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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(10) 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.

Original publication

DOI

10.1128/AAC.01554-12

Type

Journal article

Journal

Antimicrob Agents Chemother

Publication Date

12/2012

Volume

56

Pages

6379 - 6386

Keywords

1-Deoxynojirimycin, Animals, Antiviral Agents, Cell Survival, Dengue, Dengue Virus, Drug Carriers, Drug Delivery Systems, Gene Dosage, Humans, Imino Sugars, In Vitro Techniques, Liposomes, Macrophages, Mice, RNA, Viral, Real-Time Polymerase Chain Reaction