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Accepted (AM)Open Access (License Unspecified), Open
Journal article
Combination of α-glucosidase inhibitor and ribavirin for the treatment of dengue virus infection in vitro and in vivo
Antiviral research, v 89(1), pp 26-34
2011
PMID: 21073903
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Cellular α-glucosidases I and II are enzymes that sequentially trim the three terminal glucoses in the N-linked oligosaccharides of viral envelope glycoproteins. This process is essential for the proper folding of viral glycoproteins and subsequent assembly of many enveloped viruses, including dengue virus (DENV). Imino sugars are substrate mimics of α-glucosidases I and II. In this report, we show that two oxygenated alkyl imino sugar derivatives, CM-9-78 and CM-10-18, are potent inhibitors of both α-glucosidases I and II in vitro and in treated animals, and efficiently inhibit DENV infection of cultured human cells. Pharmacokinetic studies reveal that both compounds are well tolerated at doses up to 100
mg/kg in rats and have favorable pharmacokinetic properties and bioavailability in mice. Moreover, we showed that oral administration of either CM-9-78 or CM-10-18 reduces the peak viremia of DENV in mice. Interestingly, while treatment of DENV infected mice with ribavirin alone did not reduce the viremia, combination therapy of ribavirin with sub-effective dose of CM-10-18 demonstrated a significantly enhanced antiviral activity, as indicated by a profound reduction of the viremia. Our findings thus suggest that combination therapy of two broad-spectrum antiviral agents may provide a practically useful approach for the treatment of DENV infection.
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Details
- Title
- Combination of α-glucosidase inhibitor and ribavirin for the treatment of dengue virus infection in vitro and in vivo
- Creators
- Jinhong Chang - Drexel UniversityWouter Schul - NovartisTerry D. Butters - University of OxfordAndy Yip - NovartisBoping Liu - NovartisAnne Goh - NovartisSuresh B. Lakshminarayana - NovartisDominic Alonzi - University of OxfordGabriele Reinkensmeier - University of OxfordXiaoben Pan - Drexel Institute for Biotechnology and Virology Research, Department of Microbiology and Immunology, Drexel University College of Medicine, 3805 Old Easton Road, Doylestown, PA 18902, United StatesXiaowang Qu - Drexel UniversityJessica M. Weidner - Drexel UniversityLijuan Wang - Drexel UniversityWenquan Yu - Hepatitis B FoundationNigel Borune - The University of Texas Medical Branch at GalvestonMark A. Kinch - University of Illinois at ChicagoJamie E. Rayahin - University of Illinois at ChicagoRobert Moriarty - University of Illinois at ChicagoXiaodong Xu - Hepatitis B FoundationPei-Yong Shi - NovartisJu-Tao Guo - Drexel UniversityTimothy M. Block - Drexel University
- Publication Details
- Antiviral research, v 89(1), pp 26-34
- Publisher
- Elsevier
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000287065100004
- Scopus ID
- 2-s2.0-78650922795
- Other Identifier
- 991019168302004721
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- Collaboration types
- Industry collaboration
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Pharmacology & Pharmacy
- Virology