8DSR

Structure of Plasmepsin X (PM10, PMX) from Plasmodium falciparum 3D7 in complex with UCB7362

8DSR の概要

• エントリーDOI: 10.2210/pdb8dsr/pdb
• 分子名称: Plasmepsin X, (2E,6S)-6-{2-chloro-3-[(2-cyclopropylpyrimidin-5-yl)amino]phenyl}-2-imino-6-methyl-3-[(2S,4S)-2-methyloxan-4-yl]-1,3-diazinan-4-one (2 entities in total)
• 機能のキーワード: plasmepsin x, plasmodium falciparum, pm10, pmx, hydrolase
• 由来する生物種: Plasmodium falciparum 3D7
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 106466.97

構造登録者

Abendroth, J.,Lorimer, D.D. (登録日: 2022-07-22, 公開日: 2022-10-19, 最終更新日: 2024-10-16)

主引用文献

Lowe, M.A.,Cardenas, A.,Valentin, J.P.,Zhu, Z.,Abendroth, J.,Castro, J.L.,Class, R.,Delaunois, A.,Fleurance, R.,Gerets, H.,Gryshkova, V.,King, L.,Lorimer, D.D.,MacCoss, M.,Rowley, J.H.,Rosseels, M.L.,Royer, L.,Taylor, R.D.,Wong, M.,Zaccheo, O.,Chavan, V.P.,Ghule, G.A.,Tapkir, B.K.,Burrows, J.N.,Duffey, M.,Rottmann, M.,Wittlin, S.,Angulo-Barturen, I.,Jimenez-Diaz, M.B.,Striepen, J.,Fairhurst, K.J.,Yeo, T.,Fidock, D.A.,Cowman, A.F.,Favuzza, P.,Crespo-Fernandez, B.,Gamo, F.J.,Goldberg, D.E.,Soldati-Favre, D.,Laleu, B.,de Haro, T.
Discovery and Characterization of Potent, Efficacious, Orally Available Antimalarial Plasmepsin X Inhibitors and Preclinical Safety Assessment of UCB7362 .
J.Med.Chem., 65:14121-14143, 2022

PubMed Abstract: Plasmepsin 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 () to be developed. Optimization focused on improving the off-target safety profile led to the identification of that had an improved in vitro and in vivo safety profile but a shorter predicted human . is estimated to achieve 9 log 10 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.

PubMed: 36216349
DOI: 10.1021/acs.jmedchem.2c01336

実験手法

X-RAY DIFFRACTION (2.85 Å)