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Journal of Virology, October 2001, p. 8987-8998, Vol. 75, No. 19
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.19.8987-8998.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Study of the Mechanism of Antiviral Action of
Iminosugar Derivatives against Bovine Viral Diarrhea Virus
David
Durantel,1,*
Norica
Branza-Nichita,1,2
Sandra
Carrouée-Durantel,1
Terry
D.
Butters,1
Raymond A.
Dwek,1 and
Nicole
Zitzmann1
Oxford Glycobiology Institute, Department of
Biochemistry, University of Oxford, Oxford OX1 3QU, United
Kingdom,1 and Institute of Biochemistry,
Splaiul Independentei, Bucharest 77700, Romania2
Received 16 February 2001/Accepted 27 June 2001
The glucose-derived iminosugar derivatives N-butyl- and
N-nonyl-deoxynojirimycin (DNJ) have an antiviral effect
against a broad spectrum of viruses including Bovine viral
diarrhea virus (BVDV). For BVDV, this effect has been attributed
to the reduction of viral secretion due to an impairment of viral
morphogenesis caused by the ability of DNJ-based iminosugar derivatives
to inhibit ER
-glucosidases (N. Zitzmann, A. S. Mehta, S. Carrouée, 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
deoxygalactonojirimycin (DGJ), a class of iminosugars derived from
galactose which does not inhibit endoplasmic reticulum (ER)
-glucosidases. We demonstrate the lack of correlation between the
ability of long-alkyl-chain DNJ derivatives to inhibit ER
-glucosidases and their antiviral effect, ruling out ER
-glucosidase inhibition as the sole mechanism responsible. Using
short- and long-alkyl-chain DNJ and DGJ derivatives, we investigated
the mechanisms of action of these drugs. First, we excluded their potential action at the level of the replication, protein synthesis, and protein processing. Second, we demonstrated that DNJ derivatives cause both a reduction in viral secretion and a reduction in the infectivity of newly released viral particles. Long-alkyl-chain DGJ
derivatives exert their antiviral effect solely via the production of
viral particles with reduced infectivity. We demonstrate that long-alkyl-chain DNJ and DGJ derivatives induce an increase in the
quantity of E2-E2 dimers accumulated within the ER. The subsequent enrichment of these homodimers in secreted virus particles correlates with their reduced infectivity.
*
Corresponding author. Mailing address: Oxford
Glycobiology Institute, Department of Biochemistry, University of
Oxford, Oxford OX1 3QU, United Kingdom. Phone: 44-1865-275341. Fax:
44-1865-275216. E-mail: durantel{at}bioch.ox.ac.uk.
Journal of Virology, October 2001, p. 8987-8998, Vol. 75, No. 19
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.19.8987-8998.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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