Bumped Kinase Inhibitors: Novel Therapeutics for Cryptosporidiosis&Toxoplasmosis

碰撞激酶抑制剂：隐孢子虫病的新疗法

基本信息

批准号：
8692204
负责人：
WESLEY C VAN VOORHIS
金额：
$ 158.02万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-15 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8692204
关键词：
Analytical Chemistry Animal Model Animals Binding Sites Biological Availability Blood Categories Cell Culture Techniques Cell Proliferation Chemicals Clinical Cryptosporidiosis Cryptosporidium Cryptosporidium parvum Decontamination Development Diarrhea Digit structure Dose Drug Design Drug Hypersensitivity Drug Kinetics FDA approved Family suidae Feces Fetus Food Supply Funding Gatekeeping Gerbils Glycine Goals Growth Harvest Human Immunocompromised Host Infection Lead Mammalian Cell Modeling Mus Mutagenesis National Institute of Allergy and Infectious Disease Neonatal Neuraxis Oocysts Oral Organism Pharmaceutical Preparations Pharmacology Phosphotransferases Pregnant Women Process Property Rattus Reaction Relapse Resistance Rodent Model Roentgen Rays Safety Sampling Structure Symptoms Testing Therapeutic Time Toxic effect Toxicology Toxoplasma Toxoplasma gondii Toxoplasmosis Water Supply base biothreat calcium-dependent protein kinase chemical genetics compound 18 drug candidate drug development drug metabolism efficacy testing immunosuppressed in vitro testing in vivo intraperitoneal kinase inhibitor manufacturing scale-up mouse model novel therapeutics pharmacokinetic model pre-clinical prevent public health relevance scale up

项目摘要

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.

描述（由申请人提供）：隐孢子虫属。和弓形虫弓形虫也是B类Biothreat剂，因为它们的感染形式可抵抗化学失活，并且可以轻松收获并引入食品和供水中。隐孢子虫是延长和禁用腹泻的主要原因，而弓形虫可能会在对孕妇特别危险的原发性感染后引起严重的疾病。只有一种用于隐孢子虫病的FDA批准的药物，其功效是有争议的。弓形虫的治疗选择受到毒性的限制。 C. parvum和T. gondii钙依赖性蛋白激酶1（CP＆TGCDPK1）可以用所谓的凸起激酶抑制剂（BKI）选择性地靶向，这些激酶抑制剂（BKIS）不抑制哺乳动物激酶，这些BKIS可以防止隐孢子虫的生长。 BKI具有良好的口服生物利用度，药代动力学，并且易于合成。我们的铅BKI铅之一已被证明在小鼠隐孢子虫病和弓形虫病的小鼠模型中具有功效。因此，BKIS现在是用于治疗隐孢子虫病和弓形虫病的药物开发的出色铅候选者。该建议是通过临床前开发来移动BKI，并选择临床候选者。该项目的目的是拥有一个临床候选者治疗隐孢子虫病和弓形虫病的治疗准备好接受FDA IND评论，并以1-2个化合物作为备份。