Optimization of Lead BKIs for Cryptosporidiosis Therapy

用于隐孢子虫病治疗的先导 BKI 的优化

基本信息

批准号：
10322085
负责人：
WESLEY C VAN VOORHIS
金额：
$ 80.97万
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：
2021-01-01 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10322085
关键词：
3-Dimensional Address Animals Back Blood Chemical Analysis Canis familiaris Cardiac Cardiovascular system Cause of Death Characteristics Child Chondrocytes Clinical Country Cryptosporidiosis Cryptosporidium Cryptosporidium parvum Development Diarrhea Disease Dose Drug Kinetics Dysplasia Embryonic Development Fetal Development Fetal safety Grant Growth Hemorrhage Histopathology Human Immunocompromised Host Impairment In Vitro Individual Infection Interferon Type II Knockout Mice Lead MAP2K1 gene Malnutrition Mammalian Cell Metabolic Pathway Modeling Morbidity - disease rate Mus Neurologic Newborn Infant Oral Outcome Pharmaceutical Chemistry Pharmaceutical Preparations Phosphotransferases Plasma Polymorph Pregnancy Property Rattus Research Resources Safety Sampling Solubility Staphylococcus hominis Structure-Activity Relationship Symptoms Target Populations Testing Therapeutic Therapy trial Toxic effect Toxicity Tests Toxicology Vaccines Zebrafish bone calcium-dependent protein kinase cytotoxicity design dosage drug candidate efficacy testing improved in vivo inhibitor therapy kinase inhibitor lead optimization manufacturing scale-up mortality motility disorder nitazoxanide novel novel therapeutics pathogen porcine model pre-clinical programs response safety study safety testing screening

项目摘要

ABSTRACT: Optimization of Lead BKIs for Cryptosporidiosis Therapy The broad, long-term objective of this research is to develop a therapeutic for treatment of Cryptosporidium infection. Cryptosporidium infection causes persistent diarrhea (cryptosporidiosis) that is associated with increased morbidity and mortality in children and immunocompromised individuals. Cryptosporidium is one of the most important pathogens leading to poor outcomes in <2-yo malnourished children in resource poor countries, including >3-fold mortality and strong associations with stunting and impaired neurological development. The only available therapeutic, nitazoxanide, does not work in immunocompromised individuals and has <30% efficacy in malnourished children. New therapeutics for Cryptosporidium are badly needed. We have been developing bumped-kinase inhibitors (BKIs) that selectively target Cryptosporidium calcium- dependent protein kinase 1 (CDPK1) as therapeutics for cryptosporidiosis. In our program, our leads have performed very well, demonstrating efficacy at low oral dosages in mouse, calf, and piglet models of C. parvum and C. hominis, while retaining almost all the favorable safety aspects consistent with a late lead. However, safety issues with BKI leads have stopped us from developing current late leads. We now understand the safety issues associated with late BKI leads and have found these safety issues are not inextricably associated with the structure-activity relationship (SAR) of BKIs’ efficacy against cryptosporidiosis. In this proposal, we will use the efficacy and safety SAR to help drive medicinal chemistry towards a late pre-clinical lead with safety, pharmacokinetic, and efficacy properties that can be developed for treatment in the target population of <2-yo malnourished children and immunocompromised individuals. The Aims are: AIM 1) Establish late leads for cryptosporidiosis therapy, including Subaims 1A) In vitro efficacy and safety testing, 1B) IFN- γ -KO mouse nLuc-C. parvum efficacy testing, 1C) Mouse multidosing, 7d safety testing, 1D) Determine metabolites of BKIs, and, 1E) Design and synthesize new BKIs; AIM 2) Test novel late leads in calf clinical model for cryptosporidiosis; and, AIM 3) Assess advanced late leads for late safety testing, including subaims 3A) Bone safety testing, 3B) Pregnancy/developmental/fetal safety testing; 3C) Rat and dog cardiovascular (CV) safety testing, and, 3D) Pre-GLP safety and polymorph testing. At the end of the grant period, we expect to have a preclinical lead and at least one back up molecule that is ready to move into GLP safety testing, pre-GMP manufacturing scale up, and IND filing to move towards human trials for a BKI for therapy of cryptosporidiosis.

摘要：对隐孢子虫病治疗的铅BKI的优化这项研究的广泛长期目标是开发一种治疗隐孢子虫的治疗方法感染。隐孢子虫感染会导致持续性腹泻（隐孢子虫病）与儿童和免疫功能低下的个体的发病率和死亡率增加。隐孢子虫是最重要的病原体导致资源<2年营养不良的儿童的结果不佳国家，包括3倍死亡率以及与神经系统受阻和受损的紧密联系发展。唯一可用的疗法Nitazoxanide在免疫功能低下的个体中不起作用营养不良的儿童效率<30％。急需用于隐孢子虫的新疗法。我们一直在开发碰撞 - 激酶抑制剂（BKIS），这些抑制剂有选择地靶向钙孢子虫钙依赖性蛋白激酶1（CDPK1）作为隐孢子虫病的治疗。在我们的计划中，我们的潜在客户有表现很好，在小鼠，小牛和小猪模型中表现出有效性和C. hominis，同时保留了几乎所有有利的安全方面，与较晚的铅一致。然而， BKI潜在客户的安全问题使我们无法发展当前的较晚铅。我们现在了解与晚期BKI铅相关的安全问题，发现这些安全问题与不可密切相关 BKIS针对隐孢子虫病的效率的结构活性关系（SAR）。在此提案中，我们将使用效率和安全性SAR来帮助将医学化学推向安全性的晚期临床前铅，以安全性，可以开发用于<2-yo的目标群体治疗的药代动力学和效率营养不良的儿童和免疫功能低下的人。目的是：目标1）为隐孢子虫病治疗，包括Subiaims 1a）体外效率和安全测试，1B）IFN -γ -KO小鼠 NLUC-C。 parvum效率测试，1C）小鼠多能，7D安全测试，1D）确定BKIS的代谢物，以及，1E）设计和合成新的BKIS；目标2）在小牛临床模型中测试新颖的较晚铅隐孢子虫病；，AIM 3）评估晚期安全测试的高级较晚铅，包括Subiaims 3A）骨头安全测试，3B）怀孕/发育/胎儿安全测试； 3C）大鼠和狗心血管（CV）安全测试，以及3D）GLP前安全性和多晶型物测试。在赠款期结束时，我们希望有一个临床前铅和至少一个准备进入GLP安全测试的备份分子，前GMP 制造规模扩大，并提出IND申请，以朝着人体试验进行BKI治疗隐孢子虫病治疗。