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Consequences of periodic ?-to-?(3) residue replacement for immunological recognition of peptide epitopes.

ABSTRACT: Oligomers that contain both ?- and ?-amino acid residues, or "?/?-peptides", have emerged as promising mimics of signal-bearing polypeptides that can inhibit or augment natural protein-protein interactions. ?/?-Peptides that contain a sufficient proportion of ? 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 ?/?-peptides by the immune system. Prior studies have focused almost entirely on examples that contain a single ? residue; such ?/?-peptides frequently retain the immunological profile of the analogous ?-peptide. We have conducted ?-peptide vs ?/?-peptide comparisons involving higher ? residue content, focusing on molecules with ???? and ??????? 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 ?-peptide is suppressed by periodic ? ? ? replacements. Complementary studies reveal that antibodies raised against Bim BH3- or sPLA2-derived ?/?-peptides fail to recognize prototype ?-peptides displaying identical side chain repertoires. Because polypeptides containing d-?-amino acid residues are of growing interest for biomedical applications, we included the enantiomer of the sPLA2-derived ?-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 ? ? ? 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.

SUBMITTER: Cheloha RW

PROVIDER: S-EPMC4372116 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Consequences of periodic α-to-β(3) residue replacement for immunological recognition of peptide epitopes.

Cheloha Ross W RW Sullivan Jeremy A JA Wang Tong T Sand Jordan M JM Sidney John J Sette Alessandro A Cook Mark E ME Suresh M M Gellman Samuel H SH

ACS chemical biology 20150105 3

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. Pri ...[more]

PMID: 25559929

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Project description:We report high-resolution crystal structures of six new alpha/beta-peptide foldamers that have a regular alpha-residue/alpha-residue/beta-residue (alphaalphabeta) backbone repeat pattern. All of these foldamers were crystallized from aqueous solution, and all display four-helix bundle quaternary structure in the crystalline state. These oligomers are based on the well-studied 33-residue alpha-peptide GCN4-pLI, which is an engineered derivative of the dimerization domain of GCN4, a yeast transcription factor. GCN4-pLI forms a stable tetramer in solution and crystallizes as a four-helix bundle (Harbury et al. Science 1993, 262, 1401-1407). Previously we described a foldamer (designated 1 here) that was generated from GCN4-pLI by replacing every third alpha-amino acid residue with the homologous beta(3)-amino acid residue; this alphaalphabeta oligomer retains the side chain sequence of the original alpha-peptide, but the backbone contains 11 additional CH(2) units, which are evenly distributed (Horne et al. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 9151-9156). Despite the expanded backbone, 1 was found to retain the ability to form a tetrameric quaternary structure in which the individual molecules adopt an alpha-helix-like conformation. Here we compare nine analogues of 1 that have the same alphaalphabeta backbone but in which one or more of the flexible beta(3)-amino acid residues is/are replaced with an analogous cyclic beta-residue. The motivation for beta(3)-->cyclic replacements is to enhance conformational stability; however, a crystal structure of the one previously reported example (designated 2 here) revealed a "stammer" distortion of the helix-bundle architecture relative to 1. The results reported here suggest that the stammer is a peculiarity of 2, because all six of the new alpha/beta-peptides display undistorted four-helix bundle quaternary structures. More broadly, our results indicate that beta(3)-->cyclic replacements are generally well-accommodated in helix-bundle quaternary structure, but that such replacements can be destabilizing in certain instances.

Dataset Information

Consequences of periodic ?-to-?(3) residue replacement for immunological recognition of peptide epitopes.

Publications

Consequences of periodic α-to-β(3) residue replacement for immunological recognition of peptide epitopes.

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