Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh 202002, India.
Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh 202002, India.
Colloids Surf B Biointerfaces. 2022 Aug;216:112563. doi: 10.1016/j.colsurfb.2022.112563. Epub 2022 May 14.
Protein aggregation leads to several human pathologies such as Alzheimer's disease (AD), type 2 diabetes (T2D), Parkinson's disease (PD), etc. Due to the overlap in the mechanisms of type 2 diabetes and brain disorders, common effective pharmacological interventions to treat both T2D and AD is under extensive research. Therefore, major aim of research is to repurpose already established treatment of diabetes to cure AD as well. This study evaluates mechanistic insight into anti-amyloidogenic potential of anti-diabetic drug Vildagliptin (VLD) on human serum albumin fibrillation (HSA) by using biophysical, calorimetric, imaging techniques along with hemolytic assay. Dynamic light scattering (DLS) and Rayleigh light scattering (RLS) results showed presence of few small-sized aggregates in the presence of VLD which are formed by deaccelerating the amyloidogenesis as shown by thioflavin T (ThT) fluorescence and Congo red (CR) binding assay. Further, Isothermal titration calorimetry (ITC), steady state fluorescence quenching, molecular docking results revealed that VLD form complex with amyloid facilitating state of HSA and consequently mask the hydrophobic residues involved in amyloidogenesis as evident from decrease in ANS fluorescence. Differential scanning calorimetry (DSC) results confirm that VLD stabilizes the amyloid facilitating state of HSA. In addition, SEM images demonstrated that VLD alleviates the hemolytic effect induced by fibrils of HSA. This study reports VLD as a potential inhibitor of amyloid fibrillation and provides promising results to repurpose VLD as a drug candidate for the cure of Alzheimer's diseases along with diabetes.
蛋白质聚集会导致多种人类疾病，如阿尔茨海默病（AD）、2 型糖尿病（T2D）、帕金森病（PD）等。由于 2 型糖尿病和大脑紊乱的机制存在重叠，因此广泛研究了治疗这两种疾病的共同有效药物干预措施。因此，研究的主要目标是重新利用已经确立的糖尿病治疗方法来治愈 AD。本研究通过使用生物物理、量热法、成像技术以及溶血试验，评估了抗糖尿病药物维格列汀（VLD）对人血清白蛋白（HSA）纤维形成的抗淀粉样变潜力的机制见解。动态光散射（DLS）和瑞利光散射（RLS）结果表明，在 VLD 的存在下存在少量小尺寸的聚集物，这些聚集物是通过减缓淀粉样变形成的，如硫黄素 T（ThT）荧光和刚果红（CR）结合试验所示。此外，等温滴定量热法（ITC）、稳态荧光猝灭、分子对接结果表明，VLD 与人血清白蛋白形成复合物，促进其淀粉样变状态，从而掩盖了参与淀粉样变形成的疏水性残基，这从 ANS 荧光的减少中可以明显看出。差示扫描量热法（DSC）结果证实，VLD 稳定了 HSA 的促进淀粉样变状态。此外，SEM 图像表明，VLD 减轻了 HSA 纤维引起的溶血作用。本研究报告了 VLD 作为一种潜在的淀粉样纤维抑制剂，并提供了有希望的结果，即将 VLD 重新用作治疗 AD 以及糖尿病的候选药物。
