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Cellular kinase inhibitors that suppress enterovirus replication have a conserved target in the viral protein 3A similar to that of enviroxime

National Institute of Infectious Diseases

¹ E-mail: minetaro{at}nih.go.jp

Previously, we identified a cellular kinase inhibitor GW5074 that strongly inhibits poliovirus (PV) and enterovirus 71(EV71) replication although its target remained unknown. To identify the target of GW5074, we searched cellular kinase inhibitors that have anti-enterovirus activity similar or related to that of GW5074. For this aim, we performed screenings to identify cellular kinase inhibitors that could inhibit PV replication cooperatively with GW5074 or synthetically in the absence of GW5074. We have identified MEK1/2 inhibitors (SL327 and U0126), an EGFR inhibitor (AG1478) and a phosphatidylinositol 3-kinase (PI3K) inhibitor (wortmannin) as compounds with a cooperative inhibitory effect with GW5074, and an Akt1/2 inhibitor (Akt Inhibitor VIII) as a compound with a synthetic inhibitory effect with MEK1/2 inhibitors and AG1478. Individual treatment with identified kinase inhibitors did not significantly affect PV replication, but combined treatment with MEK1/2 inhibitor, AG1478 and Akt1/2 inhibitor synthetically suppressed the replication. The effect of AG1478 in this synthetic inhibition was compensated with other receptor tyrosine kinase inhibitors (IGF-1R Inhibitor II and Flt3 Inhibitor II). We isolated resistant mutants to Flt3 Inhibitor II and GW5074, and found that these mutants had cross-resistance to each treatment. These mutants had a common mutation in the viral protein 3A that causes amino acid change at amino acid position 70 (Ala to Thr), which was previously identified in resistant mutants to a potent anti-enterovirus compound enviroxime. These results suggested that cellular kinase inhibitors and enviroxime have a conserved target in the viral protein 3A to suppress enterovirus replication.

Received 23 March 2009; accepted 7 May 2009.