Dynasore Analogues for Ocular Surface Protection

7.项目总结 眼表疾病是眼科医生就诊的主要原因之一。这些条件 会严重影响视力和生活质量。症状可能包括视力模糊、不适或疼痛， 发红、发痒，严重者可因角膜疤痕致盲。许多眼表疾病是 由泪膜动态平衡丧失所引发，可归入干眼症。撕裂 功能障碍会导致脱水压力，引发类似自身免疫的“炎症恶性循环” 损害眼表屏障。恶性循环被认为是病理性疾病的核心驱动因素 过程中，会导致慢性干眼症。抗炎类固醇与小分子靶向 自身免疫T细胞功能是目前唯一获得食品和药物管理局(FDA)批准的治疗药物。 这些药物并不是对所有患者都有效，需要很长时间才能起作用，而且有令人不快的副作用。 目前的观点认为，在其他切入点打破煽动性恶性循环是新的 治疗。直接保护眼表屏障可以提供这样一个新的切入点。这应该是 通过减缓炎症恶性循环来缓解慢性干眼症，就像目前的治疗方法一样。然而， 因为它代表了一个不同的切入点，所以它可能在现有药物有效的慢性情况下有效 不是工作。一种新的好处是，在干眼的情况下，可能会非常迅速地缓解眼睛刺激 因环境和其他因素而加剧。在最近的一份出版物中，与此相关的学术实验室 Project报道了一项新的发现，Dyasore和Dygo-4A对眼睛有显著的保护作用 表面屏障。DYNASORE和DYNGO-4A属于一组靶向动力蛋白家族的小分子 GTP酶，也保护细胞和组织免受氧化应激和减少炎性细胞因子 制作。治疗干眼的Dyasore类似物的创新之处在于它们针对的是眼表屏障 损坏。目前还没有在恶性循环的这一点上起作用的治疗方法。这个 该项目的长期目标是开发一种FDA批准的基于Dyasore化合物的新药。 这一第一阶段计划将通过三个具体目标进行：1)准备一个Dyasore模拟库，以定义 结构-活性关系；2)在经过验证的人类细胞培养模型中测试类似物的活性 眼表；3)使用相关的慢性干眼小鼠模型提供概念验证。跟随 完成这一第一阶段的努力后，研究小组将选择一种先导化合物作为潜在的治疗方法 干眼症中的眼表疾病。在第二阶段，将准备更多的化合物来微调疗效。 药代动力学特性和动物试验将扩大到检查毒性或眼睛刺激，以及 寻找系统性风险敞口。最后，配方和剂量将进行微调，以最大限度地发挥功效，延长保质期 并易于使用，同时减少可能出现的任何有毒或偏离目标的影响。

7. PROJECT SUMMARY Diseases of the ocular surface are among the top reasons for visits to eye care practitioners. These conditions can severely affect eyesight and quality of life. Symptoms may include blurry vision, discomfort or pain, redness and itching, and in severe cases, blindness due to corneal scarring. Many ocular surface diseases are initiated by loss of tear film homeostasis and can be grouped under a syndrome known as dry eye. Tear dysfunction leading to desiccating stress, initiates an autoimmune-like “vicious cycle of inflammation” that damages the ocular surface barrier. The vicious cycle is recognized as the core driver of the pathologic process, leading to chronic dry eye disease. Anti-inflammatory steroids and small molecules targeting autoimmune T-cell function are currently the only Food and Drug Administration (FDA)-approved therapeutics. These drugs are not effective in all patients, take a long time to work, and have unpleasant side effects. Current opinion holds that breaking the inflammatory vicious cycle at alternative entry points is the key to new treatments. Direct protection of the ocular surface barrier could provide such a new entry point. This should relieve chronic dry eye by ramping down the inflammatory vicious cycle, like current therapeutics. However, because it represents a different entry point, it may be efficacious in chronic situations where current drugs do not work. A novel benefit is the potential for very rapid relief of eye irritation in situations where dry eye is exacerbated by environmental, and other factors. In a recent publication, the academic lab associated with this project reported the novel discovery that Dynasore and Dyngo-4A are remarkably protective of the ocular surface barrier. Dynasore and Dyngo-4A belong to a group of small molecules targeting dynamin family GTPases, which also protect cells and tissues against oxidative stress and reduce inflammatory cytokine production. The innovation of Dynasore analogues for dry eye is that they target ocular surface barrier damage. There are no such therapeutics available at this time that act at this point in the vicious cycle. The long-term goal of this project is development of a novel FDA-approved drug based on Dynasore compounds. This phase I program will proceed via three Specific Aims: 1) prepare a Dynasore analogue library to define structure-activity relationships; 2) test analogues for activity in a validated human cell culture model of the ocular surface; 3) provide proof-of-concept using a relevant mouse model for chronic dry eye. Following completion of this phase I effort, the team will have selected a lead compound as a potential treatment for ocular surface disease in dry eye. During phase II, additional compounds will be prepared to fine-tune efficacy and pharmacokinetic properties and animal testing will be expanded to examine toxicity or eye irritation, and look for systemic exposure. Finally, formulation and dosage will be fine-tuned to maximize efficacy, shelf life and ease of application, while decreasing any toxic or off target effects that may arise.