Bumped-Kinase Inhibitor Drug Development for Toxoplasmosis

文章摘要：治疗弓形虫病的蛋白激酶抑制剂药物研究进展 弓形虫感染是已知的最常见的寄生虫感染，会导致全身感染， 在免疫功能低下的人中尤其严重，会损害中枢神经系统。不清楚 对于正在经历新的感染和可能的胎儿感染的孕妇来说，存在有益的治疗方法。 蛋白激酶抑制物(BKIs)靶向钙依赖蛋白激酶1，细胞进入和释放所必需的 弓形虫的生长。我们已经开发并展示了治疗弓形虫中枢神经系统的概念验证 BKI感染和妊娠感染。然而，我们最近的线索仍然存在一些问题，比如最优 中枢神经系统的渗透性和代谢物相关的安全问题。在拟议工作的目标1中，我们将 开发BKI，保持较高的全身浓度并分布到两个中枢神经系统 (中枢神经系统)和具有可接受的用于怀孕的安全属性的胎儿。这项工作将得到 对我们的线索、计算预测和针对少数人的迭代试验有广泛的了解 遗留问题。我们将阐明相关的药效学和药代动力学(PK/PD) 有效的弓形虫治疗，这是以前在弓形虫病治疗中从未探索过的领域。一度最优 在目标2中，我们将测试BKI迟发导联对啮齿动物和 先天性弓形虫病的绵羊模型。妊娠小鼠弓形虫先天模型将有助于 在妊娠绵羊弓形虫先天性模型中优先考虑化合物的进一步研究。怀孕的绵羊 弓形虫先天模型是一种优于小鼠模型的人类弓形虫先天治疗模型 由于绵羊和人类(与老鼠)在孕期长短上相似，每只羊的胎儿数量 妊娠、先天性感染结局的相似性以及弓形虫的免疫识别。我们的 交付成果将是晚期铅BKIs，在两个先天性心脏病动物模型上证明了安全性和有效性。 弓形虫病，以推进IND批准所需的GLP毒性测试。我们成功的可能性是 通过研究这些化合物来治疗隐孢子虫病，我们的集体知识大大改进了 成熟的科学团队，以及我们在Path、AbbVie和 拜耳，他们在制药开发方面拥有数十年的经验。

Abstract: Bumped-Kinase Inhibitor Drug Development for Toxoplasmosis Toxoplasma gondii infection is the most common known parasitic infection and causes systemic infections, particularly severe in immunocompromised humans, that damage the central nervous system. No clear beneficial therapy exists for pregnant women, who are experiencing new infections and possible fetal infection. Bumped-kinase inhibitors (BKIs) target Calcium-Dependent Protein Kinase 1, necessary for cell entry and growth of T. gondii. We have developed and shown proof-of-concept for treating Toxoplasma gondii CNS infections and pregnancy infections with BKIs. However, our late leads still have some issues such as optimal CNS penetration and metabolites associated with safety issues. In Aim 1 of the proposed work, we will develop BKIs that retain high systemic concentrations and distribution to both the central nervous system (CNS) AND the fetus with acceptable safety attributes for use in pregnancy. This work will be aided by the extensive knowledge of our leads, computational predictions, and iterative experimentation addressing the few remaining issues. We will elucidate the pharmacodynamics and pharmacokinetics (PK/PD) associated with efficacious T. gondii therapy, an area that hasn’t been explored before in toxoplasmosis therapy. Once optimal BKIs are obtained and the optimal PK/PD known, in Aim 2 we will test BKI late leads for effects in rodent and ovine models of congenital toxoplasmosis. The pregnant mice T. gondii congenital model will be useful for prioritizing compounds to further study in the pregnant sheep T. gondii congenital model. The pregnant sheep T. gondii congenital model is a superior model for human T. gondii congenital therapy than the mouse model because of similarities in sheep and humans (vs. mice) in length of gestation, numbers of fetuses per pregnancy, similarities in outcomes of congenital infection, and immune recognition of T. gondii. Our deliverables will be late lead BKIs, with demonstrated safety and efficacy in two animal models of congenital toxoplasmosis, to advance to GLP toxicity testing required for IND approval. Our likelihood for success is greatly improved by our collective knowledge from working on these compounds for cryptosporidiosis and the well-established scientific team together with advisors and consultants from our partners at PATH, AbbVie, and Bayer, who have decades of experience in pharmaceutical development.