Controlling in Vitro Insulin Amyloidosis with Stable Peptide Conjugates: A Combined Experimental and Computational Study

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• 作者：Narendra Kumar Mishra ; R. N. V. Krishna Deepak ; Ramasubbu Sankararamakrishnan ; Sandeep Verma
• 刊名：Journal of Physical Chemistry B
• 出版年：2015
• 出版时间：December 17, 2015
• 年：2015
• 卷：119
• 期：50
• 页码：15395-15406
• 全文大小：858K
• ISSN：1520-5207

文摘

Insulin aggregation, to afford amyloidogenic polypeptide fibrils, is an energetically driven, well-studied phenomenon, which presents interesting biological ramifications. These aggregates are also known to form around insulin injection sites and in diabetic patients suffering from Parkinson鈥檚 disease. Such occurrences force considerable reduction in hormone activity and are often responsible for necrotic deposits in diabetic patients. Changes in physicochemical environment, such as pH, temperature, ionic strength, and mechanical agitation, affect insulin fibrillation, which also presents intrigue from the structural viewpoint. Several reports have tried to unravel underlying mechanisms concerning the aggregation process taking into account a three aromatic amino acid patch Phe^B24-Phe^B25-Tyr^B26 located in the C-terminal part of the B chain, identified as a key site for human insulin鈥搑eceptor interaction. The present study describes design and inhibitory effects of novel peptide conjugates toward fibrillation of insulin as investigated by thioflavin T assay, circular dichroism, and AFM. Possible interaction of insulin with peptide-based fibrillation inhibitors reveals an important role of hydrophobic interactions in the inhibition process. Molecular dynamics simulation studies demonstrate that inhibitor D4 interacts with insulin residues from the helix and the C-terminal extended segment of chain B. These studies present a novel approach for the discovery of stable, peptide-based ligands as novel antiamyloidogenic agents for insulin aggregation.