Chaperone therapeutics for the treatment of DPN

用于治疗 DPN 的伴侣疗法

• 批准号: 8297562
• 负责人: Brian S J Blagg
• 金额: $ 31.82万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8297562
• 关键词: Advanced Glycosylation End Products; Afferent Neurons; Affinity; Affinity Chromatography; Agonist; American; Animals; Attenuated; Attributes of Chemicals; Binding; Binding Sites; Bioavailable; Biological Assay; Blood Vessels; C-terminal; Cell physiology; Cellular Assay; Cellular Stress; Cessation of life; Chemicals; Client; Clinical; Clinical Treatment; Clinical Trials; Complex; Complications of Diabetes Mellitus; Convulsions; Data; Demyelinations; Development; Diabetes Mellitus; Diabetic Neuropathies; Diabetic mouse; Disease; Drug Kinetics; Effectiveness; Etiology; Evaluation; Event; Exhibits; FDA approved; Glucose; Goals; Heat shock proteins; Heat-Shock Proteins 90; Heat-Shock Response; Hexosamines; Human; Hyperglycemia; In Vitro; Investigation; Knockout Mice; Lead; Malignant Neoplasms; Mental Depression; Metabolic; Modeling; Molecular Chaperones; Molecular Target; Mus; N-terminal; Nerve; Nerve Degeneration; Neuroprotective Agents; Novobiocin; Oncogene Proteins; Oral; Outcome; Oxidative Stress; Pathway interactions; Peripheral Nerves; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Physiological; Play; Preparation; Procedures; Property; Protein Kinase C; Proteins; Protocols documentation; Quality of life; Relative (related person); Role; Series; Stress; Structure; Structure-Activity Relationship; Testing; Therapeutic; Toxic effect; Work; amyloid peptide; analog; base; cytotoxicity; design; diabetes control; diabetic; high throughput screening; improved; in vitro Model; in vivo; indexing; inhibitor/antagonist; neoplastic cell; neuroblastoma cell; neurotoxicity; novel; novel strategies; novel therapeutic intervention; polyol; pre-clinical; prevent; protein degradation; scaffold; small molecule; three dimensional structure

DESCRIPTION (provided by applicant): The etiology of diabetic peripheral neuropathy (DPN) initiates from an inter-related series of metabolic and vascular insults that ultimately contribute to sensory neuron degeneration. In the quest to pharmacologically manage DPN, small molecule inhibitors have been developed to target proteins regarded as "diabetes specific" as well as those that increase in multiple disease states. Such efforts have not proven successful suggesting the identification of novel targets that play a fundamental role in regulating protein integrity and preserving nerve function in the diabetic state may represent a new paradigm. Heat shock protein 90 (Hsp90) is a molecular chaperone that binds "client proteins" and promotes their folding into biologically active structures. It is also the master regulator of a cytoprotective "heat shock response", which aids the refolding of aggregated and damaged proteins that occur upon cell stress. Both the N- and C-terminal ATP binding domains of Hsp90 regulate its interaction with proteins. N-terminal inhibitors of Hsp90 exhibit potent cytotoxicity against tumor cells and are in clinical trials, but these compounds also induce a cytoprotective "heat shock response" at concentrations necessary for cytotoxicity. In contrast, we have developed potent small molecule inhibitors of the Hsp90 C-terminal domain whose neuroprotective efficacy is manifested at concentrations far below those necessary to induce neuro-toxicity. The lead compound for these inhibitors, KU- 32, is based upon novobiocin. KU-32 protects against hyperglycemia-induced death of sensory neurons and can attenuate several physiologic indices of DPN in mice through induction of the heat shock response. Unfortunately, this molecule requires significant synthetic preparation, thus preventing full elucidation of structure-activity relationships and limiting its use in animals/humans. Thus, the goal of this proposal is to provide new compounds derived from KU-32 that exhibit better neuroprotective activity and can be prepared in a minimal number of synthetic procedures. An initial screen will identify compounds with increased efficacy relative to KU-32 and lead candidates will be tested for protection against glycemic stress of sensory neurons, followed by animal studies of DPN in both wild-type and Hsp70 knockout mice. The outcome of this work will further develop and identify small molecule C-terminal Hsp90 inhibitors that decrease neurodegeneration in the absence of significant neurotoxicity. PUBLIC HEALTH RELEVANCE: Diabetic neuropathy is a common complication of diabetes that develops in about 60% of the approximately 24 million Americans afflicted with diabetes. Despite the impact of diabetic neuropathy on decreasing the quality of life, the existing FDA approved treatments are limited to drugs originally targeted to treat depression (Cymbalta) and convulsions (Lyrica). This project focuses on optimizing the effectiveness of a new class of therapeutics for the direct treatment of diabetic neuropathy.

描述（由申请人提供）：糖尿病周围神经病变（DPN）的病因始于一系列相互关联的代谢和血管损伤，最终导致 感觉神经元退化在寻求快速管理DPN的过程中，已经开发了小分子抑制剂来靶向被认为是“糖尿病特异性”的蛋白质以及在多种疾病状态中增加的蛋白质。这些努力尚未被证明是成功的，这表明鉴定在调节蛋白质完整性和保护糖尿病状态下的神经功能中起基本作用的新靶点可能代表了一种新的范例。热休克蛋白90（Hsp 90）是一种分子伴侣，其结合“客户蛋白”并促进其折叠成生物活性结构。它也是细胞保护性“热休克反应”的主要调节剂，其有助于在细胞应激时发生的聚集和受损蛋白质的重折叠。热休克蛋白90的N-和C-末端ATP结合结构域调节其与蛋白质的相互作用。热休克蛋白90的N-末端抑制剂表现出对肿瘤细胞的有效细胞毒性，并在临床试验中，但这些化合物也诱导细胞保护性的“热休克反应”在细胞毒性所需的浓度。相比之下，我们已经开发了Hsp 90 C-末端结构域的有效小分子抑制剂，其神经保护功效在远低于诱导神经毒性所需的浓度下表现出来。这些抑制剂的先导化合物KU- 32基于新生霉素。KU-32可通过诱导小鼠热休克反应，保护高血糖诱导的感觉神经元死亡，并可减轻DPN的几项生理指标。不幸的是，这种分子需要大量的合成制备，从而阻碍了结构-活性关系的充分阐明，并限制了其在动物/人类中的使用。因此，本提案的目标是提供衍生自KU-32的新化合物，其表现出更好的神经保护活性，并且可以以最少数量的合成程序制备。初步筛选将确定相对于KU-32具有增加功效的化合物，并将测试主要候选物对感觉神经元的血糖应激的保护作用，然后在野生型和Hsp 70敲除小鼠中进行DPN的动物研究。这项工作的结果将进一步开发和鉴定小分子C-末端Hsp 90抑制剂，在没有显著神经毒性的情况下减少神经变性。 公共卫生相关性：糖尿病性神经病变是糖尿病的常见并发症，其在约2400万患有糖尿病的美国人中的约60%中发展。尽管糖尿病神经病变对降低生活质量的影响，但现有的FDA批准的治疗仅限于最初针对治疗抑郁症（Cymbalta）和惊厥（Lyrica）的药物。该项目的重点是优化一类新的直接治疗糖尿病神经病变的疗法的有效性。