Discovery of a novel TLR2 signaling inhibitor with anti-viral activity.
Blockade of Toll-like receptor (TLR)-mediated inflammatory responses represents a new approach in the development of anti-inflammation therapeutics. In the present study, we have screened for TLR2-mediated inflammation inhibitors from small molecule compound libraries using a sensitive cell line stably expressing TLR2, CD14, and an NF-kappaB-driven-luciferase reporter gene. Lymphocytic choriomeningitis virus (LCMV) was used as a virus model. This arenavirus activates a TLR2/CD14-dependent NF-kappaB signaling pathway. We have identified 10 potential anti-inflammatory compounds out of 101,306 compounds. We further evaluated 1 of these positive compounds, E567. We demonstrated that compound E567 efficiently inhibits both LCMV and Herpes simplex virus 1 (HSV-1) induced cytokine responses in both human and mouse cell cultures. We also demonstrated that E567 inhibits cytokine responses in the mouse. Remarkably, E567 is also capable of inhibiting LCMV replication in mice. This is a new model for developing drugs for use in treating viral illnesses.
Zhou
Shenghua
S
Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical Center, 364 Plantation Street, Lazare Research Building, Worcester, MA 01605-2216, USA.
Cerny
Anna M
AM
Bowen
Glennice
G
Chan
Melvin
M
Knipe
David M
DM
Kurt-Jones
Evelyn A
EA
Finberg
Robert W
RW
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use; D002460:Cell Line; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D017930:Genes, Reporter; D018259:Herpesvirus 1, Human / Q000276:immunology* / Q000472:pathogenicity; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D018950:Lipopolysaccharide Receptors / Q000378:metabolism*; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008216:Lymphocytic Choriomeningitis / Q000188:drug therapy; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology* / Q000472:pathogenicity; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors*
D000998:Antiviral Agents; D007155:Immunologic Factors; D018950:Lipopolysaccharide Receptors; D016328:NF-kappa B; C495342:TLR2 protein, human; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D008156:Luciferases