Inhibition of poxvirus spreading by the anti-tumor drug Gefitinib (Iressa)

Abstract

The threat of smallpox virus as a bioterrorist weapon is raising international concerns again since the anthrax attacks in the USA in 2001. The medical readiness of treating patients suffering from such infections is a prerequisite of an effective civil defense system. Currently the only therapeutic option for the treatment of poxvirus infections relies on the virostatic nulceosid analog cidofovir, although severe side effects and drug resistant strains have been described. A growing understanding of poxvirus pathogenesis raises the possibility to explore other appropriate targets involved in the viral replication cycle. Poxvirus encoded growth factors such as the Vaccinia Growth Factor (VGF) stimulate host cells via the Epidermal Growth Factor Receptor (EGFR) and thereby facilitate viral spreading. In this study we could visualize for the first time the paracrine priming of uninfected cells for subsequent infection by orthopoxviruses directly linked to EGFR phosphorylation. Since EGFR is a well known target for anti-tumor therapy small molecules for inhibition of its tyrosine kinase (TK) activity are readily available and clinically evaluated. In this study we analyzed three different EGFR receptor tyrosine kinase inhibitors for inhibition of orthopoxvirus infection in epithelial cells. The inhibitor shown to be most effective was Gefitinib (Iressa) which is already approved as a drug for anti-tumor medication in the USA and in Europe. Thus Gefitnib may provide a new therapeutic option for single or combination therapy of acute poxvirus infections, acting on a cellular target and thus reducing the risk of viral resistance to treatment.