Conformational epitope peptide

Because conformational epitopes are not easily mimicked with linear peptides, which can elicit nonspecific antibodies, several alternative strategies such as synthetic cyclic peptides have been developed [see e.g., (18)]. A similar conformational restriction was seemingly achieved with a P-amyloid peptide that was anchored to the surface of liposomes via hydrophobic tails introduced at its both N- and C-termini. The reconstituted peptide proved highly immunogenic and elicited antibodies that could significantly prevent amyloid plaque formation in a model system (70). 

B. Lead Finding Using Conformationally Constrained Peptides Mimicking Exposed Protein Epitopes... 

In Section II.C we will present novel tricyclic xanthene derived amino acid templates, which allow the construction of libraries of cyclic conformationally constrained peptide loop mimetics using the split-and-mix method without having to use tagging and deconvolution strategies. In Section III we will focus on parallel and combinatorial approaches devoted to the synthesis of small molecule, non-peptidic compound collections, which in addition offer the possibility to incorporate structural features derived from protein epitope mapping into conformationally constrained peptide mimetics. 

Otvos, L., Jr., Urge, L., Xiang, Z.Q., et al. (1994) Glycosylation of synthetic T helper cell epitopic peptides influences their antigenic potency and conformation in a sugar location-specific manner. Biochim. Biophys. Acta 1224, 68-76. 

As many B cell epitopes are described to be conformational (Aalberse, 2000), peptides identified by sequential approaches may render limited information and might exhibit reduced antibody-binding affinity. In a very stringent definition, conformational epitopes are composed of amino acids from different loci in the allergen sequence brought into proximity by the tertiary structure of the protein. Systematic characterization of conformational epitopes is much more difficult compared to linear epitopes, because it requires knowledge of the 3D structure, which is often limited. 

Proteasomes rather than cytosolic carboxy-peptidases act to trim the C-terminal amino acids to conform the peptide to the proper size for MHC class-I presentation. Presentation from N-extended precursors is inhibited by acetylation of the terminal a-amino group at the N-terminus [354], which prevents the peptide to be cleaved by aminopeptidases e.g. leucine aminopeptidase) but not by proteasomes or endopeptidases. The TAP system transports peptides to the ER including both mature epitopes and longer precursors. It seems then that the peptides to be presented by MHC class-I can arise from N-extended precursors both in the cytosol and in the endoplasmic reticulum (ER). This assertion has been experimentally confirmed [355,356]. 

Y. Tian, et al., (2002). Structure-affinity relationships in the gp41 ELDKWA epitope for the HIV-(l) neutralizing monoclonal antibody F-2(5) effects of side-chain and backbone modifications and conformational constraints. /. Peptide Res. 59, 264—276. 

R.C. Landry, et al., (2001). Antibody recognition of a conformational epitope in a peptide antigen Fv-peptide complex of an antibody fragment specific for the mutant EGF receptor, EGFRvIII. /. Mol. Biol. 308, 883-893. 

W. Fiedler, C. Borchers, M. Macht, S.O. Dei-ninger and M. Przybylski, (1998). Molecular characterization of a conformational epitope of hen egg white lysozyme by differential chemical modification of immune complexes and mass spectrometric peptide mapping. Bio-conj. Chem. 9, 236-241. 

C. Saint-Pierre and E. Forest, (2000). Characterization of an anti-Borrelia burgdorferi OspA conformational epitope by limited proteolysis of monoclonal antibody-bound antigen and mass spectrometric peptide mapping. Protein Sci. 9, 1002-1010. 

M.A. Myers, et al., (2000). Conformational epitopes on the diabetes autoantigen GAD65 identified by peptide phage display and molecular modeling. J. Immunol. 165, 3830-3838. 

Frangione-Beebe M, Albrecht B, Dakappagari N, Rose RT, Brooks CL, Schwendeman SP, Lairmore MD, Kamnaya PT. Enhanced immunogenicity of a conformational epitope of human T-lymphotropic virus type 1 using a novel chimeric peptide. Vaccine 2000 19 1068-1081. 

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