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Updated: Apr 11, 2026

Dissecting Innate Immune Signaling in Viral Evasion of Cytokine Production
Published on: March 2, 2014
The c-Jun N-terminal kinase inhibitor SP600125 inhibits human cytomegalovirus replication
Huiping Zhang1, Xiaofeng Niu2, Zhikang Qian3
1Department of Neonatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Abstract:
Human cytomegalovirus (HCMV) is an opportunistic pathogen that causes severe diseases in congenitally infected newborns and immunocompromised patients. Currently, no vaccine is available to prevent HCMV infection. Anti-viral drugs are limited by their side effects and drug resistance. In this study, by performing a medium-sized, anti-HCMV chemical screening, we identified SP600125, CC-401, and the c-Jun N-terminal kinase (JNK) inhibitor VIII, three structurally different small molecule JNK inhibitors that effectively inhibited HCMV replication in cultured human fibroblasts (HFs). SP600125 showed its potential by inhibiting the viral replication of a HCMV laboratory strain in HFs and a HCMV clinical strain in human retinal pigment epithelial cells. Knockdown of JNK expression by RNA interference significantly impaired HCMV replication, mimicking the effect of the chemical inhibitors on virus infection. Mechanistically, SP600125 affects a very early step of the viral life cycle. Viral binding, entry, and the delivery of viral DNA into the cells were not inhibited by the compound. Instead, it suppressed the transcription of the immediate-early viral genes IE1/2 and the accumulation of their gene products. IE1/2 are among the first genes expressed after viral entry, and they are the master regulators of late phase viral gene expression. Consistent with this notion, the expression of other viral genes was also reduced after SP600125 treatment. We propose that JNK inhibitors have the potential to become a new class of anti-HCMV drug candidates, and JNK is a feasible target for the development of anti-HCMV drugs.
Insights
New JNK inhibitors show promise in combating human cytomegalovirus (HCMV) replication. These compounds target early viral gene expression, offering a potential new therapeutic strategy against HCMV infection.
Area of Science:
- Virology
- Molecular Biology
- Drug Discovery
Background:
- Human cytomegalovirus (HCMV) is a significant opportunistic pathogen causing severe disease in vulnerable populations.
- Current preventative vaccines and antiviral treatments for HCMV are limited by efficacy, side effects, and drug resistance.
Purpose of the Study:
- To identify novel small molecule inhibitors targeting HCMV replication.
- To investigate the mechanism of action and therapeutic potential of identified inhibitors.
Main Methods:
- Conducted a chemical screen to identify anti-HCMV compounds.
- Utilized cell culture models (human fibroblasts, retinal pigment epithelial cells) with HCMV laboratory and clinical strains.
- Employed RNA interference to assess the role of c-Jun N-terminal kinase (JNK).
- Analyzed viral gene transcription and protein accumulation.
Main Results:
- Identified three distinct JNK inhibitors (SP600125, CC-401, JNK inhibitor VIII) that effectively inhibit HCMV replication.
- SP600125 demonstrated efficacy against both laboratory and clinical HCMV strains.
- JNK knockdown mimicked the antiviral effects of the inhibitors, confirming JNK's role.
- SP600125 inhibited early viral gene transcription (IE1/2) and subsequent viral gene expression, without affecting viral binding, entry, or DNA delivery.
Conclusions:
- JNK inhibitors represent a potential new class of antiviral drugs against HCMV.
- JNK is a viable therapeutic target for developing novel anti-HCMV therapies.
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