Optimization of Species-Selective Reversible Proteasome Inhibitors for the Treatment of Malaria.

ABSTRACT: Malaria remains a critical global health challenge, with increasing resistance to frontline therapies necessitating novel drug targets. The proteasome has emerged as a promising target for antimalarial drug discovery. This study describes efforts to optimize a series of species-selective reversible inhibitors targeting the Plasmodium falciparum 20S proteasome. Starting from the carboxypiperidine scaffold identified through a high-throughput viability screen, we conducted iterative structure-activity relationship studies, 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 proteasome over the human c

SUBMITTER: Gahalawat S 

PROVIDER: S-EPMC12681073 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature