Antiviral effect of alpha-glucosidase inhibitors on viral morphogenesis and binding properties of hepatitis C virus-like particles
| Autor: | Christian Trepo, Nicole Zitzmann, Raymond A. Dwek, C Chapel, Fabien Zoulim, Philippe Roingeard, Jean Dubuisson, David Durantel, C Garcia |
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| Přispěvatelé: | Virus des hépatites et pathologies associées, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Morphogénèse et antigénicité du VIH et du virus des Hépatites (MAVIVH - U1259 Inserm - CHRU Tours ), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Tours, Virus, pseudo-virus: Morphogénèse et Antigénicité, Université de Tours-EA3856, Oxford Glycobiology Institute, University of Oxford [Oxford], Institut de biologie de Lille - IBL (IBLI), Université de Lille, Sciences et Technologies-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS)-Université de Lille, Droit et Santé, Assemblage et réplication du virus de l'hépatite C (ARVHC), Centre National de la Recherche Scientifique (CNRS), C. C. and D. D. were supported by the French National Agency for AIDS and Viral Hepatitis Research (ANRS). This work was supported by INSERM, the French National Agency for AIDS and Viral Hepatitis Research (ANRS) and the European Community (ViRgil LSHM-CT-2004-503359). N. Z. is supported by the Oxford Glycobiology Institute Endowment., We thank Dr Jo O'Leary for careful reading of the manuscript., Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Tours (UT)-EA3856 |
| Jazyk: | angličtina |
| Rok vydání: | 2006 |
| Předmět: |
Glycosylation
Hepacivirus viruses MESH: Antiviral Agents/pharmacology medicine.disease_cause MESH: Viral Structural Proteins/genetics 0302 clinical medicine Virus-like particle Viral Envelope Proteins Morphogenesis MESH: Animals MESH: Hepacivirus*/drug effects Enzyme Inhibitors MESH: Morphogenesis/drug effects Cells Cultured chemistry.chemical_classification 0303 health sciences MESH: Spodoptera biology virus diseases MESH: Viral Envelope Proteins/metabolism MESH: Glycosylation 3. Good health MESH: Hepacivirus*/growth & development MESH: Virion/drug effects MESH: Baculoviridae [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology MESH: Viral Envelope Proteins/genetics 030211 gastroenterology & hepatology Baculoviridae MESH: Cells Cultured MESH: Viral Envelope Proteins/chemistry MESH: Cell Line Tumor MESH: Viral Structural Proteins/metabolism MESH: Glycoside Hydrolase Inhibitors Hepatitis C virus MESH: Hepacivirus*/pathogenicity Spodoptera Antiviral Agents Virus 03 medical and health sciences MESH: Virion/metabolism Virology Calnexin Cell Line Tumor medicine Animals Humans Glycoside Hydrolase Inhibitors 030304 developmental biology Viral Structural Proteins MESH: Humans Endoplasmic reticulum Virion biology.organism_classification MESH: Enzyme Inhibitors/pharmacology chemistry Cell culture Glycoprotein |
| Zdroj: | Journal of General Virology Journal of General Virology, Microbiology Society, 2006, 87, pp.861-871. ⟨10.1099/vir.0.81503-0⟩ |
| ISSN: | 1465-2099 0022-1317 |
| Popis: | Hepatitis C virus (HCV) infections are a major public-health concern. New antiviral drugs are needed urgently to complement and improve the efficacy of current chemotherapies. The morphogenesis of HCV represents an interesting, and still unexploited, novel molecular target.α-Glucosidase inhibitors derived from the glucose analogue deoxynojirimycin (DNJ) inhibit viral morphogenesisin cellulovia perturbation of theN-glycosylation pathway and hence the misfolding of viral glycoproteins that depend on certainN-glycans for correct folding. Due to the heavyN-glycosylation of HCV glycoproteins, it was hypothesized that such inhibitors would also affect HCV morphogenesis. To study the effect ofα-glucosidase inhibitors on viral morphogenesis and binding properties, HCV virus-like particles (VLPs) were produced by using baculovirus loaded with HCV structural-protein genes. Here, it is demonstrated that, in the presence of theseα-glucosidase inhibitors, viral glycoproteins synthesized and retained in the endoplasmic reticulum (i) contain unprocessed, triglucosylatedN-glycans, (ii) are impaired in their interaction with calnexin and (iii) are at least partially misfolded. Moreover, it is shown that, although the production of VLPs is not affected byα-glucosidase inhibitors, these VLPs contain unprocessed, triglucosylatedN-glycans and potentially misfolded glycoproteins. Finally, it is demonstrated that VLPs produced in the presence ofα-glucosidase inhibitors have impaired binding properties to hepatoma cells. The inhibitors of morphogenesis studied here target steps of the HCV viral cycle that may prevent or delay viral resistance. Theseα-glucosidase inhibitors may prove to be useful molecules to fight HCV infection in combination protocols. |
| Databáze: | OpenAIRE |
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