RATIONAL SCREENING OF OLIGONUCLEOTIDE COMBINATORIAL LIBRARIES FOR DRUG DISCOVERY

Combinatorial strategies offer the potential to generate and screen ex tremely large numbers of compounds and to identify individual molecule s with a desired binding specificity or pharmacological activity. We d escribe a combinatorial strategy for oligonucleotides in which the lib rary is generated and screened without using enzymes. Freedom from enz ymes enables the use of oligonucleotide analogues. This dramatically e xtends the scope of both the compounds and the targets that may be scr eened. We demonstrate the utility of the method by screening 2'-O-Meth yl and phosphorothioate oligonucleotide analogue libraries. Compounds have been identified that bind to the activated H-ras mRNA and that ha ve potent antiviral activity against the human herpes simplex virus.