Liposome-Mediated Delivery of Iminosugars Enhances Efficacy against Dengue VirusIn Vivo

Abstract

ABSTRACTA key challenge faced by promising antiviral drugs, such as iminosugars, isin vivodelivery 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, andN-(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, freeNB-DNJ significantly enhanced survival and lowered viral load in organs and serum. Liposome-mediated delivery ofNB-DNJ, in comparison with freeNB-DNJ, resulted in a 3-log10reduction 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.