title: Controlling in Vitro Insulin Amyloidosis with Stable Peptide Conjugates: A Combined Experimental and Computational Study.
abstract: 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's 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-receptor 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.
authors.affiliation: Department of Chemistry, DST Thematic Unit of Excellence on Soft Nanofabrication and ‡Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur , Kanpur 208016 Uttar Pradesh, India.
authors.forename: Narendra Kumar
authors.initials: NK
authors.lastname: Mishra
authors.affiliation: Department of Chemistry, DST Thematic Unit of Excellence on Soft Nanofabrication and ‡Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur , Kanpur 208016 Uttar Pradesh, India.
authors.forename: R N V
authors.initials: RN
authors.lastname: Krishna Deepak
authors.affiliation: Department of Chemistry, DST Thematic Unit of Excellence on Soft Nanofabrication and ‡Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur , Kanpur 208016 Uttar Pradesh, India.
authors.forename: Ramasubbu
authors.initials: R
authors.lastname: Sankararamakrishnan
authors.affiliation: Department of Chemistry, DST Thematic Unit of Excellence on Soft Nanofabrication and ‡Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur , Kanpur 208016 Uttar Pradesh, India.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Verma
mesh_terms: D000686:Amyloidosis / Q000188:drug therapy*; D006801:Humans; D066298:In Vitro Techniques; D007328:Insulin / Q000008:administration & dosage*; D018625:Microscopy, Atomic Force; D008855:Microscopy, Electron, Scanning; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000627:therapeutic use*
chemical_list: D007328:Insulin; D010455:Peptides