Discussion

Cyclic nucleotide phosphodiesterases (PDEs) have emerged as attractive molecular targets for a novel treatment for a variety of Neglected Parasitic diseases, including African trypanosomiasis, Chagas disease, and malaria. For example, both genetic knock-down and chemical inhibition of PDE activity resulted in halted proliferation and eventually elimination of Trypanosoma brucei (Tbr), the causative agent of African sleeping sickness. The vast knowledge and generated expertise within the field of human PDEs provides a shortcut to high-affinity inhibitors of parasitic PDEs. We have brought together a public-private consortium with PDE experts, medicinal chemists and parasitologists to effectively target parasitic PDEs. In this presentation we will show our progress in developing effective approaches to combat parasitic diseases by both a phenotypic and target-based approach, with a focus on the development of parasite-selective inhibitors agains TbrPDEB1 and TbrPDEB2. X-ray cocrystal studies have enabled the identification of parasite-specific features that can be targeted to obtain parasite-selective PDE inhibitors. Altogether, this has allowed in fast optimization of hit compounds and generated TbrPDE inhibitors with trypanocidal activity. Moreover, we will also show our approach towards the development of therapeutics against T. cruzi, Leishmania and S.mansoni.
The PDE4NPD project is supported by the European Union 7th Framework Program (FP7/2007-2013) under grant agreement n° 602666 and involves ten consortium members and research labs in seven countries (www.PDE4NPD.eu).