antwerp, Belgium;  ³ University of Glasgow , UK;  ⁴ VU University Amsterdam, Netherlands;  ⁵ Wellcome Trust Centre for Molecular Parasitology,University of Glasgow, UK

Discussion

Chagas disease is primarily a disease of South and Central America, and it is caused by the protozoan parasite Trypanosoma cruzi. The available drugs benznidazole and nifurtimox are only effective against the acute stage of the disease and there are different strains of the parasites that are innately resistant to current treatment. There is therefore need for new, safer, more affordable, easy to administer and effective drugs. In order to avoid cross-resistance with current therapies, these should have a different mode of action from the existing ones. Cyclic nucleotide phosphodiesterases (PDEs) from trypanosomatids appear to be a good target. With success recorded by targeting human PDEs and also PDEs from T. brucei, we aim to target and evaluate the PDEs of T. cruzi as potential drug targets. Since T. cruzi is divided into different groups, we decided to use genomic DNA from two strains of T. cruzi (Colombiana and Y strain) that differ in their sensitivity to available chemotherapy and geographical locations. Cloning of the PDE genes from the two strains has been completed and we have started complementation assays to evaluate whether TcrPDEB1 and B2 can complement for the activity of TbrPDEB1/2. This work is part of the PDE4NPD (PhosphoDiEsterases for Neglected Parasitic Diseases) consortium. This consortium pursues target repurposing of phosphodiesterase inhibitors to shorten new drug discovery times for neglected parasitic diseases. Therefore, we rely on this consortium for genetic materials and compounds to be tested on our constructs. We intend to build on success stories from human PDE inhibitors (Maurice et al., 2014) and also from validation of T. brucei PDEs as drug targets (De Koning et al., 2012) for the evaluation and characterization of TcrPDEs as drug targets and the development of TcrPDE inhibitors. There is sufficient knowledge of the structure of this enzyme family and this can be exploited to design highly efficient parasite-specific PDE inhibitors.
Reference de Koning H. P., Gould, M. K., Sterk, G. J., Tenor, H., Kunz, S., Luginbuehl, E., et. al. (2012). Pharmacological validation of Trypanosoma brucei phosphodiesterases as novel drug targets. J. Infect. Dis. 206:229&hypen;237.
Maurice, D.H., Ke, H., Ahmad, F., Wang, Y., Chung, J., and Manganiello, V.C. (2014). Advances in targeting cyclic nucleotide phosphodiesterases. Nat Rev Drug Discov 13, 290- 314.