Bumped-Kinase Inhibitor Drug Development for Toxoplasmosis

弓形虫病的碰撞激酶抑制剂药物开发

基本信息

批准号：
10204654
负责人：
WESLEY C VAN VOORHIS
金额：
$ 70.13万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-15 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10204654
关键词：
Acute Address Animal Model Animals Area Binding Proteins Biological Assay Blood Brain Cardiac Cardiotoxicity Cardiovascular system Cells Central Nervous System Infections Central Nervous System Toxoplasmosis Characteristics Chronic Clinical Congenital Toxoplasmosis Cryptosporidiosis Cyst Development Drug Kinetics Embryonic Development Enzyme Inhibition Fetal Death Fetal Reduction Fetus Genes Goals Growth Human Immune Immunocompromised Host In Vitro Individual Infection Infectious Pregnancy Complications Invaded Knowledge Laboratories Lead Length Mammalian Cell Modeling Mus Neuraxis Outcome Parasites Parasitic infection Penetration Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Phosphotransferases Plasma Proteins Pregnancy Pregnant Women Pregnant sheep Property Proteins Rattus Resources Rodent Model Safety Series Serology Sheep Solubility Systemic infection Testing Therapeutic Toll-like receptor 11 Toxic effect Toxicity Tests Toxicology Toxoplasma Toxoplasma gondii Toxoplasmosis Vertical Disease Transmission Work Zebrafish analog calcium-dependent protein kinase congenital infection design drug development experience fetal infection fetal loss improved in vitro testing in vivo kinase inhibitor lead candidate model development mouse model novel therapeutics pathogen pharmacokinetics and pharmacodynamics pre-clinical pregnant response safety testing scaffold scale up screening sheep model stillbirth success transmission process

项目摘要

Abstract: Bumped-Kinase Inhibitor Drug Development for Toxoplasmosis Toxoplasma gondii infection is the most common known parasitic infection and causes systemic infections, particularly severe in immunocompromised humans, that damage the central nervous system. No clear beneficial therapy exists for pregnant women, who are experiencing new infections and possible fetal infection. Bumped-kinase inhibitors (BKIs) target Calcium-Dependent Protein Kinase 1, necessary for cell entry and growth of T. gondii. We have developed and shown proof-of-concept for treating Toxoplasma gondii CNS infections and pregnancy infections with BKIs. However, our late leads still have some issues such as optimal CNS penetration and metabolites associated with safety issues. In Aim 1 of the proposed work, we will develop BKIs that retain high systemic concentrations and distribution to both the central nervous system (CNS) AND the fetus with acceptable safety attributes for use in pregnancy. This work will be aided by the extensive knowledge of our leads, computational predictions, and iterative experimentation addressing the few remaining issues. We will elucidate the pharmacodynamics and pharmacokinetics (PK/PD) associated with efficacious T. gondii therapy, an area that hasn’t been explored before in toxoplasmosis therapy. Once optimal BKIs are obtained and the optimal PK/PD known, in Aim 2 we will test BKI late leads for effects in rodent and ovine models of congenital toxoplasmosis. The pregnant mice T. gondii congenital model will be useful for prioritizing compounds to further study in the pregnant sheep T. gondii congenital model. The pregnant sheep T. gondii congenital model is a superior model for human T. gondii congenital therapy than the mouse model because of similarities in sheep and humans (vs. mice) in length of gestation, numbers of fetuses per pregnancy, similarities in outcomes of congenital infection, and immune recognition of T. gondii. Our deliverables will be late lead BKIs, with demonstrated safety and efficacy in two animal models of congenital toxoplasmosis, to advance to GLP toxicity testing required for IND approval. Our likelihood for success is greatly improved by our collective knowledge from working on these compounds for cryptosporidiosis and the well-established scientific team together with advisors and consultants from our partners at PATH, AbbVie, and Bayer, who have decades of experience in pharmaceutical development.

摘要：激酶抑制剂的弓形虫病弓形虫弓形虫感染是最常见的寄生虫感染，引起全身感染，在免疫功能低下的人类中特别严重，这会损害中枢神经系统。不清楚对于正在经历新感染和可能的胎儿感染的孕妇而存在有益疗法。碰撞 - 激酶抑制剂（BKIS）靶靶依赖性蛋白激酶1，对于细胞进入和 T. gondii的生长。我们已经开发并显示了用于治疗弓形虫gondii cns的概念证明 BKIS感染和妊娠感染。但是，我们晚期的潜在客户仍然有一些问题，例如最佳中枢神经系统渗透和与安全问题相关的代谢物。在拟议工作的目标1中，我们将开发BKI，将高度全身浓度和分布到中枢神经系统（CNS）和具有可接受的安全性属性的胎儿。这项工作将由广泛了解我们的潜在客户，计算预测和迭代实验，以解决少数剩下的问题。我们将阐明与相关的药物动力学和药代动力学（PK/PD）这是一种有效的T. gondii疗法，在弓形虫病治疗之前尚未探索过一个领域。一旦最佳获得了BKIS，并且已知的最佳PK/PD，在AIM 2中，我们将测试BKI后期的铅，以确保啮齿动物的效果和怀孕的小鼠T. gondii先天性模型将对优先考虑在怀孕的绵羊T. gondii先天性模型中进一步研究化合物。怀孕的羊 T. gondii先天性模型是与小鼠模型相比，人类T. gondii先天性疗法的出色模型由于妊娠的长度上的绵羊和人类（相对于小鼠）的相似之处，胎儿数量怀孕，先天性感染结果的相似之处以及T. gondii的免疫识别。我们的可交付成果将是较晚的BKIS，在两个先天性动物模型中具有安全性和效率弓形虫病，以促进GLP毒性测试以进行IND批准。我们成功的可能性是我们的集体知识从从事这些化合物进行隐孢子虫病和与我们合作伙伴的顾问和顾问，Abbvie和拜耳，在制药开发方面拥有数十年的经验。