title: Dual-purpose linker for alpha helix stabilization and imaging agent conjugation to glucagon-like peptide-1 receptor ligands.
abstract: Peptides display many characteristics of efficient imaging agents such as rapid targeting, fast background clearance, and low non-specific cellular uptake. However, poor stability, low affinity, and loss of binding after labeling often preclude their use in vivo. Using glucagon-like peptide-1 receptor (GLP-1R) ligands exendin and GLP-1 as a model system, we designed a novel α-helix-stabilizing linker to simultaneously address these limitations. The stabilized and labeled peptides showed an increase in helicity, improved protease resistance, negligible loss or an improvement in binding affinity, and excellent in vivo targeting. The ease of incorporating azidohomoalanine in peptides and efficient reaction with the dialkyne linker enable this technique to potentially be used as a general method for labeling α helices. This strategy should be useful for imaging beta cells in diabetes research and in developing and testing other peptide targeting agents.
authors.affiliation: Department of Chemical Engineering, ‡Department of Biomedical Engineering, University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhang
authors.forename: Tejas
authors.initials: T
authors.lastname: Navaratna
authors.forename: Jianshan
authors.initials: J
authors.lastname: Liao
authors.forename: Greg M
authors.initials: GM
authors.lastname: Thurber
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000737:chemistry* / Q000378:metabolism; D000067757:Glucagon-Like Peptide-1 Receptor; D006652:Histological Techniques; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D008853:Microscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D061848:Optical Imaging; D010190:Pancreatic Neoplasms / Q000378:metabolism; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D055550:Protein Stability; D017433:Protein Structure, Secondary; D018027:Receptors, Glucagon / Q000032:analysis* / Q000378:metabolism*; D014688:Venoms / Q000737:chemistry* / Q000378:metabolism
chemical_list: C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D008024:Ligands; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide