Pharmacological chaperones for the treatment of Open-Angle Glaucoma

开角型青光眼是全球第二大致盲原因，影响近70 百万人。肌球蛋白基因的非同义突变导致最常见的 遗传性开角型青光眼，占所有病例的3-4%。致病 定位于其嗅觉调节蛋白结构域（mOLF）的突变使肌球蛋白不稳定， 其在小梁网细胞的内质网中的错误折叠和积累， 从而激活最终导致细胞死亡和疾病的细胞应激反应 进展药理分子伴侣是一种小分子，可以与蛋白质结合， 它们的天然构象，防止蛋白质的聚集或异常行为，从而 纠正疾病。在这个建议中，我们概述了一个战略，以确定一个药理伴侣 与肌球蛋白结合，稳定它，防止小梁细胞死亡， 并阻止疾病发展。与目前针对继发性的治疗相反， 症状，如眼内压，我们的方法是第一个治疗开放， 角型青光眼，纠正疾病的根本原因。 目标1 -执行基于片段的NMR筛选，以鉴定小分子mOLF结合剂 并使用X射线晶体学表征它们的结合模式。 目标2 -合成或购买精心制作的命中片段，以生成一个集中的文库， mOLF药理学伴侣。 目的3 -使用体外测定筛选和选择聚焦文库以定义 精心制作的击中碎片 我们的预期结果是2-3个先导分子符合我们定义的效价目标， 用于稳健的潜在客户优化活动的合适的起点，以识别临床候选者， 发展这样的运动将涉及增加药物化学资源，在体外 PK和ADME表征，以及在肌球蛋白相关的小鼠模型中的药理学研究 青光眼;这项工作将构成STTR II期计划。

Open-angle glaucoma is the second leading cause of blindness worldwide, affecting nearly 70 million individuals. Nonsynonymous mutations in the myocilin gene lead to the most common hereditary form of open-angle glaucoma and account for 3-4% of all cases. Disease-causing mutations, localized to its olfactomedin domain (mOLF), destabilize the myocilin protein, leading to its misfolding and accumulation in the endoplasmic reticulum of trabecular meshwork cells, thereby activating a cellular stress response that ultimately results in cell death and disease progression. Pharmacological chaperones are small molecules that bind to proteins and stabilize their native conformation, preventing aggregation or aberrant behavior of the protein, and thereby correcting disease. In this proposal, we outline a strategy to identify a pharmacological chaperone that binds to myocilin protein, stabilizing it, preventing the death of trabecular meshwork cells, and halting disease progression. In contrast to current therapies which target secondary symptoms such as intraocular pressure, our approach represents the first treatment for open- angle glaucoma that corrects the fundamental cause of disease. Aim 1 – Execute a fragment-based NMR screen to identify small molecule mOLF binders and characterize their binding modes using X-ray crystallography. Aim 2 –Synthesize or purchase elaborated hit fragments to generate a focused library of mOLF pharmacological chaperones. Aim 3 – Screen and select the focused library using in vitro assays to define SAR of elaborated hit fragments. Our expected outcomes are 2-3 lead molecules that meet our defined potency targets and are suitable starting points for a robust lead-optimization campaign to identify a clinical candidate for development. Such a campaign would involve increased medicinal chemistry resources, in vitro PK and ADME characterization, and pharmacology studies in a mouse model of myocilin-linked glaucoma; this work would constitute a STTR Phase II program.