Department of Biophysics, P-1/12 CIT Scheme VII (M), Kolkata 700054, India.
Department of Chemistry, Indian Institute of Technology Guwahati, North Guwahati 781039, India.
Biochim Biophys Acta Proteins Proteom. 2019 Apr;1867(4):405-415. doi: 10.1016/j.bbapap.2019.01.007. Epub 2019 Jan 17.
Subcutaneous insulin delivery serves as the major treatment for the ever-increasing spread of type II diabetes worldwide. However, long-term exposure to insulin results in local aggregates at the site of injection. This therapeutic concern accentuates the need to develop newer effective excipients to stabilize the insulin in pharmaceutical formulations. The fact that in normal physiological conditions, insulin interacts with the amylin hormone co-secreted from the pancreas, we targeted a peptide-mimetic approach based on the amylin sequence. The amylin-fibrillating core (NL6- NFGAIL from the human Islet Amyloid Poly-Peptide) and its derivative NFGAXL (NL6X, X = 2-aminobenzoic acid) were used as potential inhibitory peptides against insulin amyloidogenesis. The fibrillation kinetics in the presence of the inhibitors was studied using an array of biophysical and microscopic techniques. High-resolution NMR spectroscopy enabled probing of the inhibitory interaction at an atomic resolution. Our results highlight the potential of using the naturally evolved NL6 peptide as an effective inhibitor against insulin fibrillation.
皮下胰岛素给药是治疗全球日益增多的 II 型糖尿病的主要方法。然而，长期暴露于胰岛素会导致在注射部位形成局部聚集。这种治疗上的关注凸显了开发新的有效赋形剂以稳定胰岛素在药物制剂中的需求。事实上，在正常生理条件下，胰岛素与从胰腺共同分泌的胰岛淀粉样多肽激素相互作用，我们针对基于胰岛淀粉样多肽序列的肽模拟方法。使用胰岛淀粉样多肽的纤维状核心（NL6-NFGAIL 来自人胰岛淀粉样多肽）及其衍生物 NFGAXL（NL6X，X=2-氨基苯甲酸）作为潜在的抑制胰岛素淀粉样变的肽。使用一系列生物物理和显微镜技术研究了抑制剂存在下的纤颤动力学。高分辨率 NMR 光谱学能够以原子分辨率探测抑制相互作用。我们的结果突出了使用天然进化的 NL6 肽作为有效抑制剂抑制胰岛素纤颤的潜力。
