Diarrhoeal disease caused by Cryptosporidium is a major cause of morbidity and mortality in young and malnourished children from low- and middle-income countries, with no vaccine or effective treatment. Here we describe the discovery of EDI048, a Cryptosporidium PI(4)K inhibitor, designed to be active at the infection site in the gastrointestinal tract and undergo rapid metabolism in the liver. By using mutational analysis and crystal structure, we show that EDI048 binds to highly conserved amino acid residues in the ATP-binding site. EDI048 is orally efficacious in an immunocompromised mouse model despite negligible circulating concentrations, thus demonstrating that gastrointestinal exposure is necessary and sufficient for efficacy. In neonatal calves, a clinical model of cryptosporidiosis, EDI048 treatment resulted in rapid resolution of diarrhoea and significant reduction in faecal oocyst shedding. Safety and pharmacological studies demonstrated predictable metabolism and low systemic exposure of EDI048, providing a substantial safety margin required for a paediatric indication. EDI048 is a promising clinical candidate for the treatment of life-threatening paediatric cryptosporidiosis.

由隐孢子虫引起的腹泻病是低收入和中等收入国家年轻和营养不良儿童发病和死亡的主要原因，这些儿童没有疫苗或有效的治疗方法。在这里，我们描述了 EDI048 的发现，EDI048 是一种隐孢子虫 PI（4）K 抑制剂，旨在在胃肠道的感染部位发挥作用，并在肝脏中快速代谢。通过使用突变分析和晶体结构，我们表明 EDI048 与 ATP 结合位点中高度保守的氨基酸残基结合。尽管循环浓度可以忽略不计，但 EDI048 在免疫功能低下的小鼠模型中是口服有效的，因此表明胃肠道暴露是必要且足够的疗效。在新生犊牛中，隐孢子虫病的临床模型，EDI048 治疗导致腹泻迅速消退并显着减少粪便卵囊脱落。安全性和药理学研究表明，EDI048 的代谢可预测且全身暴露量低，为儿科适应症提供了所需的大量安全裕度。EDI048 是一种很有前途的临床候选药物，用于治疗危及生命的小儿隐孢子虫病。