Targeted Protein Degradation as a Novel Approach to Discover Antimalarials

Lyn-Marie Birkholtz with Erick Strauss, both of Stellenbosch University in South Africa, will develop antimalarial drugs that work by targeting parasite proteins for degradation rather than inhibiting their activity. This strategy involves creating proteolysis-targeting chimeras (PROTACs), which are linker proteins designed to bind specific parasite proteins and target them for degradation by an endogenous intracellular protease. This project builds on ongoing work with the approach applied to bacterial proteins for TB drug development. They will design and synthesize PROTACs against essential Plasmodium falciparum proteins, then evaluate their activity in phenotypic assays using drug-sensitive and drug-resistant parasite strains as well as multiple stages of parasite development. They will validate that any observed activity is due to the predicted PROTAC mechanism of action, as well as using in vitro assays to measure how effectively the parasites resist the antimalarial activity.