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Small molecule targeting CELF1 RNA-binding activity to control HSC activation and liver fibrosis
Yang Tan1, Xueqing Sun1, Yizhu Xu1
1State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210023, China.
Abstract:
CUGBP Elav-like family member 1 (CELF1), an RNA-binding protein (RBP), plays important roles in the pathogenesis of diseases such as myotonic dystrophy, liver fibrosis and cancers. However, targeting CELF1 is still a challenge, as RBPs are considered largely undruggable. Here, we discovered that compound 27 disrupted CELF1-RNA binding via structure-based virtual screening and biochemical assays. Compound 27 binds directly to CELF1 and competes with RNA for binding to CELF1. Compound 27 promotes IFN-γ secretion and suppresses TGF-β1-induced hepatic stellate cell (HSC) activation by inhibiting CELF1-mediated IFN-γ mRNA decay. In vivo, compound 27 attenuates CCl4-induced murine liver fibrosis. Furthermore, the structure-activity relationship analysis was performed and compound 841, a derivative of compound 27, was identified as a selective CELF1 inhibitor. In conclusion, targeting CELF1 RNA-binding activity with small molecules was achieved, which provides a novel strategy for treating liver fibrosis and other CELF1-mediated diseases.
Insights
Researchers developed small molecules to target the RNA-binding protein CUGBP Elav-like family member 1 (CELF1), a key factor in liver fibrosis. This approach successfully inhibited CELF1 activity and showed promise for treating fibrotic diseases.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- CUGBP Elav-like family member 1 (CELF1) is an RNA-binding protein implicated in diseases like liver fibrosis.
- Targeting RNA-binding proteins (RBPs) like CELF1 presents a significant challenge due to their perceived "undruggable" nature.
Purpose of the Study:
- To identify small molecules capable of disrupting CELF1-RNA interactions.
- To investigate the therapeutic potential of CELF1 inhibition in liver fibrosis models.
Main Methods:
- Structure-based virtual screening and biochemical assays were employed to discover CELF1 inhibitors.
- In vitro studies assessed compound effects on CELF1-RNA binding, IFN-γ secretion, and hepatic stellate cell (HSC) activation.
- In vivo experiments evaluated compound efficacy in a murine model of carbon tetrachloride (CCl4)-induced liver fibrosis.
Main Results:
- Compound 27 was identified as a CELF1 inhibitor that directly binds CELF1 and competes with RNA.
- Compound 27 promoted IFN-γ secretion and suppressed TGF-β1-induced HSC activation by inhibiting CELF1-mediated IFN-γ mRNA decay.
- Compound 27 demonstrated efficacy in attenuating CCl4-induced liