Inhibition, escape, and attenuated growth of severe acute respiratory syndrome coronavirus treated with antisense morpholino oligomers

J Virol. 2005 Aug;79(15):9665-76. doi: 10.1128/JVI.79.15.9665-9676.2005.


The recently emerged severe acute respiratory syndrome coronavirus (SARS-CoV) is a potent pathogen of humans and is capable of rapid global spread. Peptide-conjugated antisense morpholino oligomers (P-PMO) were designed to bind by base pairing to specific sequences in the SARS-CoV (Tor2 strain) genome. The P-PMO were tested for their capacity to inhibit production of infectious virus as well as to probe the function of conserved viral RNA motifs and secondary structures. Several virus-targeted P-PMO and a random-sequence control P-PMO showed low inhibitory activity against SARS coronavirus. Certain other virus-targeted P-PMO reduced virus-induced cytopathology and cell-to-cell spread as a consequence of decreasing viral amplification. Active P-PMO were effective when administered at any time prior to peak viral synthesis and exerted sustained antiviral effects while present in culture medium. P-PMO showed low nonspecific inhibitory activity against translation of nontargeted RNA or growth of the arenavirus lymphocytic choriomeningitis virus. Two P-PMO targeting the viral transcription-regulatory sequence (TRS) region in the 5' untranslated region were the most effective inhibitors tested. After several viral passages in the presence of a TRS-targeted P-PMO, partially drug-resistant SARS-CoV mutants arose which contained three contiguous base point mutations at the binding site of a TRS-targeted P-PMO. Those partially resistant viruses grew more slowly and formed smaller plaques than wild-type SARS-CoV. These results suggest PMO compounds have powerful therapeutic and investigative potential toward coronavirus infection.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 5' Untranslated Regions
  • Animals
  • Antiviral Agents / pharmacology*
  • Base Sequence
  • Chlorocebus aethiops
  • Cytopathogenic Effect, Viral
  • Drug Design
  • Drug Resistance, Viral
  • Molecular Sequence Data
  • Morpholines / pharmacology*
  • Morpholinos
  • Mutation
  • Nucleic Acid Conformation
  • Peptides
  • Serial Passage
  • Severe Acute Respiratory Syndrome
  • Severe acute respiratory syndrome-related coronavirus / drug effects*
  • Severe acute respiratory syndrome-related coronavirus / genetics
  • Severe acute respiratory syndrome-related coronavirus / growth & development
  • Transcription, Genetic / drug effects
  • Vero Cells


  • 5' Untranslated Regions
  • Antiviral Agents
  • Morpholines
  • Morpholinos
  • Peptides