New Synthetic Non-peptide Ligands for Classical Major Histocompatibility Complex Class I Molecules*

Poly-N-acylated amines, as a new class of synthetic non-peptide ligands for the murine major histocompatibility complex (MHC) class I molecule H-2Kb, were developed on the basis of the ovalbumin-derived peptide epitope SIINFEKL. Non-peptidic structural elements were introduced at the C-terminal part of the ligand and include the two dominant anchors at positions 5 and 8. Several oligomers and five different combinatorial libraries were synthesized and tested for their H-2Kb-binding capacities in an MHC stabilization assay. First, the optimal spacing and geometry of the side chains were determined using a series of oligomers with different main chain modifications. Then, based on the structure with the highest binding efficiency, randomized libraries were designed that contain 26 different aromatic, heteroaromatic, or pseudoaromatic side chains for the dominant anchor at position 5, which is deeply buried inside the MHC peptide-binding groove and is crucial for the conformational stability of the entire peptide-MHC complex. Similarly, a series of aliphatic side chains were tested for the second dominant anchor at position 8. MHC-binding and MHC-stabilizing oligomers with defined structures were derived from these libraries by deconvolution.

[1]  K. Augustyns,et al.  Investigation on the stability of the Dde protecting group used in peptide synthesis: migration to an unprotected lysine. , 2009, The journal of peptide research : official journal of the American Peptide Society.

[2]  Gnther Jung,et al.  Combinatorial Peptide and Nonpeptide Libraries , 1996 .

[3]  S. Muller,et al.  Partially modified retro-inverso pseudopeptides as non-natural ligands for the human class I histocompatibility molecule HLA-A2. , 1996, Journal of medicinal chemistry.

[4]  W. Chan,et al.  Dde — A selective primary amine protecting group: A facile solid phase synthetic approach to polyamine conjugates , 1996 .

[5]  P. Kourilsky,et al.  Efficient Binding of Reduced Peptide Bond Pseudopeptides to Major Histocompatibility Complex Class I Molecule (*) , 1995, The Journal of Biological Chemistry.

[6]  Stefan Kienle,et al.  Tolerance to Amino Acid Variations in Peptides Binding to the Major Histocompatibility Complex Class I Protein H-2Kb(*) , 1995, The Journal of Biological Chemistry.

[7]  K. Wiesmüller,et al.  Elucidation of T-cell epitopes: a synthetic approach with random peptide libraries. , 1995, Biochemical Society transactions.

[8]  S. Kienle,et al.  Decrypting the structure of major histocompatibility complex class I- restricted cytotoxic T lymphocyte epitopes with complex peptide libraries , 1995, The Journal of experimental medicine.

[9]  S. Schreiber,et al.  A tricyclic ring system replaces the variable regions of peptides presented by three alleles of human MHC class I molecules. , 1995, Chemistry & biology.

[10]  P. A. Peterson,et al.  Crystal structure of an H-2Kb-ovalbumin peptide complex reveals the interplay of primary and secondary anchor positions in the major histocompatibility complex binding groove. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[11]  D. Rognan,et al.  Rational design of nonnatural peptides as high-affinity ligands for the HLA-B*2705 human leukocyte antigen. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[12]  D. Wiley,et al.  Importance of peptide amino and carboxyl termini to the stability of MHC class I molecules. , 1994, Science.

[13]  C Kempter,et al.  Electrospray mass spectrometry and tandem mass spectrometry of synthetic multicomponent peptide mixtures: determination of composition and purity. , 1994, Analytical biochemistry.

[14]  H. Grey,et al.  T cell receptor antagonist peptides are highly effective inhibitors of experimental allergic encephalomyelitis , 1994, European journal of immunology.

[15]  P. A. Peterson,et al.  Crystal structures of two viral peptides in complex with murine MHC class I H-2Kb. , 1994, Science.

[16]  D. Wiley,et al.  The antigenic identity of peptide-MHC complexes: A comparison of the conformations of five viral peptides presented by HLA-A2 , 1993, Cell.

[17]  S R Cherry,et al.  An unnatural biopolymer. , 1993, Science.

[18]  Ronald N. Zuckermann,et al.  The chemical synthesis of peptidomimetic libraries: Current opinion in structural biology 1993, 3:580–584 , 1993 .

[19]  P. Bjorkman,et al.  Thermal stability comparison of purified empty and peptide-filled forms of a class I MHC molecule. , 1992, Science.

[20]  L Wang,et al.  Peptoids: a modular approach to drug discovery. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[21]  M. Bevan,et al.  Dissection of major histocompatibility complex (MHC) and T cell receptor contact residues in a Kb‐restricted ovalbumin peptide and an assessment of the predictive power of MHC‐binding motifs , 1992, European journal of immunology.

[22]  P. A. Peterson,et al.  Emerging principles for the recognition of peptide antigens by MHC class I molecules. , 1992, Science.

[23]  G. Jung,et al.  Retro‐Inverso Amide Bonds between Trifunctional Amino Acids , 1992 .

[24]  G. Jung,et al.  Multiple Peptide Synthesis Methods and Their Applications. New Synthetic Methods (87) , 1992 .

[25]  H. Rammensee,et al.  Allele-specific motifs revealed by sequencing of self-peptides eluted from MHC molecules , 1991, Nature.

[26]  M. Bevan,et al.  Induction of ovalbumin-specific cytotoxic T cells by in vivo peptide immunization , 1989, The Journal of experimental medicine.

[27]  M. A. Saper,et al.  Structure of the human class I histocompatibility antigen, HLA-A2 , 1987, Nature.

[28]  G. W. Anderson,et al.  t-Butyl Esters of Amino Acids and Peptides and their Use in Peptide Synthesis1 , 1960 .

[29]  T. E. Wilson,et al.  Novel biopolymers for drug discovery , 1995, Biopolymers.

[30]  U. Ragnarsson,et al.  Synthesis, properties, and use of Nin-Boc-tryptophan derivatives , 1984 .