Are trypanocidal degrader drugs possible?

Apr 26, 2023

Targeted Protein Degradation Might Present a Novel Therapeutic Approach in the Fight Against African Trypanosomiasis.

Danazumi AU, Ishmam IT, Idris S, Izert MA, Balogun EO, Górna MW.

European Journal of Pharmaceutical Sciences (2023) 106451

We are excited to present our review article on the perspective of using Targeted Protein Degradation (TPD) as a therapeutic strategy against Human African Trypanosomiasis (HAT). Currently, classical drug and vaccine development for this neglected tropical disease is still difficult, and we believe further advances might be achieved using more modern approaches such as PROTACs. PROTACs are bifunctional molecules that target proteins for degradation and these paradigm-breaking drugs have enticed researchers working on infectious diseases after showing their remarkable properties in cancer treatment.

Not long ago, our group proposed several strategies for the development of antibacterial PROTACs - and we were the first to propose direct protease recruitment, which later became reality when the first BacPROTACs were reported. The field of TPD for infectious diseases is currently in its birth and new groups have joined the efforts in developing more strategies for antibacterial and antiviral PROTACs. Similarly, we see the unexplored potential for PROTACs in fighting parasitic diseases.

Here, we teamed up with our collaborators who are expert on HAT to delineate and assess the best possible TPD approaches in trypanosomes. First, we provide a brief discussion of the current state of HAT treatment and prevention, followed by a dive into the Targeted Protein Degradation components, principles and pathways. We evaluate multiple available target proteins, compounds and TPD modalities that could enable TPD in trypanosomes. Lastly, this guided discussion is intended to spark imagination and inspire investigators researching new therapeutic approaches against trypanosomiasis, so that we might soon see the first “TrypPROTACs”.

About the first author:

Ammar joined us in February 2021 for his Master's thesis funded by NAWA Łukasiewicz programme, which he defended in June 2022. Ammar is interested in neglected tropical diseases, particularly in the prevention and treatment of Human African Trypanosomiasis. Inspired by our work on establishing Targeted Protein Degradation in bacteria, Ammar aimed to apply this concept to trypanosomes. This is Ammar's third publication with our lab, congratulations!