Targeting the PMP22 Protein to Develop Leads Against Charcot-Marie-Tooth Disease

靶向 PMP22 蛋白开发抗腓骨肌萎缩症的先导药物

• 批准号: 10331038
• 负责人: CHARLES R SANDERS
• 金额: $ 19.81万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-20 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10331038
• 关键词: Affect; Alleles; Amino Acid Sequence; Automobile Driving; Binding; Biological Assay; Cell surface; Charcot-Marie-Tooth Disease; Chloride Channels; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Delta F508 mutation; Disease; Enhancers; Failure; Feeling; Foundations; Future; Gene Proteins; Genes; Genetic Variation; Goals; Hereditary neuropathy with liability to pressure palsies; Human; Inherited; Lead; Link; Lung; Membrane; Membrane Proteins; Modeling; Motor; Mus; Mutation; Myelin; Myelin Proteins; Nerve; Neural Conduction; Neuropathy; PMP22 gene; Pathology; Patients; Peripheral; Peripheral Nervous System; Peripheral Nervous System Diseases; Persons; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacological Treatment; Preclinical Testing; Proteins; Rattus; Schwann Cells; Sensory; Structure; Surface; Syndrome; Testing; Therapeutic; Therapeutic Agents; Trisomy; VX-809; base; biophysical analysis; design; dexterity; disabling symptom; drug discovery; efficacy testing; falls; high throughput screening; in vivo; lead optimization; lead series; misfolded protein; mutant; myelination; novel therapeutics; overexpression; programs; protein expression; protein transport; response; small molecule; therapeutically effective; therapy development; trafficking

Project Summary Charcot-Marie-Tooth Disease (CMTD) is a debilitating hereditary peripheral neuropathy that afflicts 1:2500 humans. The hallmark of CTMD pathology is severely defective PNS myelin. There is currently no pharmacological treatment or cure for this disease. Over 75% of all cases of CMTD are caused by Schwann cell overexpression of wild type (WT) peripheral myelin protein (PMP22) due to trisomy, underexpression of PMP22 (for the WT/null case), or genetically dominant heterozygous (WT/mutant) mutations that alter the PMP22 protein sequence. WT PMP22 is known to properly fold and traffic with only 20% efficiency under healthy conditions. Our driving rationale is that small molecules that tune either the expression levels or in vivo folding efficiency of PMP22 have the potential to be effective therapeutic agents. Drugs that reduce expression of the protein are likely to prove effective against the most common form of CMTD (Type 1A) caused by trisomy-based overexpression. On the other hand, drugs that act as folding correctors or expression enhancers are likely to prove effective for forms of CMTD caused by underexpression and/or misfolding of PMP22. The Specific Aims of this project are designed to establish the foundations for a drug discovery program to develop therapeutic compounds for the most common forms of Charcot-Marie-Tooth Disease (CMTD), which are caused by genetic variations that impact the PMP22 gene that encodes peripheral myelin protein 22 (PMP22), a tetraspan membrane protein. These Aims are: Aim 1. Develop a primary assay that can be implemented in high throughput screening (HTS) mode to identify small molecules that alter the total expression of wild type (WT) and disease mutant forms of PMP22, or that enhance the cell surface membrane trafficking of the protein. Aim 2. Conduct primary screens to discover and characterize lead compounds that modulate total expression levels of PMP22 and/or that enhance PMP22 cell surface trafficking efficiency. Determine hit concentration-response (potency) curves. Aim 3. Conduct a secondary screen of hits using Schwann cells and test for hit efficacy in a myelination assay. Conduct biophysical studies to test whether lead compounds act in a way what involves direct binding to the PMP22 protein and also test for their impact on PMP22 protein stability. Successful completion of this project will provide a series of lead compounds that will be ready for future medicinal chemistry optimization of lead compound structures, efficacy testing in available mouse and rat models of CMTD, and pre-clinical testing.

项目摘要 Charcot-Marie-Tooth病（CMTD）是一种使人衰弱的遗传性周围神经病 人类。 CTMD病理学的标志是PNS髓磷脂的严重缺陷。目前没有 药理治疗或治愈该疾病。超过75％的CMTD案件是由 野生型（WT）外周髓磷脂蛋白（PMP22）的Schwann细胞过表达，由于三体症 PMP22（对于WT/NULL情况）或遗传上显性杂合（WT/MUTANT）的不存在 改变PMP22蛋白序列的突变。 WT PMP22已知可以正确折叠并与 在健康条件下，只有20％的效率。我们的驾驶理由是调谐的小分子 PMP22的表达水平或体内折叠效率具有有效治疗的潜力 代理商。降低蛋白质表达的药物可能证明对最常见的药物有效 CMTD（1A型）的形式是由基于三体性的过表达引起的。另一方面，毒品充当 折叠校正器或表达增强器可能对由CMTD形式有效 PMP22的不遗憾和/或错误折叠。该项目的具体目的旨在建立 药物发现计划的基础，以开发最常见的治疗化合物 charcot-marie-tooth疾病（CMTD）的形式，是由遗传变异引起的 pmp22基因编码周围髓磷脂蛋白22（PMP22），一种四膜膜蛋白。 这些目标是： 目标1。开发可以在高吞吐量筛选（HTS）中实现的主要测定法 识别改变野生型（WT）和疾病突变体总表达的小分子的模式 PMP22的形式，或增强蛋白质的细胞表面膜运输。 AIM 2。进行主要筛选以发现和表征调节总的铅化合物 PMP22和/或提高PMP22细胞表面运输效率的表达水平。确定命中 浓度响应（效力）曲线。 AIM 3。使用Schwann细胞进行次要命中的次级屏幕，并测试A中的命中功效 髓鞘化测定。进行生物物理研究以测试铅化合物是否以某种方式作用 涉及与PMP22蛋白的直接结合，还测试了它们对PMP22蛋白稳定性的影响。 该项目的成功完成将提供一系列可以准备就绪的铅化合物 为了将未来的药物化学优化铅复合结构优化，在 CMTD的可用小鼠和大鼠模型以及临床前测试。