This proposal will continuethe long-standing collaborationwith my colleague, Dr. Raymond F. Schinazi. Specifically, his laboratory will evaluate all compounds that we prepare. As interestingleads 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 =discoveryof inhibitorsof the RNA-dependent RNA polymerase of hepatitis C.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Method to Extend Research in Time (MERIT) Award (R37)
Project #
Application #
Study Section
Special Emphasis Panel (NSS)
Program Officer
Nasr, Mohamed E
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Emory University
Schools of Arts and Sciences
United States
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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
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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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