Plasmepsin V is an aspartyl protease that plays a critical role in the export of proteins bearing the Plasmodium export element (PEXEL) motif (RxLxQ/E/D) to the infected host erythrocyte, and thus the survival of the malaria parasite. Previously, development of transition state PEXEL mimetic inhibitors of plasmepsin V have primarily focused on demonstrating the importance of the P₃ Arg and P₁ Leu in binding affinity and selectivity. Here, we investigate the importance of the P₂ position by incorporating both natural and non-natural amino acids into this position and show disubstituted beta-carbon amino acids convey the greatest potency. Consequently, we show analogues with either cyclohexylglycine or phenylglycine in the P₂ position are the most potent inhibitors of plasmepsin V that impair processing of the PEXEL motif in exported proteins resulting in death of P. falciparum asexual stage parasites.

纤溶酶V是一种天冬氨酰蛋白酶，在携带带有疟原虫输出元件（PEXEL）基序的蛋白质（RxLxQ / E / D）出口到受感染的宿主红细胞以及疟疾寄生虫的存活中起关键作用。以前，纤溶酶V的过渡态PEXEL模拟抑制剂的开发主要集中于证明P ₃ Arg和P ₁ Leu在结合亲和力和选择性方面的重要性。在这里，我们通过将天然和非天然氨基酸都掺入该位置来研究P ₂位置的重要性，并表明双取代的β-碳氨基酸可发挥最大的效能。因此，我们在P中显示了带有环己基甘氨酸或苯基甘氨酸的类似物₂位是最有效的纤溶酶V抑制剂，可破坏输出蛋白中PEXEL基序的加工，导致恶性疟原虫无性阶段寄生虫死亡。