Chemical modifications of antisense morpholino oligomers enhance their efficacy against Ebola virus infection.

TitleChemical modifications of antisense morpholino oligomers enhance their efficacy against Ebola virus infection.
Publication TypeJournal Article
Year of Publication2009
AuthorsSwenson DL, Warfield KL, Warren TK, Lovejoy C, Hassinger JN, Ruthel G, Blouch RE, Moulton HM, Weller DD, Iversen PL, Bavari S
JournalAntimicrobial agents and chemotherapy
Volume53
Issue5
Pagination2089-99
Date Published2009 May
ISSN1098-6596
KeywordsAnimals, Antiviral Agents, Cercopithecus aethiops, Disease Models, Animal, Dose-Response Relationship, Drug, Ebolavirus, Female, Hemorrhagic Fever, Ebola, Humans, Male, Mice, Mice, Inbred C57BL, Morpholines, Oligonucleotides, Antisense, Rabbits, Structure-Activity Relationship, Treatment Outcome, Vero Cells, Virus Replication
Abstract

Phosphorodiamidate morpholino oligomers (PMOs) are uncharged nucleic acid-like molecules designed to inactivate the expression of specific genes via the antisense-based steric hindrance of mRNA translation. PMOs have been successful at knocking out viral gene expression and replication in the case of acute viral infections in animal models and have been well tolerated in human clinical trials. We propose that antisense PMOs represent a promising class of therapeutic agents that may be useful for combating filoviral infections. We have previously shown that mice treated with a PMO whose sequence is complementary to a region spanning the start codon of VP24 mRNA were protected against lethal Ebola virus challenge. In the present study, we report on the abilities of two additional VP24-specific PMOs to reduce the cell-free translation of a VP24 reporter, to inhibit the in vitro replication of Ebola virus, and to protect mice against lethal challenge when the PMOs are delivered prior to infection. Additionally, structure-activity relationship evaluations were conducted to assess the enhancement of antiviral efficacy associated with PMO chemical modifications that included conjugation with peptides of various lengths and compositions, positioning of conjugated peptides to either the 5' or the 3' terminus, and the conferring of charge modifications by the addition of piperazine moieties. Conjugation with arginine-rich peptides greatly enhanced the antiviral efficacy of VP24-specific PMOs in infected cells and mice during lethal Ebola virus challenge.

DOI10.1128/AAC.00936-08
Alternate JournalAntimicrob. Agents Chemother.