Abstract

On the basis of the work done in the first grant period with acyclovir (ACV) and Epstein-Barr Virus (EBV) we have constructed a project extending this work and consisting of two parts: the first describes experiments designed to evaluate and characterize virologically and biologically the effects of four promising new antiviral agents (B10LF-62, BVDU, FIAC and FMAU), all nucleoside analogs and one of them a congener of ACV, on EBV replication both in isolated nuclei and in cell culture systems. The second part deals with the mode of action of the drugs. In this part based on what we have learned from our studies with ACV we will investigate drug metabolism and purify and characterize EBV-specified DNA polymerase, a key enzyme in the drug interactions, with respect to (i) kinetics of inhibition by phosphorylated drug, (ii) the ability of drug-triphosphates to serve as substrate, (iii) effect of incubation on primer-template efficiency, (iv) question of chain termination, (v) identification of incorporated drug moieties in EBV DNA, and (vi) reversibility of drug effects correlated with impact on latent infection. Data obtained from these studies will facilitate our understanding of the molecular mechanisms of action of the drugs and help in the development of selective antiviral agents.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI017205-06
Application #
3127023
Study Section
Virology Study Section (VR)
Project Start
1980-08-01
Project End
1988-07-31
Budget Start
1985-08-01
Budget End
1986-07-31
Support Year
6
Fiscal Year
1985
Total Cost
Indirect Cost

  Institution

Name
University of North Carolina Chapel Hill
Department
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599

  Publications

Pagano, J S; Jimenez, G; Sung, N S et al. (1992) Epstein-Barr viral latency and cell immortalization as targets for antisense oligomers. Ann N Y Acad Sci 660:107-16
Lin, J C; Reefschlager, J; Herrmann, G et al. (1992) Structure-activity relationship between (E)-5-(2-bromovinyl)- and 5-vinyl-1-beta-D-arabinofuranosyluracil (BV-araU, V-araU) in inhibition of Epstein-Barr virus replication. Antiviral Res 17:43-52
Lin, J C; De Clercq, E; Pagano, J S (1991) Inhibitory effects of acyclic nucleoside phosphonate analogs, including (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine, on Epstein-Barr virus replication. Antimicrob Agents Chemother 35:2440-3
Lin, J C; Sista, N D; Besencon, F et al. (1991) Identification and functional characterization of Epstein-Barr virus DNA polymerase by in vitro transcription-translation of a cloned gene. J Virol 65:2728-31
Lin, J C; Zhang, Z X; Chou, T C et al. (1989) Synergistic inhibition of Epstein-Barr virus: transformation of B lymphocytes by alpha and gamma interferon and by 3'-azido-3'-deoxythymidine. J Infect Dis 159:248-54
Lin, J C; Machida, H (1988) Comparison of two bromovinyl nucleoside analogs, 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil and E-5-(2-bromovinyl)-2'-deoxyuridine, with acyclovir in inhibition of Epstein-Barr virus replication. Antimicrob Agents Chemother 32:1068-72
Lin, J C; Zhang, Z X; Smith, M C et al. (1988) Anti-human immunodeficiency virus agent 3'-azido-3'-deoxythymidine inhibits replication of Epstein-Barr virus. Antimicrob Agents Chemother 32:265-7
Rompalo, A M; Roberts, P; Johnson, K et al. (1988) Empirical therapy for the management of acute proctitis in homosexual men. JAMA 260:348-53
Lin, J C; Raab-Traub, N (1987) Two strains of Epstein-Barr virus (B95-8 and a P3HR-1 subclone) that lack defective genomes induce early antigen and cause abortive infection of Raji cells. J Virol 61:1985-91
Lin, J C; DeClercq, E; Pagano, J S (1987) Novel acyclic adenosine analogs inhibit Epstein-Barr virus replication. Antimicrob Agents Chemother 31:1431-3

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