Liposome-mediated delivery of iminosugars enhances efficacy against dengue virus in vivo.
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.
Department of Biochemistry, University of Oxford, Oxford, UK.
Joanna L
JL
Miller
Ruben
R
Lachica
Andrew C
AC
Sayce
James P
JP
Williams
Manisha
M
Bapat
Raymond
R
Dwek
P Robert
PR
Beatty
Eva
E
Harris
Nicole
N
Zitzmann
D017485:1-Deoxynojirimycin / Q000008:administration & dosage / Q000627:therapeutic use; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000627:therapeutic use*; D002470:Cell Survival / Q000187:drug effects; D003715:Dengue / Q000188:drug therapy* / Q000821:virology; D003716:Dengue Virus / Q000187:drug effects*; D004337:Drug Carriers; D016503:Drug Delivery Systems; D018628:Gene Dosage; D006801:Humans; D050111:Imino Sugars / Q000008:administration & dosage* / Q000627:therapeutic use*; D066298:In Vitro Techniques; D008081:Liposomes; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology; D051379:Mice; D012367:RNA, Viral / Q000096:biosynthesis / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction
D000998:Antiviral Agents; D004337:Drug Carriers; D050111:Imino Sugars; D008081:Liposomes; D012367:RNA, Viral; D017485:1-Deoxynojirimycin