Bioactive peptide design based on protein surface epitopes. A cyclic heptapeptide mimics CD4 domain 1 CC' loop and inhibits CD4 biological function

• Published in: The Journal of biological chemistry Vol. 272; no. 18; pp. 12175 - 12180
• Main Authors: Satoh, T, Aramini, J M, Li, S, Friedman, T M, Gao, J, Edling, A E, Townsend, R, Koch, U, Choksi, S, Germann, M W, Korngold, R, Huang, Z
• Format: Journal Article
• Language: English
• Published: United States 02.05.1997
• Subjects: Amino Acid Sequence; Animals; Binding Sites; CD4 Antigens - chemistry; CD4 Antigens - drug effects; Cell Adhesion - drug effects; Computer Graphics; Drug Design; Encephalomyelitis, Autoimmune, Experimental - immunology; Encephalomyelitis, Autoimmune, Experimental - physiopathology; Epitopes - chemistry; Female; Genes, MHC Class II; Graft Rejection - immunology; Graft Survival - drug effects; Graft vs Host Disease; Humans; Lymphocyte Culture Test, Mixed; Lymphocytes - immunology; Lymphocytes - radiation effects; Male; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Models, Molecular; Oligopeptides - chemical synthesis; Oligopeptides - chemistry; Oligopeptides - pharmacology; Peptides, Cyclic - chemical synthesis; Peptides, Cyclic - chemistry; Protein Structure, Secondary; Skin Transplantation - immunology
• ISSN: 0021-9258
• DOI: 10.1074/jbc.272.18.12175

The interaction between CD4 and major histocompatibility complex class II proteins provides a critical co-receptor function for the activation of CD4(+) T cells implicated in the pathogenesis of a number of autoimmune diseases and transplantation responses. A small synthetic cyclic heptapeptide was designed and shown by high resolution NMR spectroscopy to closely mimic the CD4 domain 1 CC' surface loop. This peptide effectively blocked stable CD4-major histocompatibility complex class II interaction, possessed significant immunosuppressive activity in vitro and in vivo, and strongly resisted proteolytic degradation. These results demonstrate the therapeutic potential of this peptide as a novel immunosuppressive agent and suggest a general strategy of drug design by using small conformationally constrained peptide mimics of protein surface epitopes to inhibit protein interactions and biological functions.