Rational screening of oligonucleotide combinatorial libraries for drug discovery.
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.
Ecker
D J
DJ
ISIS Pharmaceuticals, Carlsbad, CA 92008.
Vickers
T A
TA
Hanecak
R
R
Driver
V
V
Anderson
K
K
D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D001483:Base Sequence; D001665:Binding Sites; D015195:Drug Design; D015723:Gene Library; D005821:Genetic Techniques; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D009841:Oligonucleotides / Q000737:chemistry* / Q000494:pharmacology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D012313:RNA / Q000737:chemistry / Q000378:metabolism; D018139:Simplexvirus / Q000187:drug effects / Q000235:genetics
D000998:Antiviral Agents; D009841:Oligonucleotides; D012313:RNA; D016283:Proto-Oncogene Proteins p21(ras)