School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India.
School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India.
Comput Biol Chem. 2024 Oct;112:108155. doi: 10.1016/j.compbiolchem.2024.108155. Epub 2024 Jul 16.
α-Synuclein (α-syn) is an intrinsically disordered protein, linked genetically and neuropathologically to Parkinson's disease where this protein aggregates within the brain. Hence, identifying compounds capable of impeding α-syn aggregation puts forward a promising approach for the development of disease-modifying therapies. Herein, we investigated the efficacy of Ribavirin, an FDA-approved compound, in curtailing α-syn amyloid transformation, employing an array of bioinformatic tools and systematic analysis using biophysical techniques. Ribavirin shows a dose dependent anti-aggregation propensity where it effectively subdued the formation of mature fibrillar aggregates of α-syn, where even at the lowest concentration there was a 69 % reduction in the ThT maxima. Ribavirin averts the formation of mature fibrillar aggregates by interacting with the NAC domain of α-syn. Ribavirin redirects the amyloid transformation of α-syn by emanating aggregates of lower order with reduced cross β-sheet signature and revokes the formation of on-pathway amyloids. Collectively, our study puts forward the novel potency of Ribavirin as a promising molecule for therapeutic intervention in Parkinson's disease.
α-突触核蛋白（α-syn）是一种无规则卷曲的蛋白质，在遗传学和神经病理学上与帕金森病有关，这种蛋白质在大脑中聚集。因此，鉴定能够阻止 α-syn 聚集的化合物为开发疾病修饰疗法提出了一个很有前途的方法。在此，我们使用一系列生物信息学工具和生物物理技术进行系统分析，研究了 FDA 批准的化合物利巴韦林抑制 α-syn 淀粉样转化的功效。利巴韦林显示出剂量依赖性的抗聚集倾向，有效抑制 α-syn 成熟原纤维状聚集的形成，即使在最低浓度下，ThT 最大值也降低了 69%。利巴韦林通过与 α-syn 的 NAC 结构域相互作用来阻止成熟原纤维状聚集的形成。利巴韦林通过发出具有较低的交叉β-折叠特征和减少的下一级的聚集来改变 α-syn 的淀粉样转化，并取消通路上淀粉样的形成。总的来说，我们的研究提出了利巴韦林作为治疗帕金森病的有希望的分子的新潜力。
