Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183.
Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183.
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抗疟药泛酸酰胺MMV693183的临床前表征和靶点验证。
DOI：
10.1038/s41467-022-29688-5
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发表时间：
2022-04-20
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
抗药性和严重缺乏阻断传播的抗疟疾药物阻碍了疟疾的消除。在这里，我们提出泛胺MMV693183作为一种一流的乙酰辅酶A合成酶(ACAS)抑制剂进入临床前开发。我们的研究在人源化的恶性疟原虫感染小鼠模型中展示了诱人的类药物特性和体内疗效。该化合物对恶性疟原虫和间日疟原虫临床分离株具有个位数的纳摩尔体外活性，并能有效阻断恶性疟原虫对按蚊的传播。遗传和生化研究证实，ACAs是MMV693183衍生的抗代谢药物CoA-MMV693183的靶标。药代动力学-药效学模型预测，单次口服30 mg剂量就足以治愈人类的疟疾感染。对老鼠的毒理学研究表明，与预测的人类有效暴露剂量相比， >； 的安全裕度是30倍。总之，MMV693183代表了一种治疗疟疾和阻断传播的新作用模式，是进一步(临床前)开发的有前途的候选药物。在这里，德弗里斯等人。对抗疟疾化合物MMV693183进行临床前表征：该化合物针对乙酰辅酶A合成酶，在人源化小鼠中对恶性疟原虫感染具有疗效，阻止向蚊子媒介的传播，在大鼠中是安全的，药代动力学-药效学建模提供了一种潜在的人类口服给药方案。
Drug resistance and a dire lack of transmission-blocking antimalarials hamper malaria elimination. Here, we present the pantothenamide MMV693183 as a first-in-class acetyl-CoA synthetase (AcAS) inhibitor to enter preclinical development. Our studies demonstrate attractive drug-like properties and in vivo efficacy in a humanized mouse model of Plasmodium falciparum infection. The compound shows single digit nanomolar in vitro activity against P. falciparum and P. vivax clinical isolates, and potently blocks P. falciparum transmission to Anopheles mosquitoes. Genetic and biochemical studies identify AcAS as the target of the MMV693183-derived antimetabolite, CoA-MMV693183. Pharmacokinetic-pharmacodynamic modelling predict that a single 30 mg oral dose is sufficient to cure a malaria infection in humans. Toxicology studies in rats indicate a > 30-fold safety margin in relation to the predicted human efficacious exposure. In conclusion, MMV693183 represents a promising candidate for further (pre)clinical development with a novel mode of action for treatment of malaria and blocking transmission. Here, de Vries et al. perform a pre-clinical characterization of the antimalarial compound MMV693183: the compound targets acetyl-CoA synthetase, has efficacy in humanized mice against Plasmodium falciparum infection, blocks transmission to mosquito vectors, is safe in rats, and pharmacokinetic-pharmacodynamic modeling informs about a potential oral human dosing regimen.
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