School of Chemistry, University of Leeds, Leeds, U.K., LS2 9JT.
School of Biology, University of Leeds, Leeds, U.K., LS2 9JT.
J Med Chem. 2021 Feb 25;64(4):1763-1785. doi: 10.1021/acs.jmedchem.0c01721. Epub 2021 Feb 3.
Malaria poses a significant threat to approximately half of the world's population with an annual death toll close to half a million. The emergence of resistance to front-line antimalarials in the most lethal human parasite species, (), threatens progress made in malaria control. The prospect of losing the efficacy of antimalarial drugs is driving the search for small molecules with new modes of action. Asexual reproduction of the parasite is critically dependent on the recycling of amino acids through catabolism of hemoglobin (Hb), which makes metalloaminopeptidases (MAPs) attractive targets for the development of new drugs. The genome encodes eight MAPs, some of which have been found to be essential for parasite survival. In this article, we discuss the biological structure and function of each MAP within the genome, along with the drug discovery efforts that have been undertaken to identify novel antimalarial candidates of therapeutic value.
疟疾对全球约一半的人口构成重大威胁，每年的死亡人数接近 50 万。在最致命的人类寄生虫物种（）中，一线抗疟药物出现耐药性，这威胁到疟疾控制方面取得的进展。抗疟药物疗效丧失的前景促使人们寻找具有新作用模式的小分子。寄生虫的无性繁殖严重依赖于通过血红蛋白（Hb）分解代谢回收氨基酸，这使得金属氨基肽酶（MAP）成为开发新药的有吸引力的靶标。基因组编码了 8 种 MAP，其中一些 MAP 已被发现对寄生虫的生存至关重要。本文讨论了基因组中每个 MAP 的生物学结构和功能，以及为鉴定具有治疗价值的新型抗疟候选药物而开展的药物发现工作。
