Skip to main content
NCBI home page
Nucleic Acids Research logoLink to Nucleic Acids Research
. 1993 Apr 25;21(8):1853–1856. doi: 10.1093/nar/21.8.1853

Rational screening of oligonucleotide combinatorial libraries for drug discovery.

D J Ecker 1, T A Vickers 1, R Hanecak 1, V Driver 1, K Anderson 1
PMCID: PMC309424  PMID: 7684128

Abstract

Combinatorial strategies offer the potential to generate and screen extremely large numbers of compounds and to identify individual molecules with a desired binding specificity or pharmacological activity. We describe a combinatorial strategy for oligonucleotides in which the library is generated and screened without using enzymes. Freedom from enzymes enables the use of oligonucleotide analogues. This dramatically extends the scope of both the compounds and the targets that may be screened. We demonstrate the utility of the method by screening 2'-O-Methyl and phosphorothioate oligonucleotide analogue libraries. Compounds have been identified that bind to the activated H-ras mRNA and that have potent antiviral activity against the human herpes simplex virus.

Full text

PDF
1853

Selected References

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

  1. Bock L. C., Griffin L. C., Latham J. A., Vermaas E. H., Toole J. J. Selection of single-stranded DNA molecules that bind and inhibit human thrombin. Nature. 1992 Feb 6;355(6360):564–566. doi: 10.1038/355564a0. [DOI] [PubMed] [Google Scholar]
  2. Cook P. D. Medicinal chemistry of antisense oligonucleotides--future opportunities. Anticancer Drug Des. 1991 Dec;6(6):585–607. [PubMed] [Google Scholar]
  3. Denizot F., Lang R. Rapid colorimetric assay for cell growth and survival. Modifications to the tetrazolium dye procedure giving improved sensitivity and reliability. J Immunol Methods. 1986 May 22;89(2):271–277. doi: 10.1016/0022-1759(86)90368-6. [DOI] [PubMed] [Google Scholar]
  4. Eckstein F. Nucleoside phosphorothioates. Annu Rev Biochem. 1985;54:367–402. doi: 10.1146/annurev.bi.54.070185.002055. [DOI] [PubMed] [Google Scholar]
  5. Ellington A. D., Szostak J. W. In vitro selection of RNA molecules that bind specific ligands. Nature. 1990 Aug 30;346(6287):818–822. doi: 10.1038/346818a0. [DOI] [PubMed] [Google Scholar]
  6. 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]
  7. Kang C., Zhang X., Ratliff R., Moyzis R., Rich A. Crystal structure of four-stranded Oxytricha telomeric DNA. Nature. 1992 Mar 12;356(6365):126–131. doi: 10.1038/356126a0. [DOI] [PubMed] [Google Scholar]
  8. Lima W. F., Monia B. P., Ecker D. J., Freier S. M. Implication of RNA structure on antisense oligonucleotide hybridization kinetics. Biochemistry. 1992 Dec 8;31(48):12055–12061. doi: 10.1021/bi00163a013. [DOI] [PubMed] [Google Scholar]
  9. Owens R. A., Gesellchen P. D., Houchins B. J., DiMarchi R. D. The rapid identification of HIV protease inhibitors through the synthesis and screening of defined peptide mixtures. Biochem Biophys Res Commun. 1991 Nov 27;181(1):402–408. doi: 10.1016/s0006-291x(05)81433-0. [DOI] [PubMed] [Google Scholar]
  10. Pyle A. M., McSwiggen J. A., Cech T. R. Direct measurement of oligonucleotide substrate binding to wild-type and mutant ribozymes from Tetrahymena. Proc Natl Acad Sci U S A. 1990 Nov;87(21):8187–8191. doi: 10.1073/pnas.87.21.8187. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Smith F. W., Feigon J. Quadruplex structure of Oxytricha telomeric DNA oligonucleotides. Nature. 1992 Mar 12;356(6365):164–168. doi: 10.1038/356164a0. [DOI] [PubMed] [Google Scholar]
  12. Sproat B. S., Lamond A. I., Beijer B., Neuner P., Ryder U. Highly efficient chemical synthesis of 2'-O-methyloligoribonucleotides and tetrabiotinylated derivatives; novel probes that are resistant to degradation by RNA or DNA specific nucleases. Nucleic Acids Res. 1989 May 11;17(9):3373–3386. doi: 10.1093/nar/17.9.3373. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Turner D. H., Sugimoto N., Freier S. M. RNA structure prediction. Annu Rev Biophys Biophys Chem. 1988;17:167–192. doi: 10.1146/annurev.bb.17.060188.001123. [DOI] [PubMed] [Google Scholar]
  14. Vickers T., Baker B. F., Cook P. D., Zounes M., Buckheit R. W., Jr, Germany J., Ecker D. J. Inhibition of HIV-LTR gene expression by oligonucleotides targeted to the TAR element. Nucleic Acids Res. 1991 Jun 25;19(12):3359–3368. doi: 10.1093/nar/19.12.3359. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Nucleic Acids Research are provided here courtesy of Oxford University Press

RESOURCES