Antiviral chemotherapy facilitates control of poxvirus infections through inhibition of cellular signal transduction.
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.
Yang
Hailin
H
Laboratory of Immunobiology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Kim
Sung-Kwon
SK
Kim
Mikyung
M
Reche
Pedro A
PA
Morehead
Tiara J
TJ
Damon
Inger K
IK
Welsh
Raymond M
RM
Reinherz
Ellis L
EL
D000818:Animals; D002522:Chlorocebus aethiops; D004247:DNA / Q000096:biosynthesis; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006133:Growth Substances / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008297:Male; D051379:Mice; D009025:Morpholines / Q000494:pharmacology*; D011014:Pneumonia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000821:virology; D021381:Protein Transport / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl; D011799:Quinazolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D012899:Smallpox / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D014615:Vaccinia / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D014616:Vaccinia virus / Q000378:metabolism; D012901:Variola virus / Q000378:metabolism*; D014709:Vero Cells; D014764:Viral Proteins / Q000378:metabolism*
D006133:Growth Substances; D009025:Morpholines; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D014764:Viral Proteins; D004247:DNA; C420268:Canertinib; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D066246:ErbB Receptors; C493849:Cbl protein, mouse