权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
10579941
负责人：
WESLEY C VAN VOORHIS
金额：
$ 64.96万
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/10579941
关键词：
Acute Address Animal Model Animals Area Binding Proteins Biological Assay Blood Brain Cardiac Cardiotoxicity Cardiovascular system Cells Central Nervous System 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 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 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 placental infection 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.

翻译后摘要：凹凸激酶抑制剂的药物开发弓形虫病弓形虫感染是已知的最常见的寄生虫感染并引起全身感染，在免疫功能低下的人中尤其严重，会损害中枢神经系统。没有明确对于正在经历新的感染和可能的胎儿感染的孕妇，存在有益的治疗。冲击激酶抑制剂（BKI）靶向钙依赖性蛋白激酶1，这是细胞进入和 T.的生长刚地。我们已经开发并展示了治疗弓形虫CNS的概念验证感染和妊娠感染。然而，我们的后期线索仍然有一些问题，如最佳与安全性问题相关的CNS渗透和代谢物。在拟议工作的目标1中，我们将开发保持高全身浓度和分布到中枢神经系统的BKI (CNS)且胎儿在妊娠期使用时具有可接受的安全属性。这项工作将得到对我们的线索、计算预测和迭代实验的广泛了解，剩下的问题。我们将阐明与以下药物相关的药效学和药代动力学（PK/PD）：有效T.弓形虫病的治疗，这是一个在弓形虫病治疗中从未探索过的领域。一旦最佳获得BKI并已知最佳PK/PD，在目标2中，我们将测试BKI晚期先导化合物在啮齿动物中的作用，先天性弓形虫病的绵羊模型。妊娠小鼠T.弓形虫先天性模型将是有用的，优先选择化合物以进一步研究怀孕的绵羊T.弓形虫先天性模型怀孕的羊 T.弓形虫先天性模型是人弓形虫的上级模型。先天性弓形虫小鼠模型的治疗由于绵羊和人类（与小鼠）在妊娠期的相似性，妊娠、先天性感染结局的相似性以及T.刚地。我们可交付成果将是晚期电极导线BKI，在两种先天性心脏病动物模型中证明了安全性和有效性。弓形虫病，推进到IND批准所需的GLP毒性测试。我们成功的可能性是通过我们研究这些化合物治疗隐孢子虫病和隐孢子虫病的集体知识，我们的水平得到了极大的提高完善的科学团队，以及来自PATH、AbbVie和拜耳，谁拥有几十年的经验，在药物开发。