FEN INHIBITORS · Development of Kinetoplastida Flap Endonuclease Inhibitors in Search for Novel Therapeutics
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2020-02-01 → 2023-01-31
- EU contribution
- €319,401
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Development of Kinetoplastida Flap Endonuclease Inhibitors in Search for Novel Therapeutics
A group of parasites called Kinetoplastida, is responsible for three neglected tropical diseases: leishmaniasis, Chagas disease and human African trypanosomiasis (HAT, or African sleeping sickness) caused by various Leishmania species, Trypanosoma cruzi, and Trypanosoma brucei, respectively. HAT has been greatly reduced by a successful WHO campaign with an average of less than 1000 cases declared annually, but the impact of other Kinetoplastida on public health remains high. Approximately 1.3 million new cases of leishmaniasis are reported annually (mortality rate 30,000 p.a.). Similarly, there are ~8 million Chagas disease sufferers worldwide caused by T. cruzi with reported mortality and morbidity rates ~0.025 and ~30% respectively and over 65 million people at risk. Treatment of leishmaniasis relies on a small number of drugs which are toxic to the host, expensive and/or difficult to administer. Two drugs are available for treatment of Chagas disease but treatments for T. cruzi have low cure rates once the infection passes from the initial acute phase to the chronic state. The existing approved treatments for kinetoplastid diseases are widely recognised as being inadequate. This project was an early-stage drug discovery program aiming to establish test-tube screening materials and methods, followed by library screening and hit expansion to produce inhibitors of our targets that could be used in later stage drug discovery efforts. Our target enzymes are Flap endonucleases (FENs) which process the branched DNA structures (5’ flaps) arising during DNA replication. FENs are found as independent globular proteins in eukaryotes, including parasites from this study. Inhibiting FEN enzymes in any organism tested so far will lead to organism death. Specific inhibitors with good pharmacological properties, i.e. not toxic to humans, cheap to produce and with good bioavailability in vivo, would thus make potential antiparasitic drugs.
Data: CORDIS, © European Union
Project objective
We are searching for Kinetoplastida flap endonuclease (FEN) inhibitors as a base for potential therapeutics for parasite infections, for which there is significant unmet clinical need. Kinetoplastida are flagellated protists responsible for 3 neglected human diseases. We will target the FEN enzymes from Trypanasoma cruzi and Leishmania species, the organisms causing Chagas disease and leishmaniaisis respectively. FEN activity is crucial for the survival of all organisms tested so far from mouse to bacteria, including Trypanosoma. We will identify specific inhibitors of Kinetoplastida FENs as the basis for future development of urgently needed new therapeutics. This multidisciplinary structure-based inhibitor design project will involve in vitro and in silico screening, protein crystallization, rounds of inhibitor design and finally in vivo potency and toxicity experiments. The project will be overseen by Prof Sayers who has 30 years of experience with nucleases and who has founded two spin-out companies. His group is complemented through collaboration with a parasitologist Dr Helen Price (20 years research experience), who has been actively involved in developing antiparasitic agents. The experienced researcher, who has a strong protein biochemistry and crystallography background, is returning to academic research after almost 4 years outside science. Ultimately, the experienced researcher is aspiring to an academic career in translational medicine rooted in state-of-the-art basic research but with the skills and experience to synergise with the pharmaceutical sector.
Original text from CORDIS.
Participants
- THE UNIVERSITY OF SHEFFIELD · SHEFFIELDCoordinatorUnited Kingdom
Links
Data: CORDIS, © European Union