Abstract

The goal of this project is to develop new compounds of value in the study and treatment of AIDS. The approach is to synthesize oligonucleotide analogues that will penetrate cell membranes, survive attack by nucleases, and selectively inhibit HIV replication. Special attention will be given to cholesteryl conjugated derivatives and related compounds in long term cell culture systems, and subsequent efforts will be devoted to developing a practical procedure for large scale synthesis of these compounds for eventual testing in animals. New oligonucleotide analogues with potential as inhibitors of HIV will be synthesized and tested for recognition of specific RNA sequences, as inhibitors of protein synthesis in a cell free system, and as inhibitors of HIV in cell culture (short and long term). Compounds to be examined include oligonucleotide phosphoramidates (0=PNH2) and analogues with mixed cationic, methyl sulfoxide, phosphorothioate, phosphodiester, alkyl phosphotriester, phosphoramidate, and methyl phosphonate backbones.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
2U01AI024846-07
Application #
3791076
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
1992
Total Cost
Indirect Cost

  Institution

Name
Worcester Foundation for Biomedical Research
Department
Type
DUNS #
City
Shrewsbury
State
MA
Country
United States
Zip Code
01545

  Publications

Nelson, J S; Giver, L; Ellington, A D et al. (1996) Incorporation of a non-nucleotide bridge into hairpin oligonucleotides capable of high-affinity binding to the Rev protein of HIV-1. Biochemistry 35:5339-44
Gryaznov, S M; Schultz, R; Chaturvedi, S K et al. (1994) Enhancement of selectivity in recognition of nucleic acids via chemical autoligation. Nucleic Acids Res 22:2366-9
Temsamani, J; Metelev, V; Levina, A et al. (1994) Inhibition of in vitro transcription by oligodeoxynucleotides. Antisense Res Dev 4:279-84
Zamecnik, P; Aghajanian, J; Zamecnik, M et al. (1994) Electron micrographic studies of transport of oligodeoxynucleotides across eukaryotic cell membranes. Proc Natl Acad Sci U S A 91:3156-60
Herrlein, M K; Letsinger, R L (1994) Selective chemical autoligation on a double-stranded DNA template. Nucleic Acids Res 22:5076-8
Goodchild, J (1992) Enhancement of ribozyme catalytic activity by a contiguous oligodeoxynucleotide (facilitator) and by 2'-O-methylation. Nucleic Acids Res 20:4607-12
Agrawal, S (1992) Antisense oligonucleotides as antiviral agents. Trends Biotechnol 10:152-8
Metelev, V; Agrawal, S (1992) Ion-exchange high-performance liquid chromatography analysis of oligodeoxyribonucleotide phosphorothioates. Anal Biochem 200:342-6
Rapaport, E; Misiura, K; Agrawal, S et al. (1992) Antimalarial activities of oligodeoxynucleotide phosphorothioates in chloroquine-resistant Plasmodium falciparum. Proc Natl Acad Sci U S A 89:8577-80
Goodchild, J; Kohli, V (1991) Ribozymes that cleave an RNA sequence from human immunodeficiency virus: the effect of flanking sequence on rate. Arch Biochem Biophys 284:386-91

Showing the most recent 10 out of 21 publications