Rational design of CNS-permeable cathepsin L inhibitors for treatment of chronic toxoplasmosis

中枢神经系统渗透性组织蛋白酶 L 抑制剂治疗慢性弓形虫病的合理设计

基本信息

批准号：
9813831
负责人：
Vernon Bruce Carruthers
金额：
$ 45.97万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-01 至 2021-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9813831
关键词：
ABCB1 gene Ablation Address American Attenuated Biochemistry Biological Assay Blindness Blood - brain barrier anatomy Brain Brain Diseases Cathepsin L Cathepsins Cell Respiration Cells Cellular Assay Cessation of life Chemicals Chronic Crystallization Cyst Cytoplasm Dipeptides Dose Drug Kinetics Encephalitis Enzymes Genetic Goals Half-Life Heart Diseases Human Immune system In Vitro Individual Infection Intraperitoneal Injections Lead Life Liver Microsomes Lysosomes Maximum Tolerated Dose Measures Membrane Modeling Mus Myocarditis Neuropharmacology Nitriles P-Glycoprotein Parasites Parasitology Pathogenesis Penetrance Peptide Hydrolases Peripheral Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Phase Plants Posterior Uveitis Property Proteins Recombinants Reporting Risk Roentgen Rays Role Structure System Therapeutic Tissues Toxoplasma gondii Toxoplasmosis Treatment Protocols Vacuole Virulence Visual impairment Work acute infection analog base carboxypeptidase C chronic infection combat design drug development foodborne high risk improved in vitro Model inhibitor/antagonist innovation mouse model novel physical property pre-clinical preclinical development relating to nervous system small molecule inhibitor stem tool unpublished works

项目摘要

PROJECT SUMMARY The complete absence of treatment options for chronic Toxoplasma gondii (Tg) infection renders ~2 billion people at risk for reactivated toxoplasmosis. Congenitally infected individuals or those with weakened immune systems are particularly vulnerable to reactivated toxoplasmosis manifested as fatal encephalitis, myocarditis or loss of vision. As the leading cause of infectious posterior uveitis and second leading cause of foodborne deaths in the USA, reactivated toxoplasmosis could be substantially reduced in high-risk individuals by eliminating Tg tissue cysts. We used new genetic tools to identify an essential role for a cathepsin protease L (CPL) activity during chronic Tg infection, creating an exciting opportunity to exploit a new target for combatting reactivated toxoplasmosis. To begin addressing this key unmet need, we identified an initial lead dipeptide nitrile CPL inhibitor based on its potential for CNS penetrance and conducted primary SAR studies against Tg and human cathepsin L, demonstrating that we could achieve over 100-fold improvement in selectivity for the Tg enzyme in under 20 analogs. In the R21 phase we will use structure-based design to further optimize potency and selectivity along with improving stability and permeability in in vitro models, delivering one or more potent, selective, stable, and cell-permeable leads. In the R33 phase we will evaluate and further refine PK and CNS penetrance in mice before measuring maximum tolerated dose and efficacy in an established murine treatment model for chronic Tg infection. Both phases will feature first-of-their-kind assays for cyst viability developed for the studies. Upon successful completion, this project will yield one or more Tg CPL inhibitors effective for reducing or eliminating tissue cysts, thereby advancing a potential new solution for chronic Tg infection. 1

项目摘要完全没有慢性弓形虫（TG）感染的治疗选择〜2 有十亿人患有弓形虫病的风险。先天感染的人或那些有弱的人免疫系统特别容易激活重新激活的弓形虫病，表现为致命性脑炎，心肌炎或视力丧失。作为传染性后葡萄膜炎的主要原因，以及在美国的食源性死亡，在高风险中可以大大降低重新激活的弓形虫病通过消除TG组织囊肿的个体。我们使用新的遗传工具来确定一个慢性TG感染期间的组织蛋白酶蛋白酶L（CPL）活性，创造了一个令人兴奋的机会来利用A 打击重新激活弓形虫病的新目标。为了开始满足这个关键需求，我们根据CNS渗透率和对TG和人类组织蛋白酶L进行了主要的SAR研究，表明我们可以实现在20岁以下的类似物中，TG酶的选择性提高了100倍以上。在R21阶段，我们将使用基于结构的设计来进一步优化效力和选择性，并提高稳定性和体外模型中的渗透性，提供一个或多个有效，选择性，稳定和可渗透细胞的铅。在 R33阶段我们将在测量之前评估小鼠的PK和CNS渗透率在慢性TG感染的已建立的鼠类治疗模型中，最大耐受剂量和功效。这两个阶段都将采用用于研究开发的囊肿生存能力的首先实现测定。成功完成，该项目将产生一个或多个TG CPL抑制剂，可有效减少或消除组织囊肿，从而推进了慢性TG感染的潜在新解决方案。 1