Mode of interference of trisodium phosphonoformate (INN: foscarnet sodium), with influenza virus mRNA synthesis
Abstract:
Foscarnet has previously been shown to inhibit influenza RNA polymerase activity. In this report the mode of inhibition of foscarnet has been investigated by enzyme-kinetic procedures and product analysis. Foscarnet shows noncompetitive inhibition with respect to ATP, CTP, and UTP, and a mixed inhibition with respect to GTP. In the presence of foscarnet the initiation of the mRNA synthesis can still occur, but the elongation is inhibited. The block of mRNA formation by foscarnet seems to occur after the synthesis of the 12-nucleotide-long conserved sequence found at the 5 prime end of the viral message.
Insights
Foscarnet noncompetitively inhibits influenza RNA polymerase, blocking mRNA elongation after the conserved sequence initiation. This antiviral mechanism affects viral RNA synthesis.
Area of Science:
- Virology
- Molecular Biology
- Biochemistry
Background:
- Foscarnet is known to inhibit influenza RNA polymerase.
- The precise mechanism of foscarnet's inhibition requires further elucidation.
Purpose of the Study:
- To investigate the mode of inhibition of foscarnet on influenza RNA polymerase.
- To analyze the effects of foscarnet on mRNA synthesis initiation and elongation.
Main Methods:
- Enzyme-kinetic procedures were employed.
- Product analysis was conducted to determine inhibition patterns.
Main Results:
- Foscarnet exhibited noncompetitive inhibition against ATP, CTP, and UTP.
- Mixed inhibition was observed with respect to GTP.
- Foscarnet inhibited mRNA elongation but not initiation, specifically after the conserved 5' sequence.
Conclusions:
- Foscarnet acts as a mixed inhibitor of influenza RNA polymerase.
- The drug blocks viral mRNA formation by inhibiting the elongation step.
- This inhibition occurs post-initiation, after the synthesis of the conserved 12-nucleotide sequence.
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