8dsr | pdb_00008dsr
Structure of Plasmepsin X (PM10, PMX) from Plasmodium falciparum 3D7 in complex with UCB7362
Structural highlights
FunctionPLM10_PLAF7 During the asexual blood stage, processes key proteins essential for merozoite egress and invasion of host erythrocytes (PubMed:29074775, PubMed:32109369). Cleaves and activates proteases SUB1 and SUB2 (PubMed:29074775, PubMed:32109369). May process members of the EBL and Rh protein families (PubMed:32109369). Also cleaves apical membrane protein AMA1 (PubMed:29074775). During the mosquito vector stage and probably in ookinetes, cleaves CelTOS (PubMed:29074775).[1] [2] Publication Abstract from PubMedPlasmepsin X (PMX) is an essential aspartyl protease controlling malaria parasite egress and invasion of erythrocytes, development of functional liver merozoites (prophylactic activity), and blocking transmission to mosquitoes, making it a potential multistage drug target. We report the optimization of an aspartyl protease binding scaffold and the discovery of potent, orally active PMX inhibitors with in vivo antimalarial efficacy. Incorporation of safety evaluation early in the characterization of PMX inhibitors precluded compounds with a long human half-life (t1/2) to be developed. Optimization focused on improving the off-target safety profile led to the identification of UCB7362 that had an improved in vitro and in vivo safety profile but a shorter predicted human t1/2. UCB7362 is estimated to achieve 9log10 unit reduction in asexual blood-stage parasites with once-daily dosing of 50 mg for 7 days. This work demonstrates the potential to deliver PMX inhibitors with in vivo efficacy to treat malaria. Discovery and Characterization of Potent, Efficacious, Orally Available Antimalarial Plasmepsin X Inhibitors and Preclinical Safety Assessment of UCB7362.,Lowe MA, Cardenas A, Valentin JP, Zhu Z, Abendroth J, Castro JL, Class R, Delaunois A, Fleurance R, Gerets H, Gryshkova V, King L, Lorimer DD, MacCoss M, Rowley JH, Rosseels ML, Royer L, Taylor RD, Wong M, Zaccheo O, Chavan VP, Ghule GA, Tapkir BK, Burrows JN, Duffey M, Rottmann M, Wittlin S, Angulo-Barturen I, Jimenez-Diaz MB, Striepen J, Fairhurst KJ, Yeo T, Fidock DA, Cowman AF, Favuzza P, Crespo-Fernandez B, Gamo FJ, Goldberg DE, Soldati-Favre D, Laleu B, de Haro T J Med Chem. 2022 Oct 10. doi: 10.1021/acs.jmedchem.2c01336. PMID:36216349[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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