Malaria is a devastating infectious disease, which causes over 400,000 deaths per annum and impacts the lives of nearly half the world’s population. The causative agent, a protozoan parasite, replicates within red blood cells (RBCs), eventually destroying the cells in a lytic process called egress to release a new generation of parasites. These invade fresh RBCs to repeat the cycle. Egress is regulated by an essential parasite subtilisin-like serine protease called SUB1. Here, we describe the development and optimization of substrate-based peptidic boronic acids that inhibit Plasmodium falciparum SUB1 with low nanomolar potency. Structural optimization generated membrane-permeable, slow off-rate inhibitors that prevent P. falciparum egress through direct inhibition of SUB1 activity and block parasite replication in vitro at submicromolar concentrations. Our results validate SUB1 as a potential target for a new class of antimalarial drugs designed to prevent parasite replication and disease progression.

疟疾是一种毁灭性的传染病，每年导致超过 400,000 人死亡，影响着世界近一半人口的生活。致病因子是一种原生动物寄生虫，在红细胞 (RBC) 内复制，最终在称为出口的裂解过程中破坏细胞，从而释放出新一代寄生虫。这些侵入新鲜的红细胞以重复循环。出口由称为 SUB1 的必需寄生虫枯草杆菌蛋白酶样丝氨酸蛋白酶调节。在这里，我们描述了以低纳摩尔效力抑制恶性疟原虫SUB1的基于底物的肽硼酸的开发和优化。结构优化产生了可渗透膜的缓慢解离速率抑制剂，可防止P。恶性疟原虫通过在亚微摩尔浓度下直接抑制 SUB1 活性和阻断体外寄生虫复制而排出体外。我们的结果证实 SUB1 是一类旨在防止寄生虫复制和疾病进展的新型抗疟药的潜在靶标。