Optimizing CDPK1 inhibitors for chronic toxoplasmosis

项目摘要 弓形虫是一种机会致病菌，可引起免疫功能低下的患者和 婴儿由于先天性感染。在短暂的急性期后，寄生虫分化为半- 休眠的形式称为缓殖子，它居住在长寿的组织囊肿，主要位于 中枢神经系统（CNS）。尽管有强烈的免疫反应，组织囊肿没有消除， 当免疫力减弱时会有重新激活的风险。据估计，全世界约有20亿人 慢性感染T.因此，如果他们的免疫功能下降，就有重新激活的危险。在 在南美洲的许多地区，感染可导致严重和复发性眼病， 免疫活性个体。化疗可用于急性弓形虫病，其基础是以下组合： 乙胺嘧啶和磺胺嘧啶。然而，由于乙胺嘧啶的毒性， 磺胺类药物过敏反应。此外，由于致畸性，这种治疗在妊娠期间存在风险。 目前的治疗方法在控制急性感染方面是有效的，但对慢性组织囊肿阶段的效果甚微 因此不是治愈性的。虽然许多新的化合物已被证明可以抑制T。弓形虫生长 在体外，大多数对慢性阶段几乎没有影响。因此，非常需要作出新的努力， 用于治疗慢性弓形体病的化合物。 该项目的目标是确定晚期临床前线索，显示有效抑制寄生虫 体外生长，消除体内慢性感染，并具有适当的ADME和安全性特征， 进步。我们将开发有效的和选择性的TgCDPK 1抑制剂，这是一种独特的和必不可少的抑制剂。 T.刚地。在初步研究中，我们已经确定了几种先导化合物， 相对于哺乳动物激酶，对TgCDPK 1有效且具有选择性。我们将设计和合成新的类似物， 改善这些化合物效力、选择性、CNS渗透、生物利用度和ADMET-PK性质。 将使用效力、选择性和ADMET性质的具体标准来推进化合物在体内的应用。 试验.我们已经开发了新的定量测定用于监测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再活化的 中枢神经系统的弓形虫病这些里程碑的成功实现将为以下方面提供先导化合物： 未来的IND使研究的最终目标是治愈慢性弓形虫病。

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.