This proposal will continue the long-standing collaboration with my colleague, Dr. Raymond F. Schinazi. Specifically, his laboratory will evaluate all compounds that we prepare. As interesting leads develop, we will work collaboratively to optimize the antiviral profile of the material. The project will focus on the continued development of practical methodology for the synthesis of purine and pyrimidine nucleoside analogues. Specifically, these studies include the development of methodology for intramolecular 3'- transfer glycosylations, preparing 4'-thianucleosides, selective fluorination of nucleoside analogues, preparing (+)-FDOC in >99%ee and solid-phase, parallel (combinatorial) synthesis of nucleoside analogue libraries. The project will also include the continued synthesis (by the Liotta group) and evaluation (by the Schinazi group) of selected D- and L-nucleoside analogue targets which possess favorable anti-HIV / HBV / HCV _profiles. These include dideoxy purine and pyrimidine nucleoside analogues with an emphasis on fluorinated derivatives, dideoxy, didehydro purine and pyrimidine nucleoside analogs with an emphasis on fluorinated derivatives, heteranucleosides, with particular emphasis on 4'-thianucleosides. Finally, the project will also attempt to develop a rational (de novo) drug design program aimed at the discovery of inhibitors of the RNA-dependent RNA polymerase of hepatitis C.

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 #
5R37AI028731-14
Application #
6640641
Study Section
Special Emphasis Panel (ZRG1-AARR-1 (03))
Program Officer
Litterst, Charles L
Project Start
1989-07-01
Project End
2007-04-30
Budget Start
2003-05-01
Budget End
2004-04-30
Support Year
14
Fiscal Year
2003
Total Cost
$266,000
Indirect Cost
Name
Emory University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Muthu, Pravin; Lutz, Stefan (2016) Quantitative Detection of Nucleoside Analogues by Multi-enzyme Biosensors using Time-Resolved Kinetic Measurements. ChemMedChem 11:660-6
Muthu, Pravin; Chen, Hannah X; Lutz, Stefan (2014) Redesigning human 2'-deoxycytidine kinase enantioselectivity for L-nucleoside analogues as reporters in positron emission tomography. ACS Chem Biol 9:2326-33
Acker, Timothy M; Khatri, Alpa; Vance, Katie M et al. (2013) Structure-activity relationships and pharmacophore model of a noncompetitive pyrazoline containing class of GluN2C/GluN2D selective antagonists. J Med Chem 56:6434-56
Li, Yongfeng; Mao, Shuli; Hager, Michael W et al. (2007) Synthesis and evaluation of 2'-substituted cyclobutyl nucleosides and nucleotides as potential anti-HIV agents. Bioorg Med Chem Lett 17:3398-401
Mao, Shuli; Bouygues, Martin; Welch, Christopher et al. (2004) Synthesis of enantiomerically pure D-FDOC, an anti-HIV agent. Bioorg Med Chem Lett 14:4991-4
Ma, L; Hurwitz, S J; Shi, J et al. (1999) Pharmacokinetics of the antiviral agent beta-D-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine in rhesus monkeys. Antimicrob Agents Chemother 43:381-4
Abobo, C V; Ni, L; Schinazi, R F et al. (1994) Pharmacokinetics of 2',3'-dideoxy-5-fluoro-3'-thiacytidine in rats. J Pharm Sci 83:96-9
Schinazi, R F; Lloyd Jr, R M; Nguyen, M H et al. (1993) Characterization of human immunodeficiency viruses resistant to oxathiolane-cytosine nucleosides. Antimicrob Agents Chemother 37:875-81
Shewach, D S; Liotta, D C; Schinazi, R F (1993) Affinity of the antiviral enantiomers of oxathiolane cytosine nucleosides for human 2'-deoxycytidine kinase. Biochem Pharmacol 45:1540-3
Mathez, D; Schinazi, R F; Liotta, D C et al. (1993) Infectious amplification of wild-type human immunodeficiency virus from patients' lymphocytes and modulation by reverse transcriptase inhibitors in vitro. Antimicrob Agents Chemother 37:2206-11

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