Abstract

Cellular and viral nucleic acids are potential targets for therapeutic intervention in disease processes. The long range goal of this project is to develop oligonucleotide analogs and derivatives which can interact wit double-stranded nucleic acids in a predictable and sequence-specific manner.
The specific aims of the project are: A) Design and synthesized derivatives of uracil and cytosine which can interact with one or more pyrimidine-purine base pairs """"""""imbedded"""""""" in a (purine), (pyrimidine), tract of duplex DNA or RNA; B) Study the ability of these oligomers to form triplexes with double-stranded DNA target molecules; C) Synthesize oligo-2'-O-methylribonucleotides which are designed to interact with single-stranded RNA sequences via intramolecular duplex/triplex formation. These oligomers will also be further modified with alkyl imidazole functional groups in an effort to facilitate cleavage of target RNA internucleotide bond; and D) Study the ability of oligomers containing 8-oxoadenine and other base analogs prepared in Specific Aim 1 to inhibit collagenase IV gene expression in transformed human fibrosarcoma (HT1080) cells in culture. Success in these areas could lead to the rational design of therapeutic agents which act by controlling gene expression at the DNA or RNA level.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM045012-04A1
Application #
2182926
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Project Start
1990-06-05
Project End
1996-12-31
Budget Start
1994-01-01
Budget End
1994-12-31
Support Year
4
Fiscal Year
1994
Total Cost
Indirect Cost

  Institution

Name
Johns Hopkins University
Department
Biochemistry
Type
Schools of Public Health
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218

  Publications

Huang, C Y; Bi, G; Miller, P S (1996) Triplex formation by oligonucleotides containing novel deoxycytidine derivatives. Nucleic Acids Res 24:2606-13
Miller, P S; Bi, G; Kipp, S A et al. (1996) Triplex formation by a psoralen-conjugated oligodeoxyribonucleotide containing the base analog 8-oxo-adenine. Nucleic Acids Res 24:730-6
Verma, S; Miller, P S (1996) Interactions of cytosine derivatives with T.A interruptions in pyrimidine.purine.pyrimidine DNA triplexes. Bioconjug Chem 7:600-5
Miller, P S; Cushman, C D (1993) Triplex formation by oligodeoxyribonucleotides involving the formation of X.U.A triads. Biochemistry 32:2999-3004
Miller, P S; Cushman, C D (1992) Selective modification of cytosines in oligodeoxyribonucleotides. Bioconjug Chem 3:74-9
Miller, P S; Bhan, P; Cushman, C D et al. (1992) Recognition of a guanine-cytosine base pair by 8-oxoadenine. Biochemistry 31:6788-93