title: Indole derivatives inhibit hepatitis C virus replication through induction of pro-inflammatory cytokines.
abstract: Previously, we discovered a series of indole derivatives as a new class of hepatitis C virus (HCV) replication inhibitors by using a target-free chemical genetic strategy. Through a structure-activity relationship study, the compound 12e was identified as the most potent inhibitor of this class (EC50 = 1.1 μmol/l) with minimal cytotoxicity (CC50 = 61.8 μmol/l). In order to gain insight into its detailed antiviral mechanism of action, we performed PCR array analyses and found that 12e was able to activate transcription of a number of pro-inflammatory as well as antiviral cytokine genes including CXCL-8, IL-1α, TNF-α, IL-3, IRAK-1, and DDX58. Their induction by 12e was verified by individual RT-PCR analyses. In addition, 12e was found to stimulate secretion of soluble factors with anti-HCV replication activity. Among the 12e-induced pro-inflammatory cytokines, CXCL-8 showed a strong positive correlation between its transcriptional activation and antiviral potency. Interestingly, a recombinant CXCL-8 protein also reduced HCV replication, though only moderately. In conclusion, we found a novel mode of action of indole derivatives in inhibiting HCV replication, particularly the induction of pro-inflammatory cytokines.
authors: S
authors: S
authors: Lee
authors: G
authors: G
authors: Jin
authors: D
authors: D
authors: Kim
authors: S
authors: S
authors: Son
authors: K
authors: K
authors: Lee
authors: C
authors: C
authors: Lee
mesh_terms: D002460:Cell Line; D016207:Cytokines / Q000235:genetics* / Q000276:immunology; D015536:Down-Regulation / Q000187:drug effects; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology*; D006526:Hepatitis C / Q000235:genetics* / Q000276:immunology / Q000821:virology*; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D015854:Up-Regulation / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D016207:Cytokines; D007211:Indoles
keywords: hepatitis C virus; indole derivatives; replication inhibitors; CXCL-8; pro-inflammatory cytokines; transcriptional activation.