Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1995 Jul 3;92(14):6419–6423. doi: 10.1073/pnas.92.14.6419

Liquid-phase combinatorial synthesis.

H Han 1, M M Wolfe 1, S Brenner 1, K D Janda 1
PMCID: PMC41529  PMID: 7541541

Abstract

A concept termed liquid-phase combinatorial synthesis (LPCS) is described. The central feature of this methodology is that it combines the advantages that classic organic synthesis in solution offers with those that solid-phase synthesis can provide, through the application of a linear homogeneous polymer. To validate this concept two libraries were prepared, one of peptide and the second of nonpeptide origin. The peptide-based library was synthesized by a recursive deconvolution strategy [Erb, E., Janda, K. D. & Brenner, S. (1994) Proc. Natl. Acad. Sci. USA 91, 11422-11426] and several ligands were found within this library to bind a monoclonal antibody elicited against beta-endorphin. The non-peptide molecules synthesized were arylsulfonamides, a class of compounds of known clinical bactericidal efficacy. The results indicate that the reaction scope of LPCS should be general, and its value to multiple, high-throughput screening assays could be of particular merit, since multimilligram quantities of each library member can readily be attained.

Full text

PDF
6419

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bayer E., Mutter M. Liquid phase synthesis of peptides. Nature. 1972 Jun 30;237(5357):512–513. doi: 10.1038/237512a0. [DOI] [PubMed] [Google Scholar]
  2. Bonora G. M., Scremin C. L., Colonna F. P., Garbesi A. HELP (high efficiency liquid phase) new oligonucleotide synthesis on soluble polymeric support. Nucleic Acids Res. 1990 Jun 11;18(11):3155–3159. doi: 10.1093/nar/18.11.3155. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bunin B. A., Plunkett M. J., Ellman J. A. The combinatorial synthesis and chemical and biological evaluation of a 1,4-benzodiazepine library. Proc Natl Acad Sci U S A. 1994 May 24;91(11):4708–4712. doi: 10.1073/pnas.91.11.4708. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Cwirla S. E., Peters E. A., Barrett R. W., Dower W. J. Peptides on phage: a vast library of peptides for identifying ligands. Proc Natl Acad Sci U S A. 1990 Aug;87(16):6378–6382. doi: 10.1073/pnas.87.16.6378. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. DeWitt S. H., Kiely J. S., Stankovic C. J., Schroeder M. C., Cody D. M., Pavia M. R. "Diversomers": an approach to nonpeptide, nonoligomeric chemical diversity. Proc Natl Acad Sci U S A. 1993 Aug 1;90(15):6909–6913. doi: 10.1073/pnas.90.15.6909. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Ellingboe J. W., Spinelli W., Winkley M. W., Nguyen T. T., Parsons R. W., Moubarak I. F., Kitzen J. M., Von Engen D., Bagli J. F. Class III antiarrhythmic activity of novel substituted 4-[(methylsulfonyl)amino]benzamides and sulfonamides. J Med Chem. 1992 Feb 21;35(4):705–716. doi: 10.1021/jm00082a011. [DOI] [PubMed] [Google Scholar]
  7. Erb E., Janda K. D., Brenner S. Recursive deconvolution of combinatorial chemical libraries. Proc Natl Acad Sci U S A. 1994 Nov 22;91(24):11422–11426. doi: 10.1073/pnas.91.24.11422. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Fodor S. P., Read J. L., Pirrung M. C., Stryer L., Lu A. T., Solas D. Light-directed, spatially addressable parallel chemical synthesis. Science. 1991 Feb 15;251(4995):767–773. doi: 10.1126/science.1990438. [DOI] [PubMed] [Google Scholar]
  9. Geysen H. M., Rodda S. J., Mason T. J. A priori delineation of a peptide which mimics a discontinuous antigenic determinant. Mol Immunol. 1986 Jul;23(7):709–715. doi: 10.1016/0161-5890(86)90081-7. [DOI] [PubMed] [Google Scholar]
  10. Hodgson J. Pharmaceutical screening: from off-the-wall to off-the-shelf. The many routes to successful drug discovery. Biotechnology (N Y) 1993 Jun;11(6):683–688. doi: 10.1038/nbt0693-683. [DOI] [PubMed] [Google Scholar]
  11. Houghten R. A., Pinilla C., Blondelle S. E., Appel J. R., Dooley C. T., Cuervo J. H. Generation and use of synthetic peptide combinatorial libraries for basic research and drug discovery. Nature. 1991 Nov 7;354(6348):84–86. doi: 10.1038/354084a0. [DOI] [PubMed] [Google Scholar]
  12. Janda K. D. Tagged versus untagged libraries: methods for the generation and screening of combinatorial chemical libraries. Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):10779–10785. doi: 10.1073/pnas.91.23.10779. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kaiser E., Colescott R. L., Bossinger C. D., Cook P. I. Color test for detection of free terminal amino groups in the solid-phase synthesis of peptides. Anal Biochem. 1970 Apr;34(2):595–598. doi: 10.1016/0003-2697(70)90146-6. [DOI] [PubMed] [Google Scholar]
  14. Lam K. S., Salmon S. E., Hersh E. M., Hruby V. J., Kazmierski W. M., Knapp R. J. A new type of synthetic peptide library for identifying ligand-binding activity. Nature. 1991 Nov 7;354(6348):82–84. doi: 10.1038/354082a0. [DOI] [PubMed] [Google Scholar]
  15. Meo T., Gramsch C., Inan R., Höllt V., Weber E., Herz A., Riethmüller G. Monoclonal antibody to the message sequence Tyr-Gly-Gly-Phe of opioid peptides exhibits the specificity requirements of mammalian opioid receptors. Proc Natl Acad Sci U S A. 1983 Jul;80(13):4084–4088. doi: 10.1073/pnas.80.13.4084. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Stein P. D., Hunt J. T., Floyd D. M., Moreland S., Dickinson K. E., Mitchell C., Liu E. C., Webb M. L., Murugesan N., Dickey J. The discovery of sulfonamide endothelin antagonists and the development of the orally active ETA antagonist 5-(dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesulf onamide. J Med Chem. 1994 Feb 4;37(3):329–331. doi: 10.1021/jm00029a001. [DOI] [PubMed] [Google Scholar]
  17. Williard R., Jammalamadaka V., Zava D., Benz C. C., Hunt C. A., Kushner P. J., Scanlan T. S. Screening and characterization of estrogenic activity from a hydroxystilbene library. Chem Biol. 1995 Jan;2(1):45–51. doi: 10.1016/1074-5521(95)90079-9. [DOI] [PubMed] [Google Scholar]
  18. Yoshino H., Ueda N., Niijima J., Sugumi H., Kotake Y., Koyanagi N., Yoshimatsu K., Asada M., Watanabe T., Nagasu T. Novel sulfonamides as potential, systemically active antitumor agents. J Med Chem. 1992 Jun 26;35(13):2496–2497. doi: 10.1021/jm00091a018. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES