9o3e

Plasmodium falciparum 20S proteasome bound to inhibitor 159

spinqualitylabelsall models 9o3e, resolution 2.79Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9o3e is a 20 chain structure with sequence from Plasmodium falciparum 3D7. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 2.79Å Ligands: A1B74 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function Q8IAR3_PLAF7 Publication Abstract from PubMed 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 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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