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VP35 knockdown inhibits Ebola virus amplification and protects against lethal infection in mice

  1. Author:
    Enterlein, S.
    Warfield, K. L.
    Swenson, D. L.
    Stein, D. A.
    Smith, J. L.
    Gamble, C. S.
    Kroeker, A. D.
    Iversen, P. L.
    Bavari, S.
    Muhlberger, E.

  2. Author Address

    Univ Marburg, Dept Virol, D-35043 Marburg, Germany. USA, Med Res Inst Infect Dis, Frederick, MD 21702 USA. AVI BioPharma Inc, Corvallis, OR USA.;Bavari, S, Univ Marburg, Dept Virol, Hans Meerwein Str 3, D-35043 Marburg, Germany.;sina.bavari@us.army.mil muehlber@staff.uni-marburg.de
    1. Year: 2006
    2. Date: Mar
  2. Journal: Antimicrobial Agents and Chemotherapy
    1. 50
    2. 3
    3. Pages: 984-993
  4. Type of Article: Article
  5. ISSN: 0066-4804
  1. Abstract:

    Phosphorodiamidate morpholino oligomers (PMO) are a class of uncharged single-stranded DNA analogs modified such that each subunit includes a phosphorodiamidate linkage and morpholine ring. PMO antisense agents have been reported to effectively interfere with the replication of several positive-strand RNA viruses in cell culture. The filoviruses, Marburg virus and Ebola virus (EBOV), are negative-strand RNA viruses that cause up to 90% lethality in human outbreaks. There is currently no commercially available vaccine or efficacious therapeutic for any filovirus. In this study, PMO conjugated to arginine-rich cell-penetrating peptide (P-PMO) and nonconjugated PMO were assayed for the ability to inhibit EBOV infection in cell culture and in a mouse model of lethal EBOV infection. A 22-mer P-PMO designed to base pair with the translation start site region of EBOV VP35 positive-sense RNA generated sequence-specific and time- and dose-dependent inhibition of EBOV amplification in cell culture. The same oligomer provided complete protection to mice when administered before or after an otherwise lethal infection of EBOV. A corresponding nonconjugated PMO, as well as nonconjugated truncated versions of 16 and 19 base residues, provided length-dependent protection to mice when administered prophylactically. Together, these data suggest that antisense PMO and P-PMO have the potential to control EBOV infection and are promising therapeutic candidates.

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External Sources

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  2. DOI: 10.1128/aac.503.984-993.2006
  3. View record in Web of Science®
  4. WOS: 000235786300023

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