Synthetic Combinatorial Libraries: A New Tool for Drug Design

Methods for Identifying the Composition of Compounds from Peptide and/or Nonpeptide Libraries
  • Michal Lebl
  • Viktor Krchňák
  • Nikolai F. Sepetov
  • Victor Nikolaev
  • Magda Staňková
  • Petr Kočiš
  • Marcel Pátek
  • Zuzana Flegelová
  • Ronald Ferguson
  • Kit S. Lam

Abstract

Development of new leads for drug design and structure/function relationship studies were revolutionized by the introduction of combinatorial or “library” techniques (for review see e.g. (Moos et al., 1993; Gallop et al., 1994; Gordon et al., 1994)). These techniques allow for the generation and screening of millions of potentially active structures. Due to the well developed and finely tuned synthetic methodology, peptides were the first group of compounds evaluated by this new approach. However, the next logical challenge is to synthesize libraries of nonpeptidic structures. The combinatorial library approach applied at Selectide consists of three basic steps: (i) chemical synthesis based on the split synthesis method yielding a library with one test compound structure per one bead; (ii) screening of the library either using an on-bead binding assay or a multiple step release assay; and (iii) recovery of positive beads and determination of the structure of the test compound (Lam et al., 1991).

Keywords

Conformational Space Peptide Library Edman Degradation Diamino Acid Fractional Code 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Brenner, S., Lerner, R. A., 1992 Encoded combinatorial chemistry, Proc.Natl.Acad.Sci. USA 89 (June): 5381.PubMedCrossRefGoogle Scholar
  2. Bunin, B A., Plunkett, M. J. and Ellman, J. A., 1994 The combinatorial synthesis and chemical and biological evaluation of 1,4-benzodiazepine library, Proc.Natl.Acad.Sci. USA 91 (May): 4708.PubMedCrossRefGoogle Scholar
  3. Chen, C., Randall, A. L. A., Miller, B. R., Jones, D. A. and Kurth, M. J., 1994 Analogous Organic Synthesis of Small-Compound Libraries: Validation of Combinatorial Chemistry in Small-Molecule Synthesis, J.Am.Chem.Soc. 116 (6): 2661.CrossRefGoogle Scholar
  4. Cho, C. Y., Moran, E. J., Cherry, S. R., Stephans, J. C., Fodor, S. P. A., Adams, C. L., Sundaram, A., Jacobs, J. W. and Schultz, P. G., 1993 An unnatural biopolymer, Science 261 (3 Sep): 1303.PubMedCrossRefGoogle Scholar
  5. DeWitt, S. H., Kiely, J. S., Stankovic, C. J., Schroeder, M. C., Reynolds Cody, D. M. and Pavia, M. R., 1993 “Diversomers”: An approach to nonpeptide, nonoligomeric chemical diversity, Proc.Natl.Acad.Sci. USA 90: 6909.Google Scholar
  6. Gallop, M. A., Barrett, R. W., Dower, W. J., Fodor, S. P. A. and Gordon, E. M., 1994 Applications of Combinatorial Technologies to Drug Discovery.1. Background and Peptide Combinatorial Libraries, J. Med. Chem. 37 (9): 1233.PubMedCrossRefGoogle Scholar
  7. Gordon, E. M., Barrett, R. W., Dower, W. J., Fodor, S. P. A. and Gallop, M. A., 1994 Applications of combinatorial technologies to drug discovery.2. Combinatorial organic synthesis, library screening strategies, and future directions, J. Med. Chem. 37: 1385.PubMedCrossRefGoogle Scholar
  8. Kerr, J. M., Banville, S. C. and Zuckermann, R. N., 1993 Encoded combinatorial peptide libraries containing non-natural amino acids, J.Am.Chem.Soc. 115: 2529.CrossRefGoogle Scholar
  9. Lam, K. S., Salmon, S. E., Hersh, E. M., Hruby, V. J., Kazmierski, W. M. and Knapp, R. J., 1991 A new type of synthetic peptide library for identifying ligand-binding activity, Nature 354 (7 November): 82.PubMedCrossRefGoogle Scholar
