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Peptidyl-transferase inhibitors have antiviral properties by altering programmed -1 ribosomal frameshifting
J D Dinman1, M J Ruiz-Echevarria, K Czaplinski
1Department of Molecular Genetics and Microbiology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854, USA. dinman@rwja.umdnj.edu
Abstract:
The effects of two peptidyl-transferase inhibitors, anisomycin and sparsomycin, on ribosomal frameshifting efficiencies and the propagation of yeast double-stranded RNA viruses were examined. At sublethal doses in yeast cells these drugs specifically alter the efficiency of -1, but not of +1, ribosomal frameshifting. These compounds promote loss of the yeast L-A double-stranded RNA virus, which uses a programmed -1 ribosomal frameshift to produce its Gag-Pol fusion protein. Both of these drugs also change the efficiency of -1 ribosomal frameshifting in yeast and mammalian in vitro translation systems, suggesting that they may have applications to control the propagation of viruses of higher eukaryotes, which also use this translational regulatory mechanism. Our results offer a new set of antiviral agents that may potentially have a broad range of applications in the clinical, veterinary, and agricultural fields.
Insights
Anisomycin and sparsomycin specifically alter -1 ribosomal frameshifting, inhibiting yeast virus propagation. These peptidyl-transferase inhibitors show potential as broad-spectrum antiviral agents.
Area of Science:
- Molecular Biology
- Virology
- Biochemistry
Background:
- Ribosomal frameshifting is a key mechanism in viral protein synthesis.
- Programmed -1 ribosomal frameshifting is essential for producing viral fusion proteins in certain viruses, like the yeast L-A virus.
Purpose of the Study:
- To investigate the impact of peptidyl-transferase inhibitors (anisomycin and sparsomycin) on ribosomal frameshifting efficiency.
- To assess the effect of these inhibitors on the propagation of yeast double-stranded RNA viruses.
Main Methods:
- Yeast cells were treated with sublethal doses of anisomycin and sparsomycin.
- Ribosomal frameshifting efficiencies (-1 and +1) were measured in yeast and mammalian in vitro translation systems.
- The propagation of the yeast L-A double-stranded RNA virus was monitored in treated yeast cells.
Main Results:
- Anisomycin and sparsomycin specifically altered the efficiency of -1 ribosomal frameshifting, but not +1 frameshifting, in yeast cells.
- These drugs promoted the loss of the yeast L-A double-stranded RNA virus.
- The inhibitors also modified -1 ribosomal frameshifting efficiency in both yeast and mammalian in vitro translation systems.
Conclusions:
- Anisomycin and sparsomycin represent a novel class of antiviral agents targeting -1 ribosomal frameshifting.
- Their ability to inhibit viral propagation suggests potential applications for controlling viruses in clinical, veterinary, and agricultural settings.
- These findings highlight the therapeutic potential of modulating translational regulatory mechanisms in viruses.