Gonçalves Adriana F, Lima-Pinheiro Ana, Ferreira Pedro E
Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.
Life and Health Sciences Research Institute (ICVS), Biomaterials, Biodegradables and Biomimetics Research Group (3B's), PT Government Associate Laboratory, Braga, Portugal.
Front Med (Lausanne). 2024 Oct 21;11:1441352. doi: 10.3389/fmed.2024.1441352. eCollection 2024.
Malaria is a devasting parasitic disease that causes over half a million deaths every year. The necessity for prompt and thorough antimalarial drug discovery and development is accelerated by the rise in multidrug resistance and the lack of an effective vaccine. The spp. proteasome represents a prospective target for antimalarial treatment since several chemotherapy types have been shown to potently and selectively limit the growth of parasites. Combined with first-line artemisinin medicines, it creates synergy, even in the artemisinin-resistant parasites.
PRISMA guidelines were used in the development of this systematic review. A literature search was performed in March 2024 in PubMed, Science Direct, and Scopus databases, with the following keywords: ((antimalarial resistance) AND (plasmodium OR malaria) AND (proteasome)) NOT (cancer [Title/Abstract]). Only articles with the susceptibility assessment were included.
Herein, 35 articles were included in the systematic review, which was divided into two subcategories: those that studied the UPS inhibitors, which accounted for 25 articles, and those that studied genetic modifications, including knockouts, knockdowns, and mutations, in the UPS toward antimalarial resistance, accounting for 16 articles. 6 articles included both subcategories. In total, 16 categories of inhibitors were analyzed, together with two knockdowns, one knockout, and 35 mutations.
In this study, we reviewed the literature for available inhibitors and their respective susceptibility and ability to develop resistance toward spp. 26 s proteasome. The proteasome was highlighted as a potential antimalarial target and as an artemisinin partner drug. However, host toxicity and susceptibility to resistance appear as the main obstacle in the development of highly potent drugs, indicating a need for additional scrutiny during any further drug development efforts.
疟疾是一种极具破坏性的寄生虫病，每年导致超过50万人死亡。多重耐药性的增加和缺乏有效疫苗加速了迅速且全面的抗疟药物研发的必要性。由于已证明几种化疗类型能有效且选择性地限制寄生虫的生长，疟原虫属蛋白酶体成为抗疟治疗的一个潜在靶点。与一线青蒿素类药物联合使用时，即使对青蒿素耐药的寄生虫也能产生协同作用。
本系统评价的开展遵循PRISMA指南。2024年3月在PubMed、Science Direct和Scopus数据库中进行了文献检索，关键词如下：（（抗疟耐药性）AND（疟原虫属或疟疾）AND（蛋白酶体））NOT（癌症[标题/摘要]）。仅纳入具有敏感性评估的文章。
在此，35篇文章被纳入该系统评价，分为两个子类别：研究泛素蛋白酶体系统（UPS）抑制剂的文章，占25篇；研究UPS中基因修饰（包括基因敲除、基因敲低和突变）对抗疟耐药性影响的文章，占16篇。6篇文章包含这两个子类别。总共分析了16类抑制剂，以及两个基因敲低、一个基因敲除和35个突变。
在本研究中，我们查阅了文献，了解可用抑制剂及其对疟原虫属26S蛋白酶体的各自敏感性和产生耐药性的能力。蛋白酶体被强调为一个潜在的抗疟靶点以及青蒿素的联合用药。然而，宿主毒性和耐药易感性似乎是开发高效药物的主要障碍，这表明在任何进一步的药物研发工作中都需要额外的审查。
