The alkylated imino sugar, n-(n-Nonyl)-deoxygalactonojirimycin, reduces the amount of hepatitis B virus nucleocapsid in tissue culture.
n-(n-Nonyl)-deoxygalactonojirimycin (n,n-DGJ), an alkylated imino sugar, reduces the amount of HBV DNA produced within the stably transfected HBV-producing HepG2.2.15 line in culture and is under consideration for development as a human therapeutic. n,n-DGJ does not appear to inhibit HBV DNA polymerase activity or envelop antigen production (A. Mehta, S. Carrouee, B. Conyers, R. Jordan, T. Butters, R. A. Dwek, and T. M. Block, Hepatology 33:1488-1495, 2001), and the mechanism of antiviral action is unknown. In this study, the step in the virus life cycle affected by n,n-DGJ was explored. Using Northern analysis and immunoprecipitation with anti-HBc antibody, we found that, under conditions in which cell viability was not affected but viral DNA production was substantially reduced, neither the amount of HBV transcription products nor the core polypeptide was detectably reduced. However, the pregenomic RNA, endogenous polymerase activity, and core polypeptide sedimenting in sucrose gradients with a density consistent with that of assembled nucleocapsids were significantly less in the HepG2.2.15 cells incubated with n,n-DGJ. These data suggest that n,n-DGJ either prevents the maturation of HBV nucleocapsids or destabilizes the formed nucleocapsids. Although the cellular and viral mediators of this inhibition are not known, depletion of nucleocapsid has been attributed to some other compounds as well as interferon's mechanism of anti-HBV action. The similarities and differences between this alkylated imino sugar and these other mediators are discussed.
Lu
Xuanyong
X
Biochemistry and Molecular Pharmacology Department, Jefferson Center for Bio-Medical Research and Agricultural Medicine, Thomas Jefferson University, Doylestown, Pennsylvania 18901, USA. xuanyoung.lu@jefferson.edu
Tran
Trang
T
Simsek
Ender
E
Block
Timothy M
TM
D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D002499:Centrifugation, Density Gradient; D004279:DNA, Viral / Q000032:analysis; D005690:Galactose / Q000031:analogs & derivatives*; D005944:Glucosamine / Q000031:analogs & derivatives / Q000494:pharmacology*; D006515:Hepatitis B virus / Q000187:drug effects*; D006801:Humans; D050111:Imino Sugars; D019251:Nucleocapsid / Q000187:drug effects*; D010766:Phosphorylation; D012367:RNA, Viral / Q000032:analysis; D014758:Viral Core Proteins / Q000032:analysis / Q000378:metabolism
D000998:Antiviral Agents; D004279:DNA, Viral; D050111:Imino Sugars; D012367:RNA, Viral; D014758:Viral Core Proteins; C478942:n-(n-nonyl)-deoxygalactonojirimycin; D005944:Glucosamine; D005690:Galactose