Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Victoria, Australia.
Department of Medical Biology, University of Melbourne, Parkville, 3010, Victoria, Australia.
ChemMedChem. 2022 Sep 16;17(18):e202200306. doi: 10.1002/cmdc.202200306. Epub 2022 Aug 18.
Plasmepsin X (PMX) is an aspartyl protease that processes proteins essential for Plasmodium parasites to invade and egress from host erythrocytes during the symptomatic asexual stage of malaria. PMX substrates possess a conserved cleavage region denoted by the consensus motif, SFhE (h=hydrophobic amino acid). Peptidomimetics reflecting the P -P positions of the consensus motif were designed and showed potent and selective inhibition of PMX. It was established that PMX prefers Phe in the P position, di-substitution at the β-carbon of the P moiety and a hydrophobic P group which was supported by modelling of the peptidomimetics in complex with PMX. The peptidomimetics were shown to arrest asexual P. falciparum parasites at the schizont stage by impairing PMX substrate processing. Overall, the peptidomimetics described will assist in further understanding PMX substrate specificity and have the potential to act as a template for future antimalarial design.
裂殖体蛋白 X（PMX）是一种天冬氨酸蛋白酶，在疟疾有症状的无性生殖阶段，它能处理疟原虫侵入和逸出宿主红细胞所必需的蛋白质。PMX 的底物具有一个保守的切割区域，由共识基序 SFhE（h=疏水性氨基酸）表示。反映共识基序 P-P 位置的肽模拟物被设计出来，并表现出对 PMX 的有效和选择性抑制。研究结果表明，PMX 偏爱 P 位的苯丙氨酸，P 部分的β-碳上的二取代和疏水性 P 基团，这一结果得到了与 PMX 形成复合物的肽模拟物的建模支持。这些肽模拟物通过损害 PMX 底物的加工，使无性生殖的恶性疟原虫寄生虫停滞在裂殖体阶段。总的来说，所描述的肽模拟物将有助于进一步了解 PMX 底物特异性，并有可能作为未来抗疟药物设计的模板。
