Plasmepsins represent novel antimalarial drug targets. However, plasmepsin-based antimalarial drug discovery efforts in the past 2 decades have generally suffered some drawbacks including lack of translatability of target inhibition to potent parasite inhibition in vitro and in vivo as well as poor selectivity over the related human aspartic proteases. Most studies reported in this period have over-relied on the use of hemoglobinase plasmepsins I-IV (particularly I and II) as targets for the new inhibitors even though these are known to be nonessential at the asexual stage of parasite development. Therefore, future antimalarial drug discovery efforts seeking to identify plasmepsin inhibitors should focus on incorporating non-hemoglobinase plasmepsins such as V, IX, and X in their screening in order to maximize chances of success. Additionally, there is need to go beyond just target enzymatic activity profiling to establishing cellular activity, physicochemical as well as drug metabolism and pharmacokinetics properties and finally in vivo proof-of-concept while ensuring selectivity over related human host proteases.

中文翻译：

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疟疾药物发现中的血浆蛋白酶抑制剂：药物化学和靶标验证（2000年至今）。

血浆蛋白酶代表新的抗疟药靶标。然而，在过去的二十年中，基于纤溶酶的抗疟药的发现工作普遍存在一些缺点，包括在体外和体内靶标抑制作用与强效寄生虫抑制作用的可转换性缺乏，以及对相关人天冬氨酸蛋白酶的选择性差。在此期间报道的大多数研究都过分依赖使用血红蛋白酶纤溶酶I-IV（特别是I和II）作为新抑制剂的靶标，即使已知这些在寄生虫发育的无性阶段是不必要的。因此，未来寻求鉴定纤溶酶抑制剂的抗疟药物的研究工作应着重于将非血红蛋白酶纤溶酶（例如V，IX和X）纳入其筛选中，以最大程度地提高成功机会。另外，