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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
Project #
2R44CA045905-02
Application #
3506653
Study Section
Experimental Therapeutics Subcommittee 2 (ET)
Project Start
1987-09-30
Project End
1991-08-31
Budget Start
1989-09-15
Budget End
1990-08-31
Support Year
2
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Epoch Biosciences, Inc.
Department
Type
DUNS #
City
Bothell
State
WA
Country
United States
Zip Code
98021
Petrie, C R; Reed, M W; Adams, A D et al. (1992) An improved CPG support for the synthesis of 3'-amine-tailed oligonucleotides. Bioconjug Chem 3:85-7
Petrie, C R; Adams, A D; Stamm, M et al. (1991) A novel biotinylated adenylate analogue derived from pyrazolo[3,4-d]pyrimidine for labeling DNA probes. Bioconjug Chem 2:441-6