Targeting Plasmodium PI(4)K to eliminate malaria.
Targeting Plasmodium PI(4)K to eliminate malaria.
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实现消除疟疾的目标将取决于针对所有生命阶段必不可少的疟原虫途径。在这里，我们确定了一种脂激酶，磷脂酰肌醇4-激酶(PI4K)，作为咪唑并吡嗪的靶标，咪唑并吡嗪是一种新型的抗疟疾化合物，在脊椎动物宿主感染的每个阶段都能抑制多种疟原虫的细胞内发育。咪唑并吡嗪在啮齿动物疟疾模型中表现出强大的预防、治疗和传播阻断活性，对人类主要病原体恶性疟原虫和间日疟原虫的血液期野外分离株具有活性，并抑制猴寄生虫食蟹猴的肝期催眠虫。我们发现，咪唑并吡嗪通过抑制与PI4K的ATP结合口袋的相互作用，改变磷脂酰肌醇4-磷酸在细胞内的分布而发挥作用。总体而言，我们的数据将PI4K定义为疟疾的关键脆弱性，开辟了以靶标为基础的发现新途径，以确定具有理想活动概况的药物，用于预防、治疗和消除疟疾。
Achieving the goal of malaria elimination will depend on targeting Plasmodium pathways essential across all life stages. Here, we identify a lipid kinase, phosphatidylinositol 4-kinase (PI4K), as the target of imidazopyrazines, a novel antimalarial compound class that inhibits the intracellular development of multiple Plasmodium species at each stage of infection in the vertebrate host. Imidazopyrazines demonstrate potent preventive, therapeutic, and transmission-blocking activity in rodent malaria models, are active against blood-stage field isolates of the major human pathogens, P. falciparum and P. vivax, and inhibit liver stage hypnozoites in the simian parasite P. cynomolgi. We show that imidazopyrazines exert their effect through inhibitory interaction with the ATP-binding pocket of PI4K, altering the intracellular distribution of phosphatidylinositol 4-phosphate. Collectively, our data define PI4K as a key Plasmodium vulnerability, opening up new avenues of target-based discovery to identify drugs with an ideal activity profile for the prevention, treatment and elimination of malaria.
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影响因子：
12.3
作者：
Dharia NV;Sidhu AB;Cassera MB;Westenberger SJ;Bopp SE;Eastman RT;Plouffe D;Batalov S;Park DJ;Volkman SK;Wirth DF;Zhou Y;Fidock DA;Winzeler EA
通讯作者：
Winzeler EA
影响因子：
5.2
作者：
D'Alessandro, Sarah;Silvestrini, Francesco;Taramelli, Donatella
通讯作者：
Taramelli, Donatella
影响因子：
3.3
作者：
de Graaf, P;Zwart, WT;Henegouwen, PMPVE
通讯作者：
Henegouwen, PMPVE
影响因子：
56.9
作者：
MAZIER, D;BEAUDOIN, RL;LANGLOIS, P
通讯作者：
LANGLOIS, P
影响因子：
1.5
作者：
Franke-Fayard, B;Trueman, H;Janse, CJ
通讯作者：
Janse, CJ