Depletion of malaria parasite targets using heterobifunctional molecules

To combat antimalarial drug resistance, new drug candidates are needed. Unlike occupancy-driven inhibitors, heterobifunctional molecules that recruit the malaria parasite ubiquitin-proteasome system (UPS) for depletion of the target may be less prone to resistance. Here, we synthesized a library of 67 heterobifunctional molecules comprising a warhead ligand against the Plasmodium falciparum dihydrofolate reductase thymidylate synthase (DHFR-TS) protein joined to various UPS-recruiter ligands. Several compounds were identified that induced rapid depletion of DHFR-TS (greater than 50% reduction in 4 h). The NOT4 E3 ligase was identified as a parasite UPS component recruited by lead compounds.