Optimizing CDPK1 inhibitors for chronic toxoplasmosis

优化慢性弓形虫病的 CDPK1 抑制剂

基本信息

批准号：
10457052
负责人：
James W Janetka
金额：
$ 78.73万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10457052
关键词：
Achievement Acute Allergic Reaction Animal Model Binding Biological Assay Biological Availability Cells Chronic Clinic Cyst Data Disease Drug Kinetics Enzymes Family Future Gatekeeping Glycine Goals Growth Human Immune response Immune system Immunity Immunocompetent Immunocompromised Host In Vitro Individual Infant Infection Infection Control Laboratories Lead Mammalian Cell Metabolism Monitor Mus Neuraxis Oral Parasites Parasitic infection Penetration Persons Pharmaceutical Preparations Phase Phosphotransferases Plants Plasma Positioning Attribute Pregnancy Property Pyrimethamine Recurrence Resistance development Risk Safety Severities South America Specificity Sulfadiazine Teratogens Testing Tissues Toxic effect Toxoplasma gondii Toxoplasmosis acute infection analog base calcium-dependent protein kinase chemotherapy chronic infection congenital infection design efficacy testing immune function improved in vivo in vivo evaluation inhibitor mouse model opportunistic pathogen pre-clinical preservation small molecule small molecule inhibitor src-Family Kinases sulfa drug toxoplasmic encephalitis

项目摘要

PROJECT SUMMARY Toxoplasma gondii is an opportunistic pathogen that causes disease in immunocompromised patients and in infants due to congenital infections. Following a brief acute phase, the parasite differentiates into a semi- dormant form called the bradyzoite, which resides within long-lived tissue cysts that are primarily located in the central nervous system (CNS). Despite a vigorous immune response, tissue cysts are not eliminated and they pose a risk of reactivation when immunity wanes. It is estimated that ~2 billion people worldwide are chronically infected with T. gondii and hence at risk of reactivation should their immune function decline. In many regions of South America, infection can lead to severe and recurrent ocular disease in immunocompetent individuals. Chemotherapy is available for acute toxoplasmosis based on a combination of pyrimethamine and sulfadiazine. However, there are complications due to the toxicity of pyrimethamine and allergic reactions to sulfa drugs. Moreover, this treatment poses risks during pregnancy due to teratogenicity. Current treatment is effective in controlling acute infection, but has minimal effect on chronic tissue cyst stages and hence is not curative. Although a number of new compounds have been shown to inhibit T. gondii growth in vitro, most have little effect on the chronic stage. Hence, there is a major need for new efforts to identify compounds for treating chronic toxoplasmosis. The goal of this project is to identify late stage preclinical leads that show potent inhibition of parasite growth in vitro, eliminate chronic infection in vivo, and that possess appropriate ADME and safety profiles for advancement. We will develop potent and selective inhibitors of TgCDPK1, which is an unique and essential enzyme in T. gondii. In preliminary studies, we have identified several lead compounds that are both highly potent and selective for TgCDPK1 over mammalian kinases. We will design and synthesize new analogs to improve potency, selectivity, CNS penetration, bioavailability, and ADMET-PK properties of these compounds. Specific criteria for potency, selectivity and ADMET properties will be used to advance compounds to in vivo testing. We have developed new quantitative assays for monitoring inhibition of acute and chronic stages of infection and we will employ animal models for monitoring the efficacy of compounds against reactivated toxoplasmosis in the CNS. Successful achievement of these milestones will deliver lead compound(s) for future IND-enabling studies with the eventual goal of curing chronic toxoplasmosis.

项目摘要弓形虫Gondii是一种机会性病原体，可在免疫功能低下的患者中引起疾病由于先天性感染而引起的婴儿。在短暂的急性阶段之后，寄生虫分化为半休眠形式称为Bradyzoite，它位于主要位于较长的组织囊肿中中枢神经系统（CNS）。尽管有剧烈的免疫反应，但没有消除组织囊肿，它们当免疫力降低时，会产生重新激活的风险。据估计，全球约有20亿人长期感染了T. gondii，因此如果其免疫功能下降，则有重新激活的风险。在南美的许多地区，感染可能导致严重和复发的眼部疾病免疫能力的个体。化学疗法可用于急性弓形虫病嘧啶胺和磺迪嗪。但是，由于乙胺胺的毒性和对Sulfa药物的过敏反应。此外，这种治疗在怀孕期间因致畸性带来风险。当前治疗可有效控制急性感染，但对慢性组织囊肿的影响最小因此无法治愈。尽管已经显示出许多新化合物抑制巨型猪螺旋杆菌的生长在体外，大多数在慢性阶段几乎没有影响。因此，需要新的努力来确定用于治疗慢性弓形虫病的化合物。该项目的目的是确定显示寄生虫有效抑制的晚期临床前线体外生长，消除体内慢性感染，并具有适当的ADME和安全性概况进步。我们将开发出TGCDPK1的有效和选择性抑制剂，这是一个独特而必不可少的 T. gondii中的酶。在初步研究中，我们已经确定了几种高度的铅化合物哺乳动物激酶比TGCDPK1有效和选择性。我们将设计和合成新的类似物提高这些化合物的效力，选择性，CNS渗透，生物利用度和ADMET-PK特性。效力，选择性和ADMET特性的特定标准将用于推进体内化合物测试。我们开发了新的定量测定法，以监测抑制急性和慢性阶段的抑制感染，我们将采用动物模型来监测化合物对重新激活的化合物的功效中枢神经系统中的弓形虫病。这些里程碑的成功实现将为未来的辅助研究最终是治愈慢性毒质剂的目标。