Dual Use Therapeutics for Cryptosporidiosis, Toxoplasmosis, and Neosporosis

描述（由申请人提供）：迫切需要用于人和家畜的隐孢子虫病和弓形虫病的新药。隐孢子虫病引起人类和小牛的消耗性腹泻。弓形虫病是人类和家畜胎儿畸形和流产的重要原因。此外，还需要一种有效的药物用于兽医治疗新孢子虫病，这是牲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）的药物开发项目的后续。我们现在有两种有前途的临床前候选药物，它们在隐孢子虫病、弓形虫病和新孢子虫病的小鼠模型中显示出活性，因此对兽医和人类健康具有巨大的潜在价值。该项目的目标是在农业重要的家畜（牛和羊）中进行我们的新型治疗药物的疗效，药代动力学（PK）和毒性测试，以显示对动物疾病的疗效，并为人类使用的临床前药物包装收集信息。我们将把化合物的规模扩大到接近千克的数量，在弓形虫病和新孢子虫病的绵羊模型和隐孢子虫病的小牛模型中测试它们的功效。在该项目结束时，目标是获得一种临床前候选药物和一两种备用药物，以推进最终的临床前测试和供兽医和人类使用的IND/NADA注册。

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.