Chaperone therapeutics for the treatment of DPN

用于治疗 DPN 的伴侣疗法

• 批准号: 8413041
• 负责人: Brian S J Blagg
• 金额: $ 30.68万
• 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/8413041
• 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

SUMMARY 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.

概括 糖尿病周围神经病（DPN）的病因从一系列代谢 最终导致感觉神经元变性的血管损伤。追求 药理学管理DPN，已经开发出小分子抑制剂以靶向被视为的蛋白 作为“特定糖尿病”，以及在多种疾病状态中增加的糖尿病。这样的努力尚未证明 成功，表明鉴定出在调节蛋白质中起着基本作用的新型目标 糖尿病状态下的完整性和保留神经功能可能代表新的范式。热休克蛋白 90（HSP90）是一种结合“客户蛋白”并将其折叠成生物学的分子伴侣 主动结构。它也是细胞保护“热冲击反应”的主调节器，这有助于 在细胞胁迫下重新骨调整发生的聚集和受损的蛋白质。 N-和C端ATP HSP90的结合结构域调节其与蛋白质的相互作用。 HSP90的N末端抑制剂表现出强大 针对肿瘤细胞的细胞毒性，正在临床试验中，但这些化合物也诱导了细胞保护作用 细胞毒性所需浓度的“热冲击反应”。相比之下，我们发展了有力 HSP90 C末端结构域的小分子抑制剂，其神经保护功效在 远低于诱导神经毒性所需的浓度。这些抑制剂的铅化合物Ku- 32，基于Novobiocin。 KU-32可预防高血糖诱导的感觉神经元死亡和 可以通过诱导热休克反应来减轻小鼠DPN的几个生理指数。 不幸的是，该分子需要大量的合成制备，从而完全阐明 结构活动关系并限制其在动物/人类中的使用。因此，该提议的目标是 提供源自KU-32的新化合物，这些化合物表现出更好的神经保护活动，可以在 最少的合成程序。初始屏幕将识别具有提高功效的化合物 相对于KU-32和铅候选者将进行测试，以防止感觉神经元的血糖应激， 然后在野生型和HSP70敲除小鼠中对DPN进行动物研究。这项工作的结果将 进一步发展和识别小分子C末端HSP90抑制剂，这些抑制剂降低了神经退行性的抑制剂 没有明显的神经毒性。