Riske Brendan F, Luckhart Shirley, Riehle Michael A
Department of Entomology, University of Arizona, Tucson, AZ 85721, USA.
Department of Entomology, Plant Pathology and Nematology, University of Idaho, Moscow, ID 83843, USA.
Int J Mol Sci. 2023 Sep 10;24(18):13915. doi: 10.3390/ijms241813915.
Malaria parasites must acquire all necessary nutrients from the vertebrate and mosquito hosts to successfully complete their life cycle. Failure to acquire these nutrients can limit or even block parasite development and presents a novel target for malaria control. One such essential nutrient is pantothenate, also known as vitamin B5, which the parasite cannot synthesize de novo and is required for the synthesis of coenzyme A (CoA) in the parasite. This review examines pantothenate and the CoA biosynthesis pathway in the human-mosquito-malaria parasite triad and explores possible approaches to leverage the CoA biosynthesis pathway to limit malaria parasite development in both human and mosquito hosts. This includes a discussion of sources for pantothenate for the mosquito, human, and parasite, examining the diverse strategies used by the parasite to acquire substrates for CoA synthesis across life stages and host resource pools and a discussion of drugs and alternative approaches being studied to disrupt CoA biosynthesis in the parasite. The latter includes antimalarial pantothenate analogs, known as pantothenamides, that have been developed to target this pathway during the human erythrocytic stages. In addition to these parasite-targeted drugs, we review studies of mosquito-targeted allosteric enzymatic regulators known as pantazines as an approach to limit pantothenate availability in the mosquito and subsequently deprive the parasite of this essential nutrient.
疟原虫必须从脊椎动物宿主和蚊子宿主获取所有必需营养物质，才能成功完成其生命周期。无法获取这些营养物质会限制甚至阻碍寄生虫的发育，并为疟疾控制提供了一个新的靶点。泛酸（也称为维生素B5）就是这样一种必需营养物质，寄生虫无法从头合成泛酸，而泛酸是寄生虫中辅酶A（CoA）合成所必需的。本文综述了人类-蚊子-疟原虫三元组中的泛酸和CoA生物合成途径，并探讨了利用CoA生物合成途径限制人类和蚊子宿主中疟原虫发育的可能方法。这包括讨论蚊子、人类和寄生虫获取泛酸的来源，研究寄生虫在不同生命阶段和宿主资源库中获取CoA合成底物所采用的各种策略，以及讨论正在研究的破坏寄生虫中CoA生物合成的药物和替代方法。后者包括抗疟泛酸类似物，即泛硫乙胺，已开发用于在人类红细胞阶段靶向该途径。除了这些针对寄生虫的药物外，我们还综述了针对蚊子的变构酶调节剂（称为泛嗪）的研究，作为一种限制蚊子中泛酸可用性并随后剥夺寄生虫这种必需营养物质的方法。
