We will attach substituents terminating in an electrophilic alkylating moiety to certain of the heterocyclic bases in synthetic oligonucleotides for the purpose of covalent alkylation of nucleophilic sites on the complementary target strand after the initial hybrid has been formed between oligomer and target. Our criteria for a successful crosslinking oligonucleotide will be adequate speed of crosslinking, specificity of attack, stability in relevant biological conditions, and relative ease of synthesis. If these criteria can be met, oligonucleotides with these crosslinking modifications will have great potential in both the antisense oligonucleotide field of chemotherapeutic drug discovery, especially in the area of antiviral drugs, and in the DNA probe-based diagnostics filed. In the former area, the modification will give a substantial increase in potency in the inhibition of mRNA translation, and should be able to inactivate transcription and replication of specifically targeted genes. In the latter case, a dramatic increase in signal-to-noise of the assay should result since much more stringent washes may be employed.