RO 90-7501 enhances TLR3 and RLR agonist induced antiviral response.
Recognition of virus infection by innate pattern recognition receptors (PRRs), including membrane-associated toll-like receptors (TLR) and cytoplasmic RIG-I-like receptors (RLR), activates cascades of signal transduction pathways leading to production of type I interferons (IFN) and proinflammatory cytokines that orchestrate the elimination of the viruses. Although it has been demonstrated that PRR-mediated innate immunity plays an essential role in defending virus from infection, it also occasionally results in overwhelming production of proinflammatory cytokines that cause severe inflammation, blood vessel leakage and tissue damage. In our efforts to identify small molecules that selectively enhance PRR-mediated antiviral, but not the detrimental inflammatory response, we discovered a compound, RO 90-7501 ('2'-(4-Aminophenyl)-[2,5'-bi-1H-benzimidazol]-5-amine), that significantly promoted both TLR3 and RLR ligand-induced IFN-β gene expression and antiviral response, most likely via selective activation of p38 mitogen-activated protein kinase (MAPK) pathway. Our results thus imply that pharmacological modulation of PRR signal transduction pathways in favor of the induction of a beneficial antiviral response can be a novel therapeutic strategy.
Department of Microbiology and Immunology, Drexel University College of Medicine, Doylestown, Pennsylvania, United States of America.
Fang
F
Guo
Jennifer
J
Mead
Nishat
N
Aliya
Lijuan
L
Wang
Andrea
A
Cuconati
Lai
L
Wei
Kui
K
Li
Timothy M
TM
Block
Ju-Tao
JT
Guo
Jinhong
J
Chang
D000588:Amines / Q000737:chemistry / Q000494:pharmacology*; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D015153:Blotting, Western; D002460:Cell Line; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D057809:HEK293 Cells; D054884:Host-Pathogen Interactions / Q000187:drug effects; D006801:Humans; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D015394:Molecular Structure; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011070:Poly I-C / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011971:Receptors, Immunologic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051196:Toll-Like Receptor 3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014721:Vesicular stomatitis Indiana virus / Q000187:drug effects* / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C579147:(2'-(4-aminophenyl)-(2,5'-bi-1H-benzimidazol)-5-amine); D000588:Amines; D000998:Antiviral Agents; D001562:Benzimidazoles; D016328:NF-kappa B; D011971:Receptors, Immunologic; D051196:Toll-Like Receptor 3; D016899:Interferon-beta; D008156:Luciferases; D048051:p38 Mitogen-Activated Protein Kinases; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D011070:Poly I-C