ANTIINFLUENZA VIRUS ACTIVITIES OF 4-SUBSTITUTED 2,4-DIOXOBUTANOIC ACID INHIBITORS

We previously identified a series of compounds which specifically inhi bited the transcription of influenza A and B viruses (J. Tomassini, H. Selnick, M. E. Davies, M. E. Armstrong, J. Baldwin, M. Bourgeois, J. Hastings, D. Hazuda, J. Lewis, W. McClements, G. Ponticello, E. Radzil owski, G. Smith, A. Tebben, and A. Wolfe, Antimicrob. Agents Chemother . 38:2827-2837, 1994). The compounds, 4-substituted 2,4-dioxobutanoic acids, selectively targeted the cap-dependent endonuclease activity of the transcriptase complex. Additionally, several of these compounds e ffectively inhibited the replication of influenza virus but not other viruses in cell culture assays. Here, we report on the anti-influenza virus activities of other potent derivatives of the series evaluated i n both in vitro and in vivo infectivity assays. These compounds inhibi ted the replication of influenza virus in yield reduction assays, with 50% inhibitory concentrations ranging from 0.18 to 0.71 mu M. These 5 0% inhibitory concentrations were similar to those observed for inhibi tion of in vitro transcription (0.32 to 0.54 mu M). One selected compo und also elicited a dose-dependent inhibition of influenza virus repli cation in mice following an upper respiratory tract challenge. These s tudies demonstrate the antiviral efficacy of this inhibitor class and thereby establish the utility of influenza virus endonuclease as a che motherapeutic target.