Structure-based design of drugs against human pathogenic parasites of the order Trypanosomatida

• Applicant: Professor Dr. Conrad Kunick
• Subject Area: Pharmacy
• Term: from 2017 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 393709342

Unicellular Trypanosoma and Leishmania parasites cause severe infectious diseases which are designated as Neglegted Tropical Diseases by the WHO. The available medicines for treatment of these infections are limited by number and are burdened with several drawbacks. New drugs against the parasites are urgently needed. To keep the risk of cross resistance with established drugs as low as possible, the new antiinfectives should interact with biological targets which are not yet addressed.Trypanothione synthetase (TryS) is an enzyme selectively present in parasites, but not in the host cells. Neither of the established drugs addresses this biological target. Recently TryS was validated as druggable target of the parasite Leishmania infantum. N(5)-Substituted members of the paullone class were identified both as inhibitors of TryS and of proliferation of the Trypanosoma and Leishmania parasites. However, these compounds are scarcely feasible as drugs due to technological and physicochemical issues. In particular, low water solubility and insufficient bioavailability make paullones poor starting points for drug development.Based on the insights from previous work on paullones, Part A of the project aims at designing and synthesizing structurally novel, paullone-unrelated TryS inhibitors with improved technological properties. In the course of preliminary studies, antitrypanosomal paullones were identified which presumably are not targeting TryS but other intracellular structures in the parasites. Such alternative biological targets are very useful for the discovery of new antitrypanosomal agents with novel modes of action.Part B of the project is therefore directed to identify hitherto undiscovered target structures in Trypanosomatida. For this purpose, N(5)-substituted paullones for immobilization on solid supports will be synthesized and used for pull-down experiments. Furthermore, fluorophores will be coupled to N(5)-substituted paullones. The resulting compounds will be used as reagents for studies of localization and intracellular trafficking of novel target structures.

• DFG Programme: Research Grants