Giuseppe
Emeritus
[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]
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Liposome-Mediated Delivery of Iminosugars Enhances Efficacy against Dengue Virus In Vivo
Joanna L. Miller <SUP>a</SUP>, Ruben Lachica<SUP> b</SUP>, Andrew C. Sayce <SUP>a</SUP>, James P. Williams <SUP>a</SUP>, Manisha Bapat <SUP>a</SUP>, Raymond Dwek <SUP>a</SUP>, P. Robert Beatty <SUP>c</SUP>, Eva Harris <SUP>b</SUP> and Nicole Zitzmann <SUP>a</SUP>
<SUP></SUP>
Author Affiliations: <SUP>a</SUP>Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, United Kingdom; <SUP>b</SUP>Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, California, USA; <SUP>c</SUP>Department of Molecular and Cellular Biology, University of California, Berkeley, Berkeley, California, USA
ABSTRACT
A key challenge faced by promising antiviral drugs, such as iminosugars, is in vivo delivery to achieve effective levels of drug without toxicity. Four iminosugars, all deoxynojirimycin (DNJ) derivatives?N-butyl DNJ (NB-DNJ), N-nonyl DNJ, N-(9-methoxynonyl) DNJ, and N-(6′-[4″-azido-2″-nitrophenylamino]hexyl)-1-DNJ (NAP-DNJ)?potently inhibited both the percentage of cells infected with dengue virus and release of infectious virus from primary human monocyte-derived macrophages, demonstrating their efficacy in primary cells. In a lethal antibody-dependent enhancement mouse model of dengue pathogenesis, free NB-DNJ significantly enhanced survival and lowered viral load in organs and serum. Liposome-mediated delivery of NB-DNJ, in comparison with free NB-DNJ, resulted in a 3-log<SUB>10</SUB> reduction in the dose of drug sufficient to enhance animal survival. The optimizing of the effective dose in this way could liberate the therapeutic potential of many cytotoxic antivirals against both dengue virus and a wide array of other viruses.
FOOTNOTES
Received 30 July 2012. Returned for modification 3 September 2012. Accepted 5 October 2012.
Address correspondence to Nicole Zitzmann, nicole.zitzmann@bioch.ox.ac.uk.
Published ahead of print 15 October 2012
Supplemental material for this article may be found at http://aac.asm.org/.
Copyright ? 2012, American Society for Microbiology. All Rights Reserved.
-<SUP></SUP>
Author Affiliations: <SUP>a</SUP>Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, United Kingdom; <SUP>b</SUP>Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, Berkeley, Berkeley, California, USA; <SUP>c</SUP>Department of Molecular and Cellular Biology, University of California, Berkeley, Berkeley, California, USA
ABSTRACT
A key challenge faced by promising antiviral drugs, such as iminosugars, is in vivo delivery to achieve effective levels of drug without toxicity. Four iminosugars, all deoxynojirimycin (DNJ) derivatives?N-butyl DNJ (NB-DNJ), N-nonyl DNJ, N-(9-methoxynonyl) DNJ, and N-(6′-[4″-azido-2″-nitrophenylamino]hexyl)-1-DNJ (NAP-DNJ)?potently inhibited both the percentage of cells infected with dengue virus and release of infectious virus from primary human monocyte-derived macrophages, demonstrating their efficacy in primary cells. In a lethal antibody-dependent enhancement mouse model of dengue pathogenesis, free NB-DNJ significantly enhanced survival and lowered viral load in organs and serum. Liposome-mediated delivery of NB-DNJ, in comparison with free NB-DNJ, resulted in a 3-log<SUB>10</SUB> reduction in the dose of drug sufficient to enhance animal survival. The optimizing of the effective dose in this way could liberate the therapeutic potential of many cytotoxic antivirals against both dengue virus and a wide array of other viruses.
FOOTNOTES
Received 30 July 2012. Returned for modification 3 September 2012. Accepted 5 October 2012.
Address correspondence to Nicole Zitzmann, nicole.zitzmann@bioch.ox.ac.uk.
Published ahead of print 15 October 2012
Supplemental material for this article may be found at http://aac.asm.org/.
Copyright ? 2012, American Society for Microbiology. All Rights Reserved.
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