Abstract

This proposal is a continuation of the drug discovery efforts in the area of nucleosides at the University of Georgia and Emory University/VA Medical Center. This renewal application is concerned with the chemistry and biology of newly emerged L-nucleosides andis in search of novel anti-HIV agents which do not confer cross-resistance with existing nucleoside anti-HIV modalities. Recently, several L-nucleosides including 3TC, FTC, L-FddC, L-FMAU have been discovered as promising anti-HIV/anti-HBV agents. The proposed L- nucleosides will be studied in combination or as single agents against drug-resistant viral strains. Additionally, nucleoside phosphate dimers will be investigated in search of anti-HIV agents which inhibit a viral specific enzyme, integrase. The following four classes of nucleosides are proposed for synthesis and for biological and biochemical evaluation: (1) D- and L-2',3'-dideoxy- and 2',3'-didehydro-2',3'-dideoxy- nucleosides; (2) D- and L-carbocyclic nucleosides; (3) L-C-nucleosides; (4) nucleoside phosphate dimers. The long-term goal of this application is to develop novel clinically useful anti-HIV nucleosides which do not confer cross resistance with the existing anti-HIV modalities.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI032351-06
Application #
2003760
Study Section
AIDS and Related Research Study Section 4 (ARRD)
Project Start
1992-01-01
Project End
1998-12-31
Budget Start
1997-01-01
Budget End
1997-12-31
Support Year
6
Fiscal Year
1997
Total Cost
Indirect Cost

  Institution

Name
University of Georgia
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
City
Athens
State
GA
Country
United States
Zip Code
30602

  Publications

Wang, Jianing; Jin, Yunho; Rapp, Kimberly L et al. (2007) D- and L-2',3'-didehydro-2',3'-dideoxy-3'-fluoro-carbocyclic nucleosides: synthesis, anti-HIV activity and mechanism of resistance. J Med Chem 50:1828-39
Asif, Ghazia; Hurwitz, Selwyn J; Obikhod, Aleksandr et al. (2007) Pharmacokinetics of the anti-human immunodeficiency virus agent 1-(beta-D-dioxolane)thymine in rhesus monkeys. Antimicrob Agents Chemother 51:2424-9
Choo, Hyunah; Chen, Xin; Yadav, Vikas et al. (2006) Synthesis and anti-HIV activity of D- and L-thietanose nucleosides. J Med Chem 49:1635-47
Amblard, Franck; Delinsky, David; Arbiser, Jack L et al. (2006) Facile purification of honokiol and its antiviral and cytotoxic properties. J Med Chem 49:3426-7
Zhang, Hongwang; Schinazi, Raymond F; Chu, Chung K (2006) Synthesis of neplanocin F analogues as potential antiviral agents. Bioorg Med Chem 14:8314-22
Shi, Junxing; Du, Jinfa; Ma, Tianwei et al. (2005) Synthesis and in vitro anti-HCV activity of beta-D- and 1-2'-deoxy-2'-fluororibonucleosides. Nucleosides Nucleotides Nucleic Acids 24:875-9
Ray, Adrian S; Hernandez-Santiago, Brenda I; Mathew, Judy S et al. (2005) Mechanism of anti-human immunodeficiency virus activity of beta-D-6-cyclopropylamino-2',3'-didehydro-2',3'-dideoxyguanosine. Antimicrob Agents Chemother 49:1994-2001
Wang, Jianing; Jin, Yunho; Rapp, Kimberly L et al. (2005) Synthesis, antiviral activity, and mechanism of drug resistance of D- and L-2',3'-didehydro-2',3'-dideoxy-2'-fluorocarbocyclic nucleosides. J Med Chem 48:3736-48
Gadthula, Srinivas; Chu, Chung K; Schinazi, Raymond F (2005) Synthesis and anti-HIV activity of beta-D-3'-azido-2',3'-unsaturated nucleosides and beta-D-3'-azido-3'-deoxyribofuranosylnucleosides. Nucleosides Nucleotides Nucleic Acids 24:1707-27
Rais, Reem H; Al Safarjalani, Omar N; Yadav, Vikas et al. (2005) 6-Benzylthioinosine analogues as subversive substrate of Toxoplasma gondii adenosine kinase: activities and selective toxicities. Biochem Pharmacol 69:1409-19

Showing the most recent 10 out of 87 publications