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.

  • Letter
  • Published:

Generation and use of synthetic peptide combinatorial libraries for basic research and drug discovery

Abstract

EXISTING methods for the synthesis and screening of large numbers of peptides are limited by their inability to generate and screen the requisite number (millions) of individual peptides1–4 and/or their inability to generate unmodified free peptides in quantities able to interact in solution4–8. We have circumvented these limitations by developing synthetic peptide combinatorial libraries composed of mixtures of free peptides in quantities which can be used directly in virtually all existing assay systems. The screening of these heterogeneous libraries, along with an iterative selection and synthesis process, permits the systematic identification of optimal peptide ligands. Starting with a library composed of more than 34 million hexa-peptides, we present here the precise identification of an antigenic determinant recognized by a monoclonal antibody as well as the straightforward development of new potent antimicrobial peptides.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Similar content being viewed by others

References

  1. Merrifield, R. B. J. Am. chem. Soc. 85, 2149–2154 (1963).

    Article  CAS  Google Scholar 

  2. Geysen, H. M., Meloen, R. H. & Barteling, S. J. Proc. natn. Acad. Sci. U.S.A. 81, 3998–4002 (1984).

    Article  ADS  CAS  Google Scholar 

  3. Houghten, R. A. Proc. natn. Acad. Sci. U.S.A. 82, 5131–5135 (1985); US Patent 4,631,211.

    Article  ADS  CAS  Google Scholar 

  4. Fodor, S. P. A. et al. Science 251, 767–773 (1991).

    Article  ADS  CAS  Google Scholar 

  5. Geysen, H. M., Rodda, S. J. & Mason, T. J. Molec. Immun. 23, 709–715 (1986).

    Article  CAS  Google Scholar 

  6. Scott, J. K. & Smith, G. P. Science 249, 386–390 (1990).

    Article  ADS  CAS  Google Scholar 

  7. Devlin, J. J., Panganiban, L. C. & Devlin, P. E. Science 249, 404–406 (1990).

    Article  ADS  CAS  Google Scholar 

  8. Cwirla, S. E., Peters, E. A., Barrett, R. W. & Dower, W. J. Proc. natn. Acad. Sci. U.S.A. 87, 6378–6382 (1990).

    Article  ADS  CAS  Google Scholar 

  9. Houghten, R. A., Hoffman, S. R. & Niman, H. L. Vaccines 86 (eds Brown, F., Chanock, R. M. & Lerner, R. A.) 21–25 (Cold Spring Harbor Laboratory Press, New York, 1986).

    Google Scholar 

  10. Appel, J. R., Pinilla, C., Niman, H. & Houghten, R. A. J. Immun. 144, 976–983 (1990).

    CAS  PubMed  Google Scholar 

  11. Pinilla, C., Appel, J. R. & Houghten, R. A. Peptides, Proc. 21st Eur. Peptide Symp. (eds Giralt, E. & Andreu, D.) 860 (Escom Science, Leiden, the Netherlands, 1991).

    Google Scholar 

  12. Houghten, R. A., Appel, J. R. & Pinilla, C. Peptide Chemistry 1987 (eds Shiba, T. & Sakakibara, S.) 769–774 (Protein Research Foundation, Minoh-Shi, Osaka, 1987).

    Google Scholar 

  13. Houghten, R. A., Appel, J. R. & Pinilla, C. Vaccines 88 (eds Ginsberg, H., Brown, F., Lerner, R. & Chanock, R. M.) 9–12 (Cold Spring Harbor Laboratory Press, New York, 1988).

    Google Scholar 

  14. Boman, H. G. & Hultmark, D. A. Rev. Microbiol. 41, 103–126 (1987).

    Article  CAS  Google Scholar 

  15. Zasloff, M. Proc. natn. Acad. Sci. U.S.A. 84, 5449–5453 (1987).

    Article  ADS  CAS  Google Scholar 

  16. Selsted, M. E., Brown, D. M., DeLange, R. J. & Lehrer, R. I. J. biol. Chem. 258, 14485–14489 (1983).

    CAS  PubMed  Google Scholar 

  17. Cuervo, J. H., Rodriguez, B. & Houghten, R. A. Peptide Res. 1, 81–86 (1988).

    CAS  Google Scholar 

  18. Blondelle, S. E. & Houghten, R. A. Peptide Res. 4, 12–18 (1991).

    CAS  Google Scholar 

  19. Blondelle, S. E. & Houghten, R. A. Biochemistry 30, 4671–4678 (1991).

    Article  CAS  Google Scholar 

  20. Wilson, I. A. et al. Cell 37, 767–778 (1984).

    Article  CAS  Google Scholar 

  21. Gisin, B. F. Analytica chim. Acta. 58, 248–249 (1972).

    Article  CAS  Google Scholar 

  22. Kaiser, E. T., Colescott, R. L., Bossinger, C. D. & Cook, P. I. Analyt. Biochem. 34, 595–598 (1970).

    Article  CAS  Google Scholar 

  23. Tam, J. P., Heath, W. F. & Merrifield, R. B. J. Am. chem. Soc. 105, 6442–6455 (1983).

    Article  CAS  Google Scholar 

  24. Houghten, R. A., Bray, M. K., DeGraw, S. T. & Kirby, C. J. Int. J. Peptide Protein Res. 27, 673–678 (1986).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Houghten, R., Pinilla, C., Blondelle, S. et al. Generation and use of synthetic peptide combinatorial libraries for basic research and drug discovery. Nature 354, 84–86 (1991). https://doi.org/10.1038/354084a0

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/354084a0

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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