Bumped Kinase Inhibitors: Novel Therapeutics for Cryptosporidiosis&Toxoplasmosis

性状（由申请方提供）：隐孢子虫属和刚地弓形虫也是B类生物威胁剂，因为它们的感染形式抵抗化学灭活，并且可以容易地收获并引入食物和供水系统。隐孢子虫是长期和致残性腹泻的主要原因，弓形虫在初次感染后可引起严重疾病，对孕妇特别危险。FDA只批准了一种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。梭parvum和T.弓形虫钙依赖性蛋白激酶1（Cp & TgCDPK 1）可以被不抑制哺乳动物激酶的所谓的BumpedKinaseInhibitors（BKI）选择性靶向，并且这些BKI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，并且易于合成。我们的一种主要BKI已被证明在隐孢子虫病和弓形虫病的小鼠模型中有效。因此，BKI现在是用于治疗隐孢子虫病和弓形虫病的药物开发的极好的主要候选者。该提案旨在通过临床前开发推动BKI，并选择临床候选药物。该项目的目标是为隐孢子虫病和弓形虫病的治疗提供临床候选药物， 准备接受FDA IND审查，其中1-2个化合物作为备份。

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.