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-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 vira...
| Main Authors: | , , , , , |
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| Format: | Journal article |
| Language: | English |
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American Society for Microbiology
2001
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| _version_ | 1826284938733813760 |
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| author | Durantel, D Branza-Nichita, N Carrouée-Durantel, S Butters, T Dwek, R Zitzmann, N |
| author_facet | Durantel, D Branza-Nichita, N Carrouée-Durantel, S Butters, T Dwek, R Zitzmann, N |
| author_sort | Durantel, D |
| collection | OXFORD |
| description | 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 alpha-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) alpha-glucosidases. We demonstrate 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 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. |
| first_indexed | 2024-03-07T01:21:22Z |
| format | Journal article |
| id | oxford-uuid:9076bae1-1432-4fa1-a216-04339c5b4901 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T01:21:22Z |
| publishDate | 2001 |
| publisher | American Society for Microbiology |
| record_format | dspace |
| spelling | oxford-uuid:9076bae1-1432-4fa1-a216-04339c5b49012022-03-26T23:11:54ZStudy of the mechanism of antiviral action of iminosugar derivatives against bovine viral diarrhea virus.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:9076bae1-1432-4fa1-a216-04339c5b4901EnglishSymplectic Elements at OxfordAmerican Society for Microbiology2001Durantel, DBranza-Nichita, NCarrouée-Durantel, SButters, TDwek, RZitzmann, NThe 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 alpha-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) alpha-glucosidases. We demonstrate 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 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. |
| spellingShingle | Durantel, D Branza-Nichita, N Carrouée-Durantel, S Butters, T Dwek, R Zitzmann, N Study of the mechanism of antiviral action of iminosugar derivatives against bovine viral diarrhea virus. |
| title | Study of the mechanism of antiviral action of iminosugar derivatives against bovine viral diarrhea virus. |
| title_full | Study of the mechanism of antiviral action of iminosugar derivatives against bovine viral diarrhea virus. |
| title_fullStr | Study of the mechanism of antiviral action of iminosugar derivatives against bovine viral diarrhea virus. |
| title_full_unstemmed | Study of the mechanism of antiviral action of iminosugar derivatives against bovine viral diarrhea virus. |
| title_short | Study of the mechanism of antiviral action of iminosugar derivatives against bovine viral diarrhea virus. |
| title_sort | study of the mechanism of antiviral action of iminosugar derivatives against bovine viral diarrhea virus |
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