  10. Lebl, M., Krchnâk, V., S’afâr, P., Stierandovâ, A., Sepetov, N. F., Kocis, P. and Lam, K. S., 1994 Construction and screening of libraries of peptide and nonpeptide structures, in: Techniques in Protein Chemistry, Crabb, J. W., ed., Academic Press, San Diego, pp. 541–548.Google Scholar
  11. Moos, W. H., Green, G. D. and Pavia, M. R., 1993 Recent advances in the generation of molecular diversity, in: Annual Reports in Medicinal Chemistry, Bristol, J. A., ed., Academic press. Inc., San Diego, CA, pp. 315–324.Google Scholar
  12. Needels, M. C., Jones, D. G., Tate, E. H., Heinkel, G. L., Kochersperger, L. M., Dower, W. J., Barrett, R. W. and Gallop, M. A., 1993 Generation and screening of an oligonucleotide-encoded synthetic peptide library, Proc.Natl.Acad.Sci. USA 90 (Nov): 10700.PubMedCrossRefGoogle Scholar
  13. Nielsen, J., Brenner, R. A. and Janda, K. D., 1993 Synthetic methods for the implementation of encoded combinatorial chemistry, JAm.Chem.Soc. 115: 9812.CrossRefGoogle Scholar
  14. Nikolaiev, V, Stierandovâ, A., Krchfiâk, V., Seligman, B., Lam, K. S., Salmon, S. E. and Lebl, M., 1993 Peptide-encoding for structure determination of nonsequenceable polymers within libraries synthesized and tested on solid-phase supports, Pept. Res. 6: 161.PubMedGoogle Scholar
  15. Ohlmeyer, M. H., Swanson, R. N., Dillard, L. W., Reader, J. C., Asouline, G., Kobayashi, R., Wigler, M. and Still, W. C., 1993 Complex synthetic chemical libraries indexed with molecular tags, Proc.Natl.Acad.Sci. USA 90: 10922.PubMedCrossRefGoogle Scholar
  16. Sepetov, N. F., Issakova, O. L., Krchilak, V. and Lebl, M., 1992 Peptide sequencing using mass spectrometry, U.S.A., 07 /939, 811.Google Scholar
  17. Simon, R. J., Kaina, R. S., Zuckermann, R. N., Huebner, V. D., Jewell, D. A., Banville, S., Simon, N. G., Wang, L., Rosenberg, S., Marlowe, C. K., Spellmeyer, D. C., Tan, R., Frankel, A. D., Santi, D. V., Cohen, F. E. and Bartlett, P. A., 1992 Peptoids: A modular approach to drug discovery, Proc.Natl.Acad.Sci. USA 89 (October): 9367.PubMedCrossRefGoogle Scholar
  18. Stankovâ, M., Issakova, O., Sepetov, N. F., Krchnâk, V, Lam, K. S. and Lebl, M., 1994 Application of one-bead-one-structure approach to identification of nonpeptidic ligands, Drug Development Research, 33: 146.CrossRefGoogle Scholar
  19. Vâgner, J., Krchnâk, V, Sepetov, N. F., S’trop, P., Lam, K. S., Barany, G. and Lebl, M., 1994 Novel methodology for differentiation of “surface” and “interior” areas of poly(oxyethylene)-polystyrene (POE-PS) supports: Application to library screening procedures, in: Innovation and Perspectives in Solid Phase Synthesis, Epton, R., ed., Mayflower Worldwide Ltd., Birmingham, pp. 347–352.Google Scholar
  20. Youngquist, S., R, Fuentes, G., R, Lacey, M., P and Keough, T., 1994 Matrix-assisted Laser Desorption Ionization for Rapid Determination of the Sequences of Biologically Active Peptides Isolated from Support-bound Combinatorial Peptide Libraries, Rapid Comm.Mass Spectrom. 8: 77.Google Scholar

Copyright information

© Springer Science+Business Media New York 1995

Authors and Affiliations

  • Michal Lebl
    • 1
  • Viktor Krchňák
    • 1
  • Nikolai F. Sepetov
    • 1
  • Victor Nikolaev
    • 1
  • Magda Staňková
    • 1
  • Petr Kočiš
    • 1
  • Marcel Pátek
    • 1
  • Zuzana Flegelová
    • 1
  • Ronald Ferguson
    • 1
  • Kit S. Lam
    • 2
  1. 1.Selectide CorporationOro ValleyUSA
  2. 2.Arizona Cancer Center and Department of MedicineUniversity of Arizona College of MedicineTucsonUSA

Personalised recommendations