Dual Use Therapeutics for Cryptosporidiosis, Toxoplasmosis, and Neosporosis

描述(申请人提供)：人和家畜用隐孢子虫病和弓形虫病急需新药。隐孢子虫病会在人类和牛犊中引起消耗性腹泻。弓形虫病是人类和家畜胎儿畸形和流产的重要原因。此外，兽医还需要一种有效的药物来治疗新孢子虫病，这是家畜流行性流产的原因。该项目是我们成功的针对原生动物钙依赖蛋白激酶(CDPKs)的Hit-to-Lead药物开发项目的后续。我们现在有两个有希望的临床前候选药物，它们在隐孢子虫病、弓形虫病和新孢子病的小鼠模型中显示出活性，因此对兽医和人类健康都具有巨大的潜在价值。该项目的目标将是在农业上重要的家畜(牛和羊)上进行我们的新疗法的有效性、药代动力学(PK)和毒性测试，以显示对动物疾病的有效性，并为人类使用的临床前药物包收集信息。我们将把这些化合物放大到接近千克的量，在绵羊弓形虫病和新孢子虫病模型以及牛隐孢子虫病模型中测试它们的有效性。在该项目结束时，目标是拥有一个临床前候选药物和一到两个备份，以进入最终的临床前测试和IND/NADA注册，供兽医和人类使用。

DESCRIPTION (provided by applicant): New drugs are urgently needed for cryptosporidiosis and toxoplasmosis for human and domestic livestock use. Cryptosporidiosis causes wasting diarrhea in humans and calves. Toxoplasmosis is an important cause of fetal malformations and abortions in humans and domestic livestock. In addition, an effective drug is also needed for veterinary use for neosporosis, the cause of epidemic abortions in livestock. This project follows on our successful hit-to-lead drug development project, targeting protozoan Calcium Dependent Protein Kinases (CDPKs). We now have two promising pre-clinical drug candidates that show activity in mouse models of cryptosporidiosis, toxoplasmosis and neosporosis, and thus are of great potential value for both veterinary and human health. The goal of this project will be to conduct efficacy, pharmacokinetic (PK), and toxicity testing of our novel therapeutics in agriculturally-important domestic animals (cattle and sheep) to show efficacy for animal diseases and to also gather information for the preclinical drug package for human use. We will scale-up the compounds to the near kilogram quantity, test their efficacy in sheep models of toxoplasmosis and neosporosis, and in a calf model of cryptosporidiosis. In the end of this project, the goal is to have a preclinical drug candidate and one or two backups to advance to final preclinical testing and IND/NADA registration for veterinary and human use.