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：
9233010
负责人：
WESLEY C VAN VOORHIS
金额：
$ 123.06万
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/9233010
关键词：
Ames Assay Animal Model Animals Binding Sites Biological Availability Blood Categories Cell Culture Techniques Cell Proliferation Chemicals Chemistry Clinical Cryptosporidiosis Cryptosporidium Cryptosporidium parvum Crystallization Dangerousness 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 Study Phosphotransferases Pregnant Women Primary Infection Process Property Rattus Reaction Relapse Resistance Rodent Model Roentgen Rays Safety Sampling Structure Testing Therapeutic Time Toxic effect Toxicology Toxoplasma Toxoplasma gondii Toxoplasmosis Water Supply base biothreat calcium-dependent protein kinase chemical genetics clinical candidate disabling symptom drug candidate drug metabolism drug testing efficacy study efficacy testing immunosuppressed in vitro testing in vivo intraperitoneal kinase inhibitor manufacturing scale-up mouse model novel therapeutics pharmacokinetic model pre-clinical preclinical development prevent public health relevance scale up therapy development

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。弓形虫和弓形虫也是 B 类生物威胁因子，因为它们的传染性形式可以抵抗化学灭活，并且可以轻松收获并引入食品和水源中。隐孢子虫是导致长期和致残性腹泻的主要原因，而弓形虫在初次感染时可引起严重疾病，这对孕妇尤其危险。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。 C. parvum 和 T. gondii 钙依赖性蛋白激酶 1 (Cp & TgCDPK1) 可以选择性地用不抑制哺乳动物激酶的所谓的 Bumped Kinase Inhibitors (BKI) 为目标，并且这些 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、药代动力学，且易于合成。我们的一种主要 BKI 已被证明对隐孢子虫病和弓形体病小鼠模型有效。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优秀主要候选者。该提案旨在推动 BKI 进行临床前开发并选择临床候选药物。该项目的目标是找到一种治疗隐孢子虫病和弓形体病的临床候选药物，已准备好接受 FDA IND 审查，并有 1-2 个化合物作为备份。