Bumped Kinase Inhibitors: Novel Therapeutics for Cryptosporidiosis&Toxoplasmosis

描述(申请人提供)：隐孢子虫属。和弓形虫也是B类生物制剂，因为它们的感染形式能抵抗化学灭活，而且很容易收获并引入食品和水供应中。隐孢子虫是延长和致残腹泻的主要原因，弓形虫在初次感染时可导致严重疾病，对孕妇特别危险。目前只有一种FDA批准的治疗隐孢子虫病的药物，其疗效存在争议。弓形虫的治疗选择受到毒性的限制。微小隐孢子虫和弓形虫钙依赖蛋白激酶1(CP&TgCDPK1)可以选择性地被不抑制哺乳动物激酶的所谓碰碰型激酶抑制剂(BKI)靶向，这些BKI可以防止隐孢子虫和弓形虫的生长。BKI具有良好的口服生物利用度和药代动力学，且易于合成。我们的一种主要BKIs已经被证明在隐孢子虫病和弓形虫病的小鼠模型中具有疗效。因此，BKI现在是治疗隐孢子虫病和弓形虫病药物开发的极佳候选药物。这项建议是通过临床前开发和选择一个临床候选的BKIs。该项目的目标是拥有治疗隐孢子虫病和弓形虫病的临床候选药物 已经准备好接受FDA的IND审查，有1-2种化合物作为后备。

DESCRIPTION (provided by applicant): Cryptosporidium spp. and Toxoplasma gondii are also Category B biothreat agents because their infectious forms resist chemical inactivation and can be easily harvested and introduced into food and water supplies. Cryptosporidium are a major cause of prolonged and disabling diarrhea and Toxoplasma can cause a serious illness upon primary infection that is particularly dangerous to pregnant women. There is only one FDA- approved drug for cryptosporidiosis, and its efficacy is controversial. Therapeutic options for Toxoplasma are limited by toxicity. The C. parvum and T. gondii calcium dependent protein kinase 1 (Cp & TgCDPK1) can be selectively targeted with so-called Bumped Kinase Inhibitors (BKIs) that do not inhibit mammalian kinases, and these BKIs prevent the growth of cryptosporidium and toxoplasma. The BKIs have good oral bioavailability, pharmacokinetic, and are easy to synthesize. One of our lead BKIs has been shown to have efficacy in mouse models of cryptosporidiosis and toxoplasmosis. Thus BKIs are now excellent lead candidates for drug development for the therapy of cryptosporidiosis and toxoplasmosis. This proposal is to move the BKIs through pre-clinical development and select a clinical candidate. The goal of this project is to have a clinical candidate for the therapy of cryptosporidiosis and toxoplasmosis that is ready to undergo FDA IND review, with 1-2 compounds as backups.