Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Research Article
  • Published:

Synthetic CD4 exocyclic peptides antagonize CD4 holoreceptor binding and T cell activation

Nature Biotechnology volume 14, pages 472–475 (1996)Cite this article

Abstract

We have developed peptide analogs to analyze precise human CD4 substructures involved in MHC class II binding. Forms of the complementarity determining-like regions (CDRs) of the D1 domain of human CD4 were reproduced as synthetic aromatically modified exocyclic (AME) analogs and tested for their ability to block CD4-MHC II interactions and T cell activation. The exocyclic derived from CDRS (residues 82-89) of human CD4, which specifically associated with CD4 on the T cell surface to create a heteromeric CD4 complex, blocked IL-2 production and antagonized the normal function of the CD4 receptor. The approach of creating novel synthetic antagonistic receptor complexes may represent a new receptor specific pharmaceutical approach to modulate biological function.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Gay, D., Maddon, P., Sekaly, R., Talle, M.A., Godfrey, M., Long, E. et al. 1987. Functional interaction between human T-cell protein CD4 and the major histo-compatibility complex HLA-DR antigen. Nature 328: 626–629.

    Article  CAS  Google Scholar 

  2. Wang, J.H., Yan, Y.W., Garrett, T.P., Liu, J.H., Rodgers, D.W., et al. 1990. Atomic structure of a fragment of human CD4 containing two immunoglobulin-like domains. Nature 348: 411–418.

    Article  CAS  Google Scholar 

  3. Ryu, S.E., Kwong, P.D., Truneh, A., Porter, T.G., Arthos, J., Rosenberg, M. et al. 1990. Crystal structure of an HIV-binding recombinant fragment of human CD4. Nature 348: 419–426.

    Article  CAS  Google Scholar 

  4. Moebius, U., Pallai, P., Harrison, S.C., and Reinherz, E.L. 1993. Delineation of an extended surface contact area on human CD4 involved in MHC class II major histocompatibility complex binding. Proc. Natl. Acad. Sci. USA 90: 8259–8263.

    Article  CAS  Google Scholar 

  5. Barber, E.K., Dasgupta, J.D., Schlossman, S.R., Trevillyan, J.M. and Rudd, C.E. 1989. The CD4 and CD8 antigens are coupled to a protein-tyrosine kinase (p56lck) that phosphorylates the CD3 complex. Proc. Natl. Acad. Sci. USA 86: 3277–3281.

    Article  CAS  Google Scholar 

  6. Hussey, R.E., Richardson, N.E., Kowalski, M., Brown, N.R., Chang, H.-C., Siliciano, R.F. et al. 1988. A soluble CD4 protein selectively inhibits HIV replication and syncytium. Nature 331: 78–81.

    Article  CAS  Google Scholar 

  7. Sakihama, T., Smolyar, A. and Reinherz, E.L. 1995. Oligomerization of CD4 is required for stable binding to class II major histocompatibility complex proteins but not for interaction with human immunodeficiency virus gp120. Proc. Natl. Acad. Sci. USA 92: 6444–6448.

    Article  CAS  Google Scholar 

  8. Field, B., Ober, B., Malchiodi, E., Lebedeva, M., Braden, B., Ysern, X. et al. 1995. Crystal structure of the Vα domain of a T cell antigen receptor. Science 270: 1821–1824.

    Article  Google Scholar 

  9. Konig, R., Shen, X. and Germain, R.N. 1995. Involvement of both major histocompatibility complex class II alpha and beta chains in CD4 function indicates a role for ordered oligomerization in T cell activation. J. Exp. Med. 182: 779–787.

    Article  CAS  Google Scholar 

  10. Langedijk, J.P., Puijk, W.C., van, H.W., and Meloen, R.H. 1993. Location of CD4 dimerization site explains critical role of CDR3-like region in HIV-1 infection and T-cell activation and implies a model for complex of coreceptor-MHC. J. Biol. Chem. 268: 16875–16878.

    CAS  PubMed  Google Scholar 

  11. Dougall, W.C. and Greene, M.I. 1994. Biological studies and potential therapeutic applications of monoclonal antibodies and small molecules reactive with the neulc-erbB-2 protein. Cell Biophysics 25: 209–218.

    Article  Google Scholar 

  12. Saragovi, H.U., Fitzpatrick, D., Raktabutr, A., Nakanishi, H., Kahn, M. and Greene, M.I. 1991. Design and synthesis of a mimetic from an antibody complementarity-determining region. Science 253: 792–795.

