Inhibition of genetic expression by the direct interaction of probe molecules with specifically targeted sequences of DNA or mRNA is a fundamental approach to the chemotherapeutic treatment of viral and oncogenic diseases. Selective inhibition of gene expression using antisense oligonucleotides exploits the base-pairing capability of DNA or mRNA to escort the antisense probe to a targeted sequence of nucleic acids, thereby making this approach to chemotherapy exceptionally specific. The studies described in this proposal use a """"""""modified nucleic acid"""""""" strategy for template-directed covalent alkylation of DNA. This process will be achieved by the chemical synthesis of suitably functionalized modified nucleic acids, the incorporation of these bases into oligonucleotides, and the post-synthetic attachment of an electrophilic tether. Upon duplex formation with a complementary oligonucleotide strand, a covalent cross-link will be formed between the probe oligonucleotide and a nucleophilic group on the complementary strand. The consequence of this process will be the creation of an indelible lesion that will irreversibly mask the genetic information contained within the targeted oligonucleotide molecule. Such covalent oligonucleotide probes could provide the basis for a valuable new class of highly specific pharmacological agents for antisense inhibition of oncogenic, genetic, and viral diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29GM047991-04
Application #
2022606
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Project Start
1995-01-01
Project End
1999-12-31
Budget Start
1997-01-01
Budget End
1997-12-31
Support Year
4
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Ohio State University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
098987217
City
Columbus
State
OH
Country
United States
Zip Code
43210
Coleman, R S; Pires, R M (1999) Site-specific formation of abasic lesions in DNA. Nucleosides Nucleotides 18:2141-6