The overall goal of this Interactive Research Project Grant (IRPG) is to develop new antiviral nucleosides, for use in combination against human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infections. As a first step, the applicant wishes to focus on a new compound discovered in his laboratory that has dual potent and selective activity against HIV/HBV. b-D-2',3'-Didehydro-2',3'-dideoxy-5-fluorocytidine (D-D4FC) and related molecules will be studied extensively at the biochemical, virological, molecular therapeutical, and pharmacological level in cell-free and cellular systems. The activity of D-D4FC will be tested against a panel of well characterized clinical isolates of HIV in primary human lymphocytes. HIV-1 resistant to other nucleoside analogs will also be tested for cross-resistance to D-D4FC. Based on the cross-resistance pattern, D-D4FC will be evaluated in double and triple combinations with AZT, 3TC, (-)-FTC, d4T, ddI, ddC, a protease inhibitor such as indinavir, and a nonnucleoside reverse transcriptase inhibitor, such as nevirapine. Moreover, the relative rate for the emergence of resistance to D-D4FC will be determined and compared with 3TC [or (-)-FTC] and AZT. D-D4FC is currently being evaluated in a woodchuck hepatitis virus model by the NIAID. This application proposes to conduct combination studies of D-D4FC with 3TC, DAPD and (-)-FTC, compounds with dual anti-HIV and anti-HBV activity in HBV transfected cells. The potency and selectivity of the 5'-triphosphate of D-D4FC will be compared to the L-enantiomer and related nucleotides by studying the inhibition of the HIV-1 reverse transcriptase, the HBV DNA polymerase, and several human DNA polymerases. Radiolabeled D-D4FC and L-D4FC will be synthesized and their cellular pharmacology will be determined in order to gain insight into their different biological properties.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI041980-01
Application #
2432844
Study Section
Special Emphasis Panel (ZRG5-AAR (04))
Project Start
1997-08-01
Project End
2000-07-31
Budget Start
1997-08-01
Budget End
1998-07-31
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Emory University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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