    Article  CAS  Google Scholar 

  13. Scheirle, A., Takacs, B., Kremer, L., Marin, F. and Sinigaglia, F. 1992. Peptide binding to soluble HLA-DR4 molecules produced by insect cells. J. Immunol. 149: 1994–1999.

    CAS  PubMed  Google Scholar 

  14. Konig, R., Huang, L.Y. and Germain, R.N. 1992. MHC class II interaction with CD4 mediated by a region analogous to the MHC class I binding site for CD8. Nature 356: 796–798.

    Article  CAS  Google Scholar 

  15. Cammarota, G., Scheirle, A., Takacs, B., Doran, D.M., Knorr, R., Bannwarth, W., Guardiola, J. et al. 1992. Identification of a CD4 binding site on the beta 2 domain of HLA-DR molecules. Nature 356: 799–801.

    Article  CAS  Google Scholar 

  16. Piatier-Tonneau, D., Gastinel, L.N., Amblard, R., Wojcik, M., Vaigot, P. and Auffray, C. 1991. Interaction of CD4 with HLA class II antigens and HIV gp120. Immunogenetics 34: 121–128.

    Article  CAS  Google Scholar 

  17. Marrack, P., Endres, R., Shimonkevitz, R., Zlotnik, A., Dialynas, D., Fitch, R. and Kappler, J. 1983. The major histocompatibility complex-restricted antigen receptor on T cells. II. Role of the L3T4 product. J. Exp. Med. 158: 1077–91.

    Article  CAS  Google Scholar 

  18. Jameson, B.A., McDonnell, J.M., Marini, J.C. and Korngold, R. 1994. A rationally designed CD4 analogue inhibits experimental allergic encephalo-myletis. Nature 368: 744–746.

    Article  CAS  Google Scholar 

  19. Habeeb, F.F. 1973. A sensitive method for localization of disulfide containing peptides in column effluents. Anal. Bioch. 56: 60–65.

    Article  CAS  Google Scholar 

  20. Ponder, J.W. and Richards, F.M. 1987. Tertiary templates for proteins. Use of packing criteria in the enumeration of allowed sequences for different structural classes. J. Mol. Biol. 193: 775–791.

    Article  CAS  Google Scholar 

  21. Shimonkevitz, R., Kappler, J., Marrack, P. and Grey, H. 1983. Antigen recognition by H-2-restricted T cells. I. Cell-free antigen processing. J. Exp. Med. 158: 303–316.

    Article  CAS  Google Scholar 

  22. Sette, A., Sidney, J., Albertson, M., Miles, C., Colon, S.M., Pedrazzini, T., Lamont, A.G. and Grey, H.M. 1990. A novel approach to the generation of high affinity class ll-binding peptides. J. Immunol. 145: 1809–1813.

    CAS  PubMed  Google Scholar 

  23. Mosmann, T. 1983. Rapidcolormetric assay for cellular growth and survival: application to proliferarion and cytotoxic assays. J. Immunol. Methods 65: 55.

    Article  CAS  Google Scholar 

  24. Traunecker, A., Luke, W. and Karjalainen, K. 1988. Soluble CD4 molecules neutralize human immunodeficiency virus type 1. Nature 331: 84–86.

    Article  CAS  Google Scholar 

Download references

Author information

Author notes

  1. Mark I. Greene: Corresponding author.

Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine,

    Ramachandran Murali, Ajit Mahapatra, Fuqing Zhang & Curtis C. Maier

  2. Department of Pharmacology, School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104–6082

    Xin Zhang

  3. Génétique Moléculaire et Biologie du Développement, UPR 420, Centre National de la Recherche Scientifique, Villejuif, France

    Dominique Piatier-Tonneau & Charles Auffray

  4. Department of Pharmacology, McGill University, Canada

    H. Saragovi

Authors
  1. Xin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dominique Piatier-Tonneau
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Charles Auffray
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ramachandran Murali
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ajit Mahapatra
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fuqing Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Curtis C. Maier
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. H. Saragovi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Mark I. Greene
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, X., Piatier-Tonneau, D., Auffray, C. et al. Synthetic CD4 exocyclic peptides antagonize CD4 holoreceptor binding and T cell activation. Nat Biotechnol 14, 472–475 (1996). https://doi.org/10.1038/nbt0496-472

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nbt0496-472

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing