Plasmepsin Inhibitory Activity and Structure-Guided Optimization of a Potent Hydroxyethylamine-Based Antimalarial Hit
Plasmepsin Inhibitory Activity and Structure-Guided Optimization of a Potent Hydroxyethylamine-Based Antimalarial Hit
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DOI：
10.1021/ml4004952
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发表时间：
2014-04-01
影响因子：
4.2
通讯作者：
Jirgensons, Aigars
中科院分区：
文献类型：
--
作者：
Jaudzems, Kristaps;Tars, Kaspars;Jirgensons, Aigars
从葛兰素史克细胞筛选活动中鉴定的抗疟疾HIT 1SR(TCMDC-134674)对消化液泡血浆蛋白(PLM I、II和IV)的抑制活性进行了评估。发现它是一种有效的PLM IV抑制剂，对组织蛋白酶D没有选择性，解决了与PLM 11结合的1SR的共晶结构，为设计更有效和更有选择性的类似物提供了结构洞察力。结构指导的优化导致了结构简化的类似物17和18被鉴定为两者的低纳米分子抑制物，纤溶酶蛋白PLM IV活性和红细胞中恶性疟原虫的生长。
Antimalarial hit 1SR (TCMDC-134674) identified in a GlaxoSmithKline cell based screening campaign was evaluated for inhibitory activity against the digestive vacuole plasmepsins (Plm I, II, and IV). It was found to be a potent Plm IV inhibitor with no selectivity over Cathepsin D. A cocrystal structure of 1SR bound to Plm 11 was solved, providing structural insight for the design of more potent and selective analogues. Structure-guided optimization led to the identification of structurally simplified analogues 17 and 18 as low nanomolar inhibitors of both, plasmepsin Plm IV activity and P. falciparum growth in erythrocytes.