Inhibition of hepatitis B virus DNA replication by imino sugars without the inhibition of the DNA polymerase: therapeutic implications.
Previously we have shown that the imino sugar inhibitor of N-linked glycan processing, N-nonyl-deoxynojirimycin (N-nonyl-DNJ), had antiviral activity in the woodchuck model of chronic hepatitis B virus (HBV) infection. In studying the mechanism of action of this compound, it was discovered that imino sugars could inhibit HBV secretion without inhibiting N-linked glycoprocessing. Although N-nonyl-DNJ is an inhibitor of the endoplasmic reticulum (ER) glucosidase, here it is shown that N-nonyl-DNJ retained antiviral activity at concentrations that had no significant impact on ER glucosidase function. Taken together, these results suggested that N-nonyl-DNJ possessed an antiviral activity attributable to a function other than an impact on glycoprocessing. This hypothesis was confirmed by experiments showing that N-nonyl-deoxygalactojirimycin (N-nonyl-DGJ), an alkyl derivative of galactose with no impact on glycoprocessing, retains anti-HBV activity. The data suggest that N-nonyl-DGJ exerts its antiviral action at a point before viral envelopment and may prevent the proper encapsidation of the HBV pregenomic RNA.
Mehta
A
A
Department of Biochemistry and Molecular Pharmacology, The Jefferson Center, Jefferson Medical College, Doylestown, PA 18901, USA. anand.mehta@mail.tju.edu
Carrouée
S
S
Conyers
B
B
Jordan
R
R
Butters
T
T
Dwek
R A
RA
Block
T M
TM
D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives / Q000494:pharmacology*; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002417:Cattle; D002460:Cell Line; D004261:DNA Replication / Q000187:drug effects*; D004279:DNA, Viral / Q000037:antagonists & inhibitors / Q000187:drug effects*; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism*; D015684:Gene Products, pol / Q000037:antagonists & inhibitors / Q000378:metabolism; D065089:Glycoside Hydrolase Inhibitors; D006515:Hepatitis B virus / Q000235:genetics*; D007425:Intracellular Membranes / Q000378:metabolism; D011134:Polysaccharides / Q000378:metabolism
D000998:Antiviral Agents; D004279:DNA, Viral; D015684:Gene Products, pol; D065089:Glycoside Hydrolase Inhibitors; C112150:N-nonyl-1-deoxynojirimycin; C066027:P protein, Hepatitis B virus; D011134:Polysaccharides; D017485:1-Deoxynojirimycin; D004259:DNA-Directed DNA Polymerase