Department of Chemistry & Physics, Lincoln University, Lincoln University, Baltimore, PA, United States.
Department of Chemical and Biomolecular Engineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA, United States.
Curr Top Med Chem. 2019;18(23):2022-2028. doi: 10.2174/1568026619666181130133548.
Malaria is a major global health concern with the majority of cases reported in regions of South-East Asia, Eastern Mediterranean, Western Pacific, the Americas, and Sub-Saharan Africa. The World Health Organization (WHO) estimated 216 million worldwide reported cases of malaria in 2016. It is an infection of the red blood cells by parasites of the genus Plasmodium with most severe and common forms caused by Plasmodium falciparum (P. falciparum or Pf) and Plasmodium vivax (P. vivax or Pv). Emerging parasite resistance to available antimalarial drugs poses great challenges to treatment. Currently, the first line of defense includes artemisinin combination therapies (ACTs), increasingly becoming less effective and challenging to combat new occurrences of drug-resistant parasites. This necessitates the urgent need for novel antimalarials that target new molecular pathways with a different mechanism of action from the traditional antimalarials. Several new inhibitors and potential drug targets of the parasites have been reported over the years. This review focuses on the malarial aspartic proteases known as plasmepsins (Plms) as novel drug targets and antimalarials targeting Plms. It further discusses inhibitors of hemoglobin-degrading plasmepsins Plm I, Plm II, Plm IV and Histo-aspartic proteases (HAP), as well as HIV protease inhibitors of plasmepsins.
疟疾是全球主要的卫生关注点，大多数病例报告发生在东南亚、东地中海、西太平洋、美洲和撒哈拉以南非洲地区。世界卫生组织（WHO）估计，2016 年全球有 2.16 亿例疟疾病例报告。它是一种寄生虫感染红细胞的疾病，寄生虫属于疟原虫属，最严重和常见的形式是由恶性疟原虫（P. falciparum 或 Pf）和间日疟原虫（P. vivax 或 Pv）引起。寄生虫对现有抗疟药物的耐药性不断出现，给治疗带来了巨大挑战。目前，一线防御措施包括青蒿素联合疗法（ACTs），但这种疗法的效果越来越差，难以应对新出现的耐药寄生虫。因此，迫切需要新型抗疟药物，这些药物针对新的分子途径，具有与传统抗疟药物不同的作用机制。多年来，已经报道了几种新的寄生虫抑制剂和潜在的药物靶点。本综述重点介绍疟原虫天冬氨酸蛋白酶，即疟原虫肽酶（Plms）作为新型药物靶点和针对 Plms 的抗疟药物。进一步讨论了血红蛋白降解 Plms Plm I、Plm II、Plm IV 和组织天冬氨酸蛋白酶（HAP）的抑制剂，以及 Plms 的 HIV 蛋白酶抑制剂。
