title: Consequences of periodic α-to-β(3) residue replacement for immunological recognition of peptide epitopes.
abstract: Oligomers that contain both α- and β-amino acid residues, or "α/β-peptides", have emerged as promising mimics of signal-bearing polypeptides that can inhibit or augment natural protein-protein interactions. α/β-Peptides that contain a sufficient proportion of β residues evenly distributed along the sequence can be highly resistant to enzymatic degradation, which is favorable with regard to in vivo applications. Little is known, however, about recognition of α/β-peptides by the immune system. Prior studies have focused almost entirely on examples that contain a single β residue; such α/β-peptides frequently retain the immunological profile of the analogous α-peptide. We have conducted α-peptide vs α/β-peptide comparisons involving higher β residue content, focusing on molecules with αααβ and ααβαααβ backbone repeat patterns. Among analogues of an 18-mer derived from the Bim BH3 domain and an 8-mer derived from secreted phospholipase-2 (sPLA2), we find that recognition by antibodies raised against the prototype α-peptide is suppressed by periodic α → β replacements. Complementary studies reveal that antibodies raised against Bim BH3- or sPLA2-derived α/β-peptides fail to recognize prototype α-peptides displaying identical side chain repertoires. Because polypeptides containing d-α-amino acid residues are of growing interest for biomedical applications, we included the enantiomer of the sPLA2-derived α-peptide in these studies; this d-peptide is fully competent as a hapten, but the resulting antibodies do not cross react with the enantiomeric peptide. Among analogues of the 9-mer CD8(+) T-cell viral epitope GP33, we observe that periodic α → β replacements suppress participation in the MHC I + peptide + T-cell receptor ternary complexes that activate cytotoxic T-lymphocytes, due in part to disruption of MHC binding.
authors.forename: Ross W
authors.initials: RW
authors.lastname: Cheloha
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Sullivan
authors.forename: Tong
authors.initials: T
authors.lastname: Wang
authors.forename: Jordan M
authors.initials: JM
authors.lastname: Sand
authors.affiliation: ⊥La Jolla Institute for Allergy and Immunology, La Jolla, California United States.
authors.forename: John
authors.initials: J
authors.lastname: Sidney
authors.affiliation: ⊥La Jolla Institute for Allergy and Immunology, La Jolla, California United States.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
authors.forename: Mark E
authors.initials: ME
authors.lastname: Cook
authors.forename: M
authors.initials: M
authors.lastname: Suresh
authors.forename: Samuel H
authors.initials: SH
authors.lastname: Gellman
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies / Q000737:chemistry* / Q000276:immunology / Q000302:isolation & purification; D000918:Antibody Specificity; D000956:Antigens, Viral / Q000737:chemistry* / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry* / Q000276:immunology; D000072224:Bcl-2-Like Protein 11; D001665:Binding Sites; D002645:Chickens; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000737:chemistry* / Q000276:immunology; D006801:Humans; D007700:Kinetics; D008565:Membrane Proteins / Q000737:chemistry* / Q000276:immunology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000276:immunology; D054467:Phospholipases A2 / Q000737:chemistry* / Q000276:immunology; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry* / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000276:immunology; D013237:Stereoisomerism; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology
chemical_list: D000906:Antibodies; D000956:Antigens, Viral; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D000939:Epitopes; D008565:Membrane Proteins; D009842:Oligopeptides; D011518:Proto-Oncogene Proteins; D011948:Receptors, Antigen, T-Cell; D054467:Phospholipases A2