Optimizing CDPK1 inhibitors for chronic toxoplasmosis

项目总结 弓形虫是一种机会性病原体，可在免疫功能低下的患者和 婴儿因先天感染。在短暂的急性期之后，寄生虫分化为半 休眠的形式称为缓殖体，它驻留在长寿的组织包囊中，这些包囊主要位于 中枢神经系统(CNS)。尽管有强烈的免疫反应，但组织囊肿并未被消除，它们 当免疫力减弱时会有重新激活的风险。据估计，全球约有20亿人 长期感染弓形虫，因此如果他们的免疫功能下降，就有重新激活的风险。在……里面 在南美洲的许多地区，感染可导致严重和复发的眼病 有免疫能力的人。化疗可用于急性弓形虫病，其基础是 乙胺嘧啶和磺胺嘧啶。然而，由于乙胺嘧啶的毒性和并发症， 对磺胺类药物过敏反应。此外，由于致畸作用，这种治疗在怀孕期间会带来风险。 目前的治疗方法对控制急性感染是有效的，但对慢性组织囊肿期的影响很小。 因此不能治愈。尽管一些新化合物已被证明可以抑制弓形虫的生长 在体外，大多数药物对慢性期几乎没有影响。因此，主要需要作出新的努力，以确定 治疗慢性弓形虫病的化合物。 该项目的目标是确定对寄生虫有有效抑制作用的晚期临床前线索。 体外生长，消除体内慢性感染，并具有适当的ADME和安全配置文件 进步。我们将开发有效的和选择性的TgCDPK1抑制剂，这是一个独特的和必不可少的 弓形虫中的酶。在初步研究中，我们已经确定了几种先导化合物，它们都是高度 对TgCDPK1的有效和选择性高于哺乳动物的激酶。我们将设计和合成新的类似物来 提高这些化合物的效力、选择性、中枢神经系统渗透性、生物利用度和ADMET-PK性能。 药效、选择性和适配性的特定标准将用于将化合物推进到体内 测试。我们已经开发了新的定量分析方法来监测急性和慢性阶段的抑制 感染，我们将使用动物模型来监测化合物对再激活的疗效 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目标提供领先化合物(S) 未来支持IND的研究，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.