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

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
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 115 Issue 2 Pg. 379-87 (Feb 2005) ISSN: 0021-9738 [Print] United States
• PMID: 15690085 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Growth Substances
• Morpholines
• Proto-Oncogene Proteins
• Quinazolines
• Viral Proteins
• DNA
• Canertinib
• Proto-Oncogene Proteins c-cbl
• Ubiquitin-Protein Ligases
• ErbB Receptors
• Cbl protein, mouse

Topics

• Animals
• Chlorocebus aethiops
• DNA (biosynthesis)
• ErbB Receptors (antagonists & inhibitors, metabolism)
• Growth Substances (metabolism)
• HeLa Cells
• Humans
• Male
• Mice
• Morpholines (pharmacology)
• Pneumonia (drug therapy, metabolism, pathology, virology)
• Protein Transport (drug effects)
• Proto-Oncogene Proteins (metabolism)
• Proto-Oncogene Proteins c-cbl
• Quinazolines (pharmacology)
• Signal Transduction (drug effects)
• Smallpox (drug therapy, metabolism, pathology)
• T-Lymphocytes (immunology)
• Ubiquitin-Protein Ligases (metabolism)
• Vaccinia (drug therapy, immunology, pathology)
• Vaccinia virus (metabolism)
• Variola virus (metabolism)
• Vero Cells
• Viral Proteins (metabolism)