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Antiviral Res 2011 Jul;91(1):1-10

Interference of ribosomal frameshifting by antisense peptide nucleic acids suppresses SARS coronavirus replication.

Ahn DG, Lee W, Choi JK, Kim SJ, Plant EP, Almazán F, Taylor DR, Enjuanes L, Oh JW

Abstract

The programmed -1 ribosomal frameshifting (-1 PRF) utilized by eukaryotic RNA viruses plays a crucial role for the controlled, limited synthesis of viral RNA replicase polyproteins required for genome replication. The viral RNA replicase polyproteins of severe acute respiratory syndrome coronavirus (SARS-CoV) are encoded by the two overlapping open reading frames 1a and 1b, which are connected by a -1 PRF signal. We evaluated the antiviral effects of antisense peptide nucleic acids (PNAs) targeting a highly conserved RNA sequence on the - PRF signal. The ribosomal frameshifting was inhibited by the PNA, which bound sequence-specifically a pseudoknot structure in the -1 PRF signal, in cell lines as assessed using a dual luciferase-based reporter plasmid containing the -1 PRF signal. Treatment of cells, which were transfected with a SARS-CoV-replicon expressing firefly luciferase, with the PNA fused to a cell-penetrating peptide (CPP) resulted in suppression of the replication of the SARS-CoV replicon, with a 50% inhibitory concentration of 4.4¿M. There was no induction of type I interferon responses by PNA treatment, suggesting that the effect of PNA is not due to innate immune responses. Our results demonstrate that -1 PRF, critical for SARS-CoV viral replication, can be inhibited by CPP-PNA, providing an effective antisense strategy for blocking -1 PRF signals.


Category: Journal Article
PubMed ID: #21549154 DOI: 10.1016/j.antiviral.2011.04.009
Includes FDA Authors from Scientific Area(s): Biologics
Entry Created: 2011-10-03 Entry Last Modified: 2012-08-29
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