Optimization of species-selective reversible proteasome inhibitors for the treatment of malaria

Malaria remains a critical global health challenge, with increasing resistance to frontline therapies necessitating novel drug tar-gets. The proteasome has emerged as a promising avenue for antimalarial drug discovery. This study describes the optimization of species-selective reversible inhibitors targeting the Plasmodium falciparum 20S proteasome. Starting from the carboxypiper-idine scaffold identified through a high-throughput viability screen, we conducted iterative structure-activity relationship stud-ies, leading to the development of highly potent and selective inhibitors with good oral bioavailability. Lead compounds demonstrated nanomolar potency against P. falciparum blood-stage parasites and selective inhibition of the parasite pro-teasome over the human counterpart. Cryo-EM structural studies confirmed binding at the β5 subunit, while in vivo pharma-cokinetic studies identified promising candidates for further development. These findings support proteasome inhibition as a viable strategy for novel antimalarial drug development.