Design, Synthesis, and Optimization of Macrocyclic Peptides as Species-Selective Antimalaria Proteasome Inhibitors

With over 200 million cases and close to half a million deaths each year, malaria is a threat to global health, particularly in developing countries. Plasmodium falciparum, the parasite that causes the most severe form of the disease, has developed resistance to all antimalarial drugs. Resistance to the first-line antimalarial artemisinin and to artemisinin combination therapies is widespread in Southeast Asia and is emerging in sub-Saharan Africa. The P. falciparum proteasome is an attractive antimalarial target because its inhibition kills the parasite at multiple stages of its life cycle and restores artemisinin sensitivity in parasites that have become resistant through mutation in Kelch K13. Here, we detail our efforts to develop noncovalent, macrocyclic peptide malaria proteasome inhibitors, guided by structural analysis and pharmacokinetic properties, leading to a potent, species-selective, metabolically stable inhibitor.每年造成超2亿例发病、近50万例死亡的疟疾，是全球公共卫生的重大威胁，在发展中国家形势尤为严峻。引发最重症疟疾的病原体恶性疟原虫（Plasmodium falciparum），已对所有抗疟药物产生耐药性。一线抗疟药物青蒿素（artemisinin）及其联合疗法的耐药性已在东南亚广泛流行，并在撒哈拉以南非洲出现蔓延趋势。恶性疟原虫蛋白酶体（P. falciparum proteasome）是极具吸引力的抗疟靶点：抑制该蛋白酶体可在寄生虫生命周期的多个阶段杀灭病原体，还能恢复因Kelch K13基因突变产生耐药性的虫株对青蒿素的敏感性。本文详述了我们依托结构分析与药代动力学特性指导，开发非共价大环肽类疟疾蛋白酶体抑制剂的研究历程，最终获得了一款强效、物种选择性优异且代谢稳定性良好的抑制剂。