Inhibition of human rhinovirus-induced cytokine production by AG7088, a human rhinovirus 3C protease inhibitor.
Symptom severity in patients with human rhinovirus (HRV)-induced respiratory illness is associated with elevated levels of the inflammatory cytokines interleukin-6 (IL-6) and IL-8. AG7088 is a novel, irreversible inhibitor of the HRV 3C protease. In this study, AG7088 was tested for its antiviral activity and ability to inhibit the production of IL-6 and IL-8 in a human bronchial epithelial cell line, BEAS-2B. Infection of BEAS-2B cells with HRV 14 resulted in the production of both infectious virus and the cytokines IL-6 and IL-8. Treatment of HRV 14-infected cells with AG7088 resulted in a statistically significant (P, <0.05) dose-dependent reduction in the levels of infectious virus as well as IL-6 and IL-8 released into the cell supernatant compared to the results obtained for compound-free infected cells. AG7088 was also able to inhibit the replication of HRV 2 and 16 in BEAS-2B cells. In time-of-addition studies, AG7088 could be added as late as 14 to 26 h after HRV 14 infection of BEAS-2B cells and still result in a statistically significant (P, <0.05) reduction in the levels of infectious virus, IL-6, and IL-8 compared to the results obtained for compound-free infected cells. These findings have implications for the development of an antirhinovirus agent that may not only block virus replication but also diminish symptoms.
Zalman
L S
LS
Agouron Pharmaceuticals, Inc., San Diego, CA 92121, USA. zalman@agouron.com
Brothers
M A
MA
Dragovich
P S
PS
Zhou
R
R
Prins
T J
TJ
Worland
S T
ST
Patick
A K
AK
D000086042:3C Viral Proteases; D000998:Antiviral Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000187:drug effects / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D010649:Phenylalanine / Q000031:analogs & derivatives; D011760:Pyrrolidinones / Q000494:pharmacology*; D012229:Rhinovirus / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D013997:Time Factors; D014633:Valine / Q000031:analogs & derivatives; D014764:Viral Proteins
D000998:Antiviral Agents; D015853:Cysteine Proteinase Inhibitors; D016207:Cytokines; D007555:Isoxazoles; D011760:Pyrrolidinones; D014764:Viral Proteins; D010649:Phenylalanine; D003546:Cysteine Endopeptidases; D000086042:3C Viral Proteases; D014633:Valine; C118874:rupintrivir