INHIBITION OF CAP (M(7)GPPPXM)-DEPENDENT ENDONUCLEASE OF INFLUENZA-VIRUS BY 4-SUBSTITUTED 2,4-DIOXOBUTANOIC ACID COMPOUNDS

Synthesis of influenza virus mRNA is primed by capped and methylated ( cap 1, m(7)GpppXm) RNAs which the virus derives by endonucleolytic cle avage from RNA polymerase II transcripts in host cells. The conserved nature of the endonucleotytic processing provides a unique target for the development of antiviral agents for influenza viruses. A series of 4-substituted 2,4-dioxobutanoic acid compounds has been identified as selective inhibitors of this activity in both influenza A and B virus es. These inhibitors exhibited 50% inhibitory concentrations in the ra nge of 0.2 to 29.0 mu M for cap-dependent influenza virus transcriptio n and had no effect on the activity of other viral and cellular polyme rases when tested at 100- to 500-fold higher concentrations. The compo unds did not inhibit the initiation or elongation of influenza virus m RNA synthesis but specifically inhibited the cleavage of capped RNAs b y the influenza virus endonuclease and were not inhibitory to the acti vities of other nucleases. Additionally, the compounds specifically in hibited replication of influenza A and B viruses in cell culture with potencies comparable to the 50% inhibitory concentrations obtained for transcription.