Wednesday, November 22, 2006

Chemotherapy for Poxvirus

BioDefense Anonymous Coward writes "Antiviral medications typically target enzymes encoded by the virus, such as reverse transcriptase or proteases. Now, viral dependence on host cell functions is being exploited. Poxviruses, the largest known animal viruses (~200 genes), encode growth factors that bind cellular receptors and increase virulence. For example, the smallpox growth factor tightly binds ErbB-1 (0.14 nM), the cell's epidermal growth factor receptor that also binds smallpox itself. Yang et al. now report the identification of a small molecule inhibitor of the ErbB-1 protein tyrosine kinase. The inhibitor is a synthetic molecule, called CI-1033, that blocks the ATP-binding site of ErbB-1 (IC50 = 0.8 nM). Although CI-1033 did not inhibit replication of a related poxvirus, vaccinia virus, it reduced ErbB-1 activity and intercellular spreading. The most convincing proof of principle came from mice treated with CI-1033 before exposure. They were protected from an otherwise fatal pneumonia following infection with vaccinia. The window of protection is narrow and protection required continuous treatment.
Most human tumors possess ErbB abnormalities, a fact that has promoted the development of orally-administered, small molecule inhibitors for cancer therapy (Gleevec, Iressa). This paper suggests a potential dual use for these medications. Fauci and Challberg provide a comprehensive introduction. See also the thorough review of poxviruses growth and antivirals from Harrison et al.
Full Text Yang et al. J. Clin. Invest. 115:379-387 "Antiviral chemotherapy facilitates control of poxvirus infections through inhibition of cellular signal transduction".

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