Exploiting Diversity-Oriented Chemical Synthesis for Combating Chronic Parasitic Infection

总结 我们研究的总体目标是鉴定具有适当效力、选择性和特异性的小分子抑制剂。 治疗慢性弓形虫病的安全性。弓形虫是一种广泛存在于动物体内的寄生虫， 会导致人类的机会性感染虽然健康的人控制感染，但他们不能 完全消灭它并保持慢性感染。并发症的发生是由于慢性 免疫功能低下患者的感染和怀孕期间寄生虫可以交叉感染的新感染 胎盘屏障并感染发育中的胎儿据估计，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。 现有的T.弓形虫只能有效抑制急性感染，但不能根除 慢性组织囊肿阶段。在初步研究中，我们进行了一个高通量筛选的多样性， 化合物的小分子文库，并确定了许多非常有效的抑制剂（低纳摩尔EC50）， 寄生虫体外生长。此外，这些高效力的先导物中的几种作用于感染的慢性阶段， 抑制弓形体病免疫受损小鼠模型中感染再活化。活性 这些化合物来自一个多样性导向的合成（DOS）库，该库是使用现代合成技术合成的。 方法的不对称有机化学，因此，他们是丰富的立体化学多样性。拟议 研究将集中在两个系列，显示出低nM的抑制T.弓形虫生长我们将开发 基于T.现有类似物对弓形虫生长的抑制作用。我们将设计和 合成新类似物以优化效力、安全性、代谢、脑渗透和药代动力学 特性.遗传学和基因组学方法将用于鉴定潜在的耐药性， 这些线索的作用机制。我们还将使用我们开发的动物模型 监测化合物对抗再活化弓形体病的功效。成功实现这些 这些目标将为未来的临床研究确定线索，旨在开发新的药物来根除慢性 弓形虫病

Summary The overall goal of our study is to identify small molecule inhibitors with appropriate potency, selectivity, and safety profiles to cure chronic toxoplasmosis. Toxoplasma gondii is a widespread parasite of animals that causes opportunistic infections in humans. Although healthy individuals control the infection, they are not able to completely eliminate it and remain chronically infected. Complications occur due to reactivation of chronic infections in immunocompromised patients and new infections during pregnancy when the parasite can cross the placental barrier and infect the developing fetus. 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. Existing chemotherapy for T. gondii is only effective at suppressing acute infection, but is unable to eradicate the chronic tissue-cyst stages. In preliminary studies, we have conducted a high throughput screen of a diverse small molecule library of compounds and identified a number of very potent inhibitors (low nanomolar EC50) of parasite growth in vitro. Additionally, several of these highly potent leads act on chronic stages of infection and suppress reactivation of infection in an immunocompromised mouse model of toxoplasmosis. The active compounds come from a diversity-oriented synthetic (DOS) library that was synthesized using modern methods of asymmetric organic chemistry, hence they are rich in stereochemical diversity. The proposed studies will focus on two series that display low nM potency in inhibiting T. gondii growth. We will develop structure activity relationships based on T. gondii growth inhibition by existing analogs. We will then design and synthesize new analogs to optimize potency, safety, metabolic, brain penetration, and pharmacokinetic properties. Genetic and genomic approaches will be used to identify potential resistance and confirm mechanisms of action of these leads. We will also employ animal models that we have developed for monitoring the efficacy of compounds against reactivated toxoplasmosis. Successful achievement of these goals will define leads for future clinical studies aimed at developing new drugs to eradicate chronic toxoplasmosis.