Structural highlights
FunctionPublication Abstract from PubMedMalaria 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 counterpart. Cryo-EM structural studies confirmed binding at the beta5 subunit, while in vivo pharmacokinetic studies identified promising candidates for further development. These findings support proteasome inhibition as a viable strategy for novel antimalarial drug development. Optimization of Species-Selective Reversible Proteasome Inhibitors for the Treatment of Malaria.,Gahalawat S, Ray S, Zhang X, Deng X, Han Y, Chen Z, Lawong A, Shackleford DM, Katneni K, Chen G, Li P, Ng A, Zhong L, Hu M, McInerney M, Wang W, Saunders J, Collins D, Jayaseelan J, Noack CL, C Maity B, De N, Laleu B, Campbell SF, Phillips MA, Charman SA, Ready JM J Med Chem. 2025 Oct 28. doi: 10.1021/acs.jmedchem.5c02394. PMID:41148577[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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