DESIGNING SELECTIVE INHIBITORS OF CALCIUM-DEPENDENT KINASES IN PARASITES

描述（由申请方提供）：弓形虫和微小隐孢子虫是重要的机会致病菌，可在免疫功能低下的人群中引起毁灭性疾病。两者都能引起食物或水传播的感染，因此也是对健康个体的威胁。严重感染T.弓形虫通常发生在免疫功能低下的患者中，包括HIV感染、癌症化疗、器官移植或子宫内感染的婴儿。此外，新的研究表明，严重的眼部疾病也可能发生在健康的成年人身上。隐孢子虫也会在免疫功能低下的患者中引起严重的结肠炎，缺乏有效的治疗方法阻碍了治疗。隐孢子虫还已知由于受污染的家庭供水而在健康个体中引起使人衰弱的疾病的广泛爆发。由于缺乏有效药物和/或对现有药物不耐受，这些寄生虫引起的感染的治疗变得复杂。因此，需要开发新的治疗剂来治疗这些寄生虫的感染。本课题的目标是开发钙依赖性蛋白激酶（CDPK）家族寄生虫特异性激酶的小分子抑制剂。CDPKs是植物样蛋白激酶，在动物细胞中没有发现，但它们在顶复门寄生虫中扩增。我们最近使用分子遗传学和化学生物学方法的研究表明，CDPK 1是寄生虫生长所必需的。我们还证明，CDPK 1是特异性和有效地抑制了庞大的ATP类似物，这对宿主激酶的活性有限。我们将继续寻找具有更大效力的改进的抑制剂，用于选择性抑制T细胞的CDPK 1。gondii和C.使用生物化学、分子遗传学、化学生物学和药物化学方法的组合来研究parvum。我们还将设计，合成和测试新的抑制剂，改善体内治疗的药理学特性。将评价选择性抑制剂在弓形虫病啮齿动物模型中预防急性和慢性感染的能力。

DESCRIPTION (provided by applicant): Toxoplasma gondii and Cryptosporidium parvum are important opportunistic pathogens that cause devastating disease in immunocompromised humans. Both are capable of causing food or waterborne infections and hence are also a threat to healthy individuals. Severe infections with T. gondii typically occur in immunocompromised patients, including HIV infection, cancer chemotherapy, organ transplant, or infants infected in utero. Additionally, new studies indicate that severe ocular disease can also occur in healthy adults. Cryptosporidium also causes severe diarrheal disease in immunocompromised patients and treatment is hampered by the lack of effective therapy. Cryptosporidium has also been known to cause widespread outbreaks of debilitating illness in healthy individuals due to contaminated domestic water supplies. Treatment of infections caused by these parasites is complicated by lack of effective medicines and/or intolerance to currently available drugs. Hence, there is a need to develop new therapeutic agents to treat infections with these parasites. The goal of our project is to develop small molecule inhibitors of parasite-specific kinases belonging to the calcium-dependent protein kinase (CDPK) family. CDPKs are plant-like protein kinases that are not found in animal cells, yet they are expanded in apicomplexan parasites. Our recent studies using molecular genetic and chemical biology approaches reveal that CDPK1 is essential for parasite growth. We have also demonstrated that CDPK1 is specifically and potently inhibited by bulky ATP analogs, which have limited activity against host kinases. We will pursue identification of improved inhibitors with greater potency for selective inhibition of CDPK1 from T. gondii and C. parvum using a combination of biochemical, molecular genetic, chemical biology and medicinal chemistry approaches. We will also design, synthesize, and test new inhibitors with improved pharmacological properties for in vivo treatment. Selective inhibitors will be evaluated for their ability to prevent acute and chronic infection in a rodent model for toxoplasmosis.