title: Exploring peptide mimics for the production of antibodies against discontinuous protein epitopes.
abstract: Peptide "mimics" (mimotopes) of linear protein epitopes and carbohydrate epitopes have been successfully used as immunogens to elicit cross-reactive antibodies against their cognate epitopes; however, immunogenic mimicry has been difficult to achieve for discontinuous protein epitopes. To explore this, we developed from phage-displayed peptide libraries optimized peptide mimics for three well-characterized discontinuous epitopes on hen egg lysozyme and horse cytochrome c. The peptides competed with their cognate antigens for antibody binding, displayed affinities in the nM range, and shared critical binding residues with their native epitopes. Yet, while immunogenic, none of the peptides elicited antibodies that cross-reacted with their cognate antigens. We analyzed the 3-D structure of the site within each discontinuous epitope that shared critical binding residues with its peptide mimic, and observed that in each case it formed a ridge-like patch on the epitope; in no case did it cover most or all of the epitope. Thus, the peptides' lack of immunogenic mimicry could be attributed to their inability to recapitulate the topological features of their cognate epitopes. Our results suggest that direct peptide immunizations are not a practical strategy for generating targeted antibody responses against discontinuous epitopes.
authors.affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada.
authors.forename: Melita B
authors.initials: MB
authors.lastname: Irving
authors.forename: Lisa
authors.initials: L
authors.lastname: Craig
authors.forename: Alfredo
authors.initials: A
authors.lastname: Menendez
authors.forename: Beechanahalli P
authors.initials: BP
authors.lastname: Gangadhar
authors.forename: Marinieve
authors.initials: M
authors.lastname: Montero
authors.forename: Nienke E
authors.initials: NE
authors.lastname: van Houten
authors.forename: Jamie K
authors.initials: JK
authors.lastname: Scott
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology*; D000918:Antibody Specificity / Q000276:immunology*; D000941:Antigens / Q000276:immunology*; D000939:Epitopes / Q000276:immunology*; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D018716:Molecular Mimicry / Q000276:immunology; D009113:Muramidase / Q000276:immunology*; D010455:Peptides / Q000276:immunology*; D017434:Protein Structure, Tertiary / Q000502:physiology
chemical_list: D000906:Antibodies; D000941:Antigens; D000939:Epitopes; D010455:Peptides; D009113:Muramidase