Inhibition of alphavirus infection in cell culture and in mice with antisense morpholino oligomers

Slobodan Paessler, Rene Rijnbrand, David A. Stein, Haolin Ni, Nadezhda E. Yun, Natallia Dziuba, Viktoriya Borisevich, Alexey Seregin, Yinghong Ma, Robert Blouch, Patrick L. Iversen, Michele A. Zacks

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

The genus Alphavirus contains members that threaten human health, both as natural pathogens and as potential biological weapons. Peptide-conjugated phosphorodiamidate morpholino oligomers (PPMO) enter cells readily and can inhibit viral replication through sequence-specific steric blockade of viral RNA. Sindbis virus (SINV) has low pathogenicity in humans and is regularly utilized as a model alphavirus. PPMO targeting the 5′-terminal and AUG translation start site regions of the SINV genome blocked the production of infectious SINV in tissue culture. PPMO designed against corresponding regions in Venezuelan equine encephalitis virus (VEEV) were likewise found to be effective in vitro against several strains of VEEV. Mice treated with PPMO before and after VEEV infection were completely protected from lethal outcome while mice receiving only post-infection PPMO treatment were partially protected. Levels of virus in tissue samples correlated with animal survival. Uninfected mice suffered no apparent ill-effects from PPMO treatment. Thus, PPMO appear promising as candidates for therapeutic development against alphaviruses.

Original languageEnglish (US)
Pages (from-to)357-370
Number of pages14
JournalVirology
Volume376
Issue number2
DOIs
StatePublished - Jul 5 2008

Keywords

  • Antisense therapy
  • Antiviral agents
  • Morpholino oligomers
  • Pathogenic alphaviruses
  • Sindbis virus
  • Venezuelan equine encephalitis virus

ASJC Scopus subject areas

  • Virology

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