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

用于非手术治疗白内障的小分子α-晶状体蛋白激活剂

• 批准号: 9337462
• 负责人: Sridhar G Prasad
• 金额: $ 13.68万
• 依托单位: PLEX PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9337462
• 关键词: Address; Africa; Aging; Alcohol dehydrogenase; Area; Back; Bilateral; Biological Assay; Blindness; COS-7 Cell; Caring; Cataract; Cataract Extraction; Cell Culture Techniques; Cells; Child; Chlorobenzene; Client; Corneal edema; Crystalline Lens; Crystallins; Data; Developed Countries; Developing Countries; Development; Diabetes Mellitus; Drug Delivery Systems; Endophthalmitis; Enzymes; Eye; Family; Far East; Formulation; Fructose; Goals; Heat shock proteins; Hereditary Disease; High Pressure Liquid Chromatography; Human; In Vitro; Keratoplasty; Lasers; Lead; Libraries; Modeling; Molecular Chaperones; Muramidase; Operative Surgical Procedures; Organ Culture Techniques; Oryctolagus cuniculus; Patients; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phase; Physiological; Pre-Clinical Model; Prevention; Proteins; Public Health; Pyrazoles; Retinal Detachment; Risk Factors; Safety; Series; Smoking; Solubility; Source; Structure; Structure-Activity Relationship; Synthesis Chemistry; Testing; Tissues; Trauma; Treatment Efficacy; Ultraviolet Rays; Uveitis; Visual impairment; World Health Organization; aged; alpha-Crystallins; analog; base; blind; cost effective; cytotoxicity; design; effective intervention; experimental study; glycation; in vivo; innovation; iterative design; lens; lens capsule; lens protein; lens transparency; light scattering; low and middle-income countries; member; mutant; phase 1 study; prevent; small molecule; uptake

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.

项目摘要 白内障，眼镜镜的阴影造成了48％的世界失明。根据世界 卫生组织有近1800万人双侧对全球白内障的视野。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 通常认为是安全的，存在重大并发症：（i）30-50％的美国患者患有 白内障手术的开发在两年内对后镜头囊的不良化，需要激光 治疗; （ii）0.8％的视网膜脱离； （iii）0.6-1.3％的角膜水肿住院或需要 角膜移植和（iv）约1％带有内嗜性。另外，在许多遥控器中 世界发展中和发达地区的贫困地区，人们仍然对白内障蒙蔽， 首先是由于无法获得眼保健。结果，白内障相关的失明高达50％或 在世界上贫穷和偏远地区，发达国家只有5％。 α-晶状体 （AC）是三个主要的眼镜镜头之一，是小热冲击的代表成员 蛋白质（SHSP）家族。 AC用作分子伴侣，保护损伤或老化的晶状体蛋白和 聚集的酶，否则会导致光散射和白内障形成。很好 确定AC的链酮样活性（CLA）对于晶状体透明度至关重要，可以假设是 保持最佳或增加的伴侣活性可能有助于预防或减慢白内障。这 我们提案的理由是基于这样的观察结果，即天然的小分子药物 来源可以防止alpha晶体A链（AAC）的CLA损失，并可以延迟白内障的形成 临床前模型。据估计，将白内障形成延迟10年可以降低视力 护理费用增加50％。此外，我们的初步数据支持以下假设 代表CAP01023系列的分子专门增加了AAC CLA并保持透明度 白内障模型的器官培养实验中的眼镜。因此，我们建议的基本目标是 发现AAC的潜在小分子激活剂将发展为安全且具有成本效益的非手术 治疗以延迟和/或反向白内障相关的失明，具体目的是：（目标1）结构 基于AAC的小分子激活剂的基于设计，商业采集和合成； （目标2）评估 使用体外糖基和前体细胞培养的特定目标1的AAC激活剂的治疗效率 实验和（目标3）。评估特定目标2的化合物，以进行初步体内安全性和效率 使用离体器官培养白内障模型。第一阶段研究的里程碑是发现2-4效力 EC50≤50UM的AAC的激活剂，显示在兔眼镜中是安全的，保持透镜的澄清≥12 器官培养实验中的天数，伴随化合物摄取和汇总形式的减少 凸耳客户蛋白水平。