Abstract

The long-term goal of this application is to study the antiviral, biochemical, and pharmacological profiles of new b-D- and b-L chiral nucleosides.
The specific aims of the current application are concerned with these studies on b-D-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine (D-D4FC) and the related class of D-2',3'-didehydro-2',3'-dideoxy-2'-fluoronucleosides (D-2'-F-d4Ns). Both in vitro and in vivo investigations are proposed. The rationale for the choice of these compounds for the studies proposed is based on the observation of the discovery that certain 2',3'-didehydro-2',3'-dideoxynucleosides (d4N) and their 2'-fluoro analogs are antiviral agents that possess selective activity against the M184V HIV-1 variants, that lack cross-resistance with some known antiviral agents, and that have dual antiviral activity against HIV-1 and HBV.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
2R37AI041980-04
Application #
6215891
Study Section
Special Emphasis Panel (ZRG1-AARR-1 (05))
Program Officer
Litterst, Charles L
Project Start
1997-08-01
Project End
2005-07-31
Budget Start
2000-08-01
Budget End
2001-07-31
Support Year
4
Fiscal Year
2000
Total Cost
$192,000
Indirect Cost

  Institution

Name
Emory University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322

  Publications

Herman, Brian D; Schinazi, Raymond F; Zhang, Hong-wang et al. (2012) Substrate mimicry: HIV-1 reverse transcriptase recognizes 6-modified-3'-azido-2',3'-dideoxyguanosine-5'-triphosphates as adenosine analogs. Nucleic Acids Res 40:381-90
Schinazi, Raymond F; Bassit, Leda; Clayton, Marcia M et al. (2012) Evaluation of single and combination therapies with tenofovir disoproxil fumarate and emtricitabine in vitro and in a robust mouse model supporting high levels of hepatitis B virus replication. Antimicrob Agents Chemother 56:6186-91
Nie, Ting; Detorio, Mervi; Schinazi, Raymond F (2011) Universal profiling of HIV-1 pol for genotypic study and resistance analysis across subtypes. Antivir Ther 16:1267-75
Zhang, Hong-wang; Zhou, Longhu; Coats, Steven J et al. (2011) Synthesis of purine modified 2'-C-methyl nucleosides as potential anti-HCV agents. Bioorg Med Chem Lett 21:6788-92
Zhang, Hong-Wang; Detorio, Mervi; Herman, Brian D et al. (2011) Synthesis, antiviral activity, cytotoxicity and cellular pharmacology of l-3'-azido-2',3'-dideoxypurine nucleosides. Eur J Med Chem 46:3832-44
Cho, Jong Hyun; Amblard, Franck; Coats, Steven J et al. (2011) Efficient synthesis of nucleoside aryloxy phosphoramidate prodrugs utilizing benzyloxycarbonyl protection. Tetrahedron 67:5487-5493
Roy, Vincent; Obikhod, Aleksandr; Zhang, Hong-Wang et al. (2011) Synthesis and anti-HIV evaluation of 3'-triazolo nucleosides. Nucleosides Nucleotides Nucleic Acids 30:264-70
Kennedy, Edward M; Gavegnano, Christina; Nguyen, Laura et al. (2010) Ribonucleoside triphosphates as substrate of human immunodeficiency virus type 1 reverse transcriptase in human macrophages. J Biol Chem 285:39380-91
Zhang, Hong-Wang; Coats, Steven J; Bondada, Lavanya et al. (2010) Synthesis and evaluation of 3'-azido-2',3'-dideoxypurine nucleosides as inhibitors of human immunodeficiency virus. Bioorg Med Chem Lett 20:60-4
Rodriguez-Perez, Tatiana; Fernandez, Susana; Sanghvi, Yogesh S et al. (2010) Chemoenzymatic syntheses and anti-HIV-1 activity of glucose-nucleoside conjugates as prodrugs. Bioconjug Chem 21:2239-49

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