title: Design of bioactive peptides based on antibody hypervariable region structures. Development of conformationally constrained and dimeric peptides with enhanced affinity.
abstract: The variable regions of antibody molecules bind antigens with high affinity and specificity. This binding is imparted largely by the hypervariable portions of the variable region. Hypervariable regions typically fold into reverse turn or loop structures. Peptides derived from antibody hypervariable region sequences can bind antigens with similar specificity, albeit with markedly lower affinity. In this study, cyclic and dimeric peptide analogs of an anti-idiotypic/antireceptor antibody hypervariable region were developed. This antibody (87.92.6) binds to reovirus type 3 receptors on cells as well as to a neutralizing anti-reovirus type 3 monoclonal antibody (9B.G5). The cyclic peptides were utilized to probe the optimal conformation for binding to both the receptor and 9B.G5. By dimerizing or constraining the conformation of these peptides, higher affinity binding was produced. By utilizing several different cyclic peptides, the optimal conformation for binding was established. The conformationally optimized cyclic peptide possessed greater than 40-fold higher affinity for the receptor and the idiotype than the linear analog. This study suggests that conformationally constrained and dimeric peptides derived from antibody hypervariable loop sequences can bind antigens (including receptors) with reasonable affinity. hypervariable loop sequences can bind antigens (including
authors.affiliation: Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia.
authors.forename: W V
authors.initials: WV
authors.lastname: Williams
authors.forename: T
authors.initials: T
authors.lastname: Kieber-Emmons
authors.forename: J
authors.initials: J
authors.lastname: VonFeldt
authors.forename: M I
authors.initials: MI
authors.lastname: Greene
authors.forename: D B
authors.initials: DB
authors.lastname: Weiner
mesh_terms: D000595:Amino Acid Sequence; D000906:Antibodies / Q000276:immunology*; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000276:immunology; D011487:Protein Conformation; D011863:Radioimmunoassay; D013379:Substrate Specificity
chemical_list: D000906:Antibodies; D010456:Peptides, Cyclic