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Journal of Virology, April 2001, p. 3527-3536, Vol. 75, No. 8
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.8.3527-3536.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Antiviral Effect of N-Butyldeoxynojirimycin against Bovine Viral Diarrhea Virus Correlates with Misfolding of E2 Envelope Proteins and Impairment of Their Association into E1-E2 Heterodimers

Norica Branza-Nichita,1,2 David Durantel,1 Sandra Carrouée-Durantel,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, Sector 6, Bucharest, Romania2

Received 28 November 2000/Accepted 29 January 2001

The iminosugar N-butyldeoxynojirimycin (NB-DNJ), an endoplasmic reticulum alpha -glucosidase inhibitor, has an antiviral effect against bovine viral diarrhea virus (BVDV). In this report, we investigate the molecular mechanism of this inhibition by studying the folding pathway of BVDV envelope glycoproteins in the presence and absence of NB-DNJ. Our results show that, while the disulfide-dependent folding of E2 glycoprotein occurs rapidly (2.5 min), the folding of E1 occurs slowly (30 min). Both BVDV envelope glycoproteins associate rapidly with calnexin and dissociate with different kinetics. The release of E1 from the interaction with calnexin coincides with the beginning of E1 and E2 association into disulfide-linked heterodimers. In the presence of NB-DNJ, the interaction of E1 and E2 with calnexin is prevented, leading to misfolding of the envelope glycoproteins and inefficient formation of E1-E2 heterodimers. The degree of misfolding and the lack of association of E1 and E2 into disulfide-linked complexes in the presence of NB-DNJ correlate with the dose-dependent antiviral effect observed for this iminosugar.

* 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: nic{at}glycob.ox.ac.uk.

Journal of Virology, April 2001, p. 3527-3536, Vol. 75, No. 8
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.8.3527-3536.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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Copyright © 2001 by the American Society for Microbiology. All rights reserved.