Small molecule activators of alpha-crystallin for non-surgical treatment of cataracts

项目摘要 白内障，眼睛晶状体的混浊造成了48%的世界失明。《世界报》 世界卫生组织有近1800万人因白内障而双眼失明。白内障很容易 通过手术治疗，被认为是最具成本效益的干预措施之一。虽然白内障手术 通常被认为是安全的，但有显著的并发症：(I)美国30%-50%的患者 白内障手术在两年内出现晶状体后囊膜混浊，需要激光治疗 治疗；(Ii)0.8%的人有视网膜脱离；(Iii)0.6%-1.3%的人因角膜水肿而住院或需要 角膜移植和(Iv)约1%的患者出现眼内炎。此外，在许多偏远和 世界上发展中和欠发达地区的贫困地区，人们仍然因为白内障而失明， 主要原因是无法获得眼部护理。因此，与白内障相关的失明高达50%或 世界上贫穷和偏远地区的这一比例更高，而发达国家仅为5%。α-结晶蛋白 (Ac)是眼晶状体三大晶状体蛋白之一，是小热休克的代表性成员 蛋白质(SHSP)家族。AC作为分子伴侣，保护受损或老化的晶状体蛋白和 酶的聚集，否则会导致光散射和白内障的形成。这很好 已证实AC的伴侣样活性(CLA)对晶状体透明度至关重要，并假设 保持最佳的或增加的伴侣活性可能有助于预防或减缓白内障。这个 我们建议的理由是基于观察到来自天然的小分子药理物质 来源可防止α晶体蛋白A链(AAC)共轭亚油酸的丢失，并可延缓白内障的形成 临床前模型。据估计，将白内障形成推迟10年会降低视力。 医疗费用减少50%。此外，我们的初步数据支持这样的假设，即类药物合成的小分子 代表CAP01023系列的分子专门增加了AAC CLA并保持了 白内障模型器官培养实验中的眼晶状体。因此，我们建议的基本目标是 发现有效的AAC小分子激活剂将开发成安全且经济有效的非手术 治疗延缓和/或扭转白内障相关失明，具体目标是：(目标1)结构 AAC小分子激活剂的基础设计、商业获取和合成；(目标2)评估 体外糖基化和体外细胞培养法检测AAC特异性激活剂的疗效 实验和(目标3)。从特定目标2评估化合物在体内的初步安全性和有效性 采用体外器官培养的白内障模型。第一阶段研究的里程碑是发现2-4种有效 含EC50≤50uM的AAc激活剂在兔眼晶状体中是安全的，保持晶状体对≥12的澄清度 在器官培养实验中伴随的化合物摄取和聚集形式的减少 透镜状客户蛋白质水平。

Project Summary Cataract, the clouding of the eye lens is responsible for 48% of world blindness. According to World Health Organization nearly 18 million people are bilaterally blind from cataract in the world. Cataract is easily treated by surgery and is considered as one of the most cost-effective interventions. Although cataract surgery is generally considered to be safe, there are significant complications: (i) 30-50% of patients in the US having cataract surgery develop opacification of the posterior lens capsule within two years and require laser treatment; (ii) 0.8% have retinal detachments; (iii) 0.6-1.3% are hospitalized for corneal edema or require corneal transplantation and (iv) about 1% are presented with endophthalmitis. In addition, in many remote and poor areas of the developing and under-developed regions of the world, people still remain blind from cataract, primarily due to lack of access to eye care. As a result of which, cataract related blindness is as high as 50% or more in poor and remote regions of the world compared to only 5% in developed countries. Alpha-crystallin (AC) is one of the three major eye lens crystallins and is a representative member of the small heat shock protein (sHsp) family. AC serves as molecular chaperone, protecting damaged or aged lens proteins and enzymes from aggregation that would otherwise lead to light scattering and cataract formation. It is well established that chaperone-like activity (CLA) of AC is critical for lens transparency and it is hypothesized that maintaining optimal or increasing chaperone activity might aid in the prevention or slowing of cataract. The rationale of our proposal is based on the observation that small molecule pharmacological agents from natural sources can prevent the loss of CLA of Alpha crystallin A-chain (AAC) and can delay cataract formation in preclinical models. It has been estimated that delaying cataract formation by 10 years can reduce the vision care expense by 50%. In addition, our preliminary data supports the hypothesis that drug-like synthetic small molecules representing the CAP01023 series specifically increases AAC CLA and maintains transparency of the eye lens in organ culture experiments of cataract model. Therefore, the basic goal of our proposal is to discover potent small molecule activators of AAC to be developed into safe and cost-effective non-surgical treatment to delay and/or reverse cataract related blindness, and the specific aims are: (Aim 1) Structure based design, commercial acquisition and synthesis of small molecule activators of AAC; (Aim 2) Assess therapeutic efficacy of AAC activators from Specific Aim 1 using in vitro glycation and ex-vivo cell culture experiments and (Aim 3). Assess compounds from Specific Aim 2 for preliminary in vivo safety and efficacy using ex vivo organ culture cataract models. The milestone for the Phase I studies is to discover 2-4 potent activators of AAC with EC50 ≤ 50uM, shown to be safe in rabbit eye lens, maintain clarification of lens for ≥12 days in organ culture experiments with concomitant compound uptake and decrease in aggregated forms of lenticular client protein levels.