title: High affinity binding of conformationally constrained synthetic oligomers to an antigen-specific antibody: Discovery of a diagnostically useful synthetic ligand for murine Type 1 diabetes autoantibodies.
abstract: 'Antigen surrogates' are synthetic, non-natural molecules that recognize the antigen-binding sites of antibodies. These molecules are of interest as replacements for native antigens as antibody 'capture agents' in ELISA-like assays of potential diagnostic utility, for example when the antibody is indicative of a disease state. Antigen surrogates for disease-related antibodies can be mined from one-bead one-compound (OBOC) libraries by first denuding the library of ligands for antibodies present in the serum of control patients or animals, followed by screening the remainder of the library against serum from individuals with a particular disease of interest. Most of the work in this area has been done with peptoids (oligomers of N-alkylated glycine), which provide antibody ligands with only modest affinity and selectivity. Here, we explore the hypothesis that this is due to the 'floppiness' of the peptoid backbone by creating libraries of peptoid-like molecules that have conformation-restricting structural elements inserted into their backbones. Indeed, we show here that these libraries can provide high affinity and selectivity antigen surrogates and that this much-improved binding is completely dependent on conformational restriction of the oligomer chain.
authors.affiliation: The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, United States.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Doran
authors.affiliation: The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, United States.
authors.forename: Yu
authors.initials: Y
authors.lastname: Gao
authors.affiliation: The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, United States.
authors.forename: Scott
authors.initials: S
authors.lastname: Simanski
authors.affiliation: The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, United States.
authors.forename: Patrick
authors.initials: P
authors.lastname: McEnaney
authors.affiliation: The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, United States. Electronic address: kodadek@scripps.edu.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kodadek
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000032:analysis* / Q000276:immunology*; D001666:Binding Sites, Antibody / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000175:diagnosis* / Q000276:immunology*; D055808:Drug Discovery; D008024:Ligands; D051379:Mice; D008968:Molecular Conformation; D015394:Molecular Structure; D034444:Peptoids / Q000138:chemical synthesis / Q000737:chemistry* / Q000276:immunology*; D013329:Structure-Activity Relationship
chemical_list: D001323:Autoantibodies; D008024:Ligands; D034444:Peptoids
keywords: Antigen surrogate; NOD mouse; OBOC library screening; Peptide tertiary amide; Type 1 diabetes