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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：
10090142
负责人：
WESLEY C VAN VOORHIS
金额：
$ 83.45万
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/10090142
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 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：用于隐孢子虫病治疗的铅BKI的优化本研究的广泛、长期目标是开发一种治疗隐孢子虫病的药物感染隐孢子虫感染引起持续性腹泻（隐孢子虫病），儿童和免疫功能低下者的发病率和死亡率增加。隐孢子虫是一种导致资源贫乏地区2岁以下营养不良儿童预后不良的最重要病原体包括>3倍的死亡率以及与发育迟缓和神经功能受损的密切关联发展唯一可用的治疗，硝唑尼特，不工作，在免疫功能低下的个人对营养不良儿童的疗效<30%。迫切需要新的隐孢子虫疗法。我们一直在开发选择性靶向隐孢子虫钙的缓冲激酶抑制剂（BKI），依赖性蛋白激酶1（CDPK 1）作为隐孢子虫病的治疗剂。在我们的项目中，我们的线索在小鼠、小牛和仔猪C. parvum 和C.人类，同时保留了几乎所有有利的安全方面与后期领先一致。然而，在这方面， BKI电极导线的安全性问题阻止了我们开发当前的晚期电极导线。我们现在知道，与晚期BKI电极导线相关的安全性问题，并发现这些安全性问题并非必然相关与BKI对隐孢子虫病的功效的结构-活性关系（SAR）。在本提案中，我们将使用有效性和安全性SAR帮助推动药物化学朝着后期临床前安全领先的方向发展，药代动力学和功效特性，可以开发用于在<2-yo的目标群体中治疗。营养不良的儿童和免疫力低下的人。目的是：目的1）建立后期线索，隐孢子虫病治疗，包括Subaims 1A）体外疗效和安全性试验，1B）IFN- γ -KO小鼠 nLuc-C。1C）小鼠多次给药，7天安全性测试，1D）确定BKI的代谢物，和，1 E）设计和合成新的BKI; AIM 2）在小牛临床模型中测试新型晚期电极导线，隐孢子虫病;和，AIM 3）评估晚期安全性试验的晚期电极导线，包括子目标3A）骨安全性试验，3B）妊娠/发育/胎仔安全性试验; 3C）大鼠和犬心血管（CV）安全性 3D）Pre-GLP安全性和多晶型物测试。在资助期结束时，我们预计将有一个临床前先导化合物和至少一种备用分子，准备进入GLP安全性测试，GMP前生产规模扩大，IND申请转向BKI治疗隐孢子虫病的人体试验。