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Antiviral chemotherapy facilitates control of poxvirus infections through inhibition of cellular signal transduction
Hailin Yang, … , Raymond M. Welsh, Ellis L. Reinherz
Hailin Yang, … , Raymond M. Welsh, Ellis L. Reinherz
Published February 1, 2005
Citation Information: J Clin Invest. 2005;115(2):379-387. https://doi.org/10.1172/JCI23220.
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Article Infectious disease

Antiviral chemotherapy facilitates control of poxvirus infections through inhibition of cellular signal transduction

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Abstract

The EGF-like domain of smallpox growth factor (SPGF) targets human ErbB-1, inducing tyrosine phosphorylation of certain host cellular substrates via activation of the receptor’s kinase domain and thereby facilitating viral replication. Given these findings, low molecular weight organic inhibitors of ErbB-1 kinases might function as antiviral agents against smallpox. Here we show that CI-1033 and related 4-anilinoquinazolines inhibit SPGF-induced human cellular DNA synthesis, protein tyrosine kinase activation, and c-Cbl association with ErbB-1 and resultant internalization. Infection of monkey kidney BSC-40 and VERO-E6 cells in vitro by variola strain Solaimen is blocked by CI-1033, primarily at the level of secondary viral spreading. In an in vivo lethal vaccinia virus pneumonia model, CI-1033 alone promotes survival of animals, augments systemic T cell immunity and, in conjunction with a single dose of anti-L1R intracellular mature virus particle-specific mAb, fosters virtually complete viral clearance of the lungs of infected mice by the eighth day after infection. Collectively, these findings show that chemical inhibitors of host-signaling pathways exploited by viral pathogens may represent potent antiviral therapies.

Authors

Hailin Yang, Sung-Kwon Kim, Mikyung Kim, Pedro A. Reche, Tiara J. Morehead, Inger K. Damon, Raymond M. Welsh, Ellis L. Reinherz

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Figure 1

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Structure of ErbB tyrosine kinase inhibitors. (A) Chemical structures of...
Structure of ErbB tyrosine kinase inhibitors. (A) Chemical structures of ErbB tyrosine kinase inhibitors. (B) Molecular model of CI-1033 interaction with the ErbB-1 kinase domain. The upper panel shows the model of the noncovalently bound CI-1033 in the ATP-binding site of the tyrosine kinase ErbB-1 (protein data bank: 1M17) crystal structure. The Tarceva compound was removed, and CI-1033 was manually modeled into the site. The backbone of the kinase is shown as a ribbon diagram along with the atoms of Cys773. The lower panel shows the model of the covalently bound CI-1033 in the ATP-binding site. The atoms are shown as stick models with carbon atoms colored white, oxygen atoms red, nitrogen atoms dark blue, sulfur atoms yellow, and hydrogen atoms light blue.
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