Pharmacological chaperones for the treatment of Open-Angle Glaucoma

治疗开角型青光眼的药理学伴侣

• 批准号: 9909736
• 负责人: Leah Nicole MAKLEY
• 金额: $ 22.5万
• 依托单位: VIEWPOINT THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9909736
• 关键词: Affect; Amyloid; Behavior; Binding; Blindness; Cardiomyopathies; Cataract; Cell Death; Cell model; Cell secretion; Cells; Cellular Stress; Cellular Stress Response; Cessation of life; Chemicals; Chemistry; Clinical Treatment; Clinical Trials; Crystallization; Development; Disease; Disease Progression; Endoplasmic Reticulum; Fabry Disease; Future; Genes; Glaucoma; Goals; In Vitro; Individual; Inherited; Lead; Libraries; Ligands; Link; Molecular Chaperones; Molecular Conformation; Open-Angle Glaucoma; Outcome; Pharmaceutical Chemistry; Pharmacology; Pharmacology Study; Phase; Physiologic Intraocular Pressure; Prealbumin; Proteins; Public Health; Published Comment; Resources; Roentgen Rays; Signal Transduction; Small Business Technology Transfer Research; Structure; Symptoms; Therapeutic; TimeLine; Trabecular meshwork structure; United States; Work; X-Ray Crystallography; alpha-Crystallins; analog; base; clinical candidate; disease-causing mutation; in vitro Assay; lead optimization; mouse model; myocilin; nonsynonymous mutation; olfactomedin; prevent; programs; protein misfolding; scaffold; small molecule; theories

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.

开角型青光眼是全球第二大致盲原因，影响了近70%的人。 百万人。Myocin基因的非同义突变导致最常见的 遗传性开角型青光眼，占全部病例的3-4%。致病 突变，定位于其分子内结构域(Molf)，破坏了myoclin蛋白的稳定性，导致 由于它的错误折叠和在小梁细胞内质网中的堆积， 从而激活细胞应激反应，最终导致细胞死亡和疾病 进步。药理伴侣是与蛋白质结合并稳定的小分子。 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。在这项提案中，我们概述了一种确定药理伴侣的策略 它能与肌球蛋白结合，稳定它，防止小梁细胞死亡， 并阻止疾病的发展。与目前针对继发性心脏病的治疗不同 症状，如眼压，我们的方法是第一次治疗开放的 房角型青光眼，纠正疾病的根本原因。 目标1-执行基于片段的核磁共振筛查以识别小分子Molf结合剂 并用X射线结晶学表征了它们的结合方式。 目标2-合成或购买精心制作的热门片段，以生成一个专题库 Molf药理伴侣。 Aim 3-使用体外实验筛选和选择聚焦文库以确定 精心制作的热门片段。 我们的预期结果是2-3个铅分子达到我们定义的效力目标，并 为确定临床候选对象而开展的强有力的线索优化活动的合适起点 发展。这样的运动将涉及增加体外药物化学资源。 霉菌素连接小鼠模型的PK和ADME特征及药理学研究 青光眼；这项工作将构成STTR第二阶段计划。