Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan 48202, USA.
J Med Chem. 2010 May 27;53(10):4234-47. doi: 10.1021/jm100233b.
Four aspartyl proteases known as plasmepsins are involved in the degradation of hemoglobin by Plasmodium falciparum, which causes a large percentage of malaria deaths. The enzyme plasmepsin II (Plm II) is the most extensively studied of these aspartyl proteases and catalyzes the initial step in the breakdown of hemoglobin by the parasite. Several groups have reported the design, synthesis, and evaluation of reversible peptidomimetic inhibitors of Plm II as potential antimalarial agents. We now report four peptidomimetic analogues, compounds 6-9, which are rationally designed to act as mechanism-based inhibitors of Plm II. Three of these analogues produce potent irreversible inactivation of the enzyme with IC(50) values in the low nanomolar range. Of these three compounds, two retain the low micromolar IC(50) values of the parent compound in Plasmodium falciparum (clone 3D7) infected erythrocytes. These analogues are the first examples of fully characterized mechanism-based inactivators for an aspartyl protease and show promise as novel antimalarial agents.
四种天冬氨酸蛋白酶，即裂殖体蛋白（Plasmepsins），参与恶性疟原虫（Plasmodium falciparum）对血红蛋白的降解，这是导致大部分疟疾死亡的原因。裂殖体蛋白酶 II（Plm II）是这些天冬氨酸蛋白酶中研究最广泛的，它催化寄生虫对血红蛋白的初始降解步骤。有几个研究小组已经报道了裂殖体蛋白酶 II 的可还原肽模拟物抑制剂的设计、合成和评估，作为潜在的抗疟药物。我们现在报告了四个肽模拟物类似物，化合物 6-9，它们被合理设计为裂殖体蛋白酶 II 的基于机制的抑制剂。这三个类似物中有三个产生了强的不可逆失活酶的作用，IC50 值在低纳摩尔范围内。在这三种化合物中，两种在感染恶性疟原虫（克隆 3D7）的红细胞中保留了母体化合物的低微摩尔 IC50 值。这些类似物是第一个完全表征的基于机制的天冬氨酸蛋白酶失活剂的例子，并有望成为新型抗疟药物。
