Study of the mechanism of antiviral action of iminosugar derivatives against bovine viral diarrhea virus

The glucose-derived iminosugar derivatives N-butyl- and N-nonyl-deoxynojiri mycin (DNJ) have an antiviral effect against a broad spectrum of viruses in cluding Bovine viral diarrhea virus (BVDV). For BVDV, this effect has been attributed to the reduction of viral secretion due to an impairment of vira l morphogenesis caused by the ability of DNJ-based iminosugar derivatives t o inhibit ER alpha -glucosidases (N. Zitzmann, A. S. Mehta, S. Carrouee, T. D. Butters, F. M. Platt, J. McCauley, B. S. Blumberg, R. A. Dwek, and T. M . Block, Proc. Natl. Acad. Sci. USA 96:11878-11882, 1999). Here we present the antiviral features of newly designed DNJ derivatives and report for the first time the antiviral activity of long-alkyl-chain derivatives of deoxy galactonojirimycin (DGJ), a class of iminosugars derived from galactose whi ch does not inhibit endoplasmic reticulum (ER) alpha -glucosidases. We demo nstrate the lack of correlation between the ability of long-alkyl-chain DNJ derivatives to inhibit ER alpha -glucosidases and their antiviral effect, ruling out ER alpha -glucosidase inhibition as the sole mechanism responsib le. Using short- and long-alkyl-chain DNJ and DGJ derivatives, we investiga ted the mechanisms of action of these drugs. First, we excluded their poten tial action at the level of the replication, protein synthesis, and protein processing. Second, we demonstrated that DNJ derivatives cause both a redu ction in viral secretion and a reduction in the infectivity of newly releas ed viral particles. Long-alkyl-chain DGJ derivatives exert their antiviral effect solely via the production of viral particles with reduced infectivit y. We demonstrate that long-alkyl-chain DNJ and DGJ derivatives induce an i ncrease in the quantity of E2-E2 dimers accumulated within the ER. The subs equent enrichment of these homodimers in secreted virus particles correlate s with their reduced infectivity.