Expanding therapeutic opportunities for neurodegenerative diseases: A perspective on the important role of phenotypic screening.,Bioorganic & Medicinal Chemistry

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Expanding therapeutic opportunities for neurodegenerative diseases: A perspective on the important role of phenotypic screening.
Bioorganic & Medicinal Chemistry ( IF 3.3 ) Pub Date : 2019-12-18 , DOI: 10.1016/j.bmc.2019.115239
Susanne E Swalley ₁

Affiliation

Over the last 20 years, there have been remarkably few FDA-approved first-in-class drugs for neurodegenerative diseases. Debilitating conditions such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis have no effective disease-modifying therapeutics on the market, signifying an area of high unmet medical need where novel approaches are needed. Using a phenotypic screening approach, two separate groups discovered small molecule non-antisense oligonucleotide splice modulators for spinal muscular atrophy, a severe monogenetic disease that causes the degeneration ofalpha motor neuronsin the spinal cord. These compounds function by a novel mechanism: selective stabilization of the interaction of U1 small nuclear ribonucleic protein (snRNP), a core component of the spliceosome, with the 5' splice site of a pre-mRNA. The ability of the phenotypic screening approach to uncover a previously unknown mechanism and reveal a new druggable target class has broader implications for other neurodegenerative diseases.

中文翻译：

扩大神经退行性疾病的治疗机会：表型筛选的重要作用的观点。

在过去的20年中，很少有FDA批准用于神经退行性疾病的一流药物。诸如阿尔茨海默氏病，帕金森氏病和肌萎缩性侧索硬化之类的使人衰弱的疾病在市场上没有有效的缓解疾病的疗法，这表明需要新方法的医疗需求高度未得到满足。使用表型筛选方法，两个独立的小组发现了脊髓肌萎缩症的小分子非反义寡核苷酸剪接调节剂，脊髓肌萎缩症是一种严重的单基因疾病，会导致脊髓中的α运动神经元变性。这些化合物通过新机制发挥作用：选择性稳定U1小核糖核酸蛋白（snRNP）（剪接体的核心成分）与5'的相互作用前mRNA的剪接位点。表型筛选方法揭示以前未知的机制并揭示新的可治疗靶标类别的能力对其他神经退行性疾病具有更广泛的意义。

更新日期：2019-12-19

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