Antimalarial PROTACs to Combat Artemisinin Resistance

Artemisinin-resistant P. falciparum strains compromise the treatment of malaria, a global health treat. Antimalarial PROTACs have the potential to induce the PfK13-mediated proteolysis of artemisinins protein target (PfPI3K), and hence overcome resistance.

Malaria is a deadly vector-borne disease caused by protozoans of the genus Plasmodium (chiefly P. falciparum, Pf), transmitted to humans through bites of infected Anopheles mosquitoes. Worldwide, this tropical disease is endemic to 84 countries with about 247 million cases reported in 2021, for 619,000 deaths. The WHO recommended first-line treatment for uncomplicated malaria is artemisinin-based combination therapies (ACTs), a cocktail consisting of a fast-acting artemisinin derivative and a long-acting partner drug (e.g., amodiaquine).

The emergence of Pf strains resistant to ACTs in the past few years, poses a significant global health threat. Experimental evidence suggest that artemisinin derivatives potently inhibit the Pf kinase called phosphatidylinositol-3-kinase (PfPI3K) and ACT resistance is associated with mutations on the Pf E3 ligase called Kelch 13 (PfK13), resulting in the reduced polyubiquitination and proteolysis of PfPI3K. Thus, new strategies are required to curb the spread of Pf resistant strains.

One of such is proteolysis-targeting chimeras (PROTACs) — heterobifunctional molecules consisting of three parts: a ligand that binds to a protein of interest (PfPI3K), another ligand that recruits an E3 ubiquitin ligase (PfK13), and a connecting linker. Proximity-induced polyubiquitination of PfPI3K by PfK13 would lead to the proteolysis of PfPI3K by the ubiquitin-proteasome system. PROTACs have an event-driven mechanism of action and are superior to occupancy-driven small-molecule inhibitors, due to their catalytic nature, higher potency, longer duration of action, reduced dosing frequency, higher selectivity, and reduced toxicity. Leveraging this strategy could lead to the development of a new class of antimalarials that induce the proteolysis of PfPI3K, to overcome ACT resistance.

Image courtesy of Aurélien F. A. Moumbock; adapted from Rosenthal & Ng (ACS Infect. Dis. 2020, DOI: 10.1021/acsinfecdis.9b00527) and Duran-Frigola et al. (J. Am. Chem. Soc. 2023, DOI: 10.1021/jacs.2c11098). Copyright of the American Chemical Society, licensed under CC-BY 4.0 (http://creativecommons.org/licenses/by/4.0/).

Group 

Clarissa Gillmann, Lindau Alumna 2019
Sora Matsumoto, Young Scientist 2023
Petra Nnamani, Lindau Alumna 2014
Masato Ogishi, Young Scientist 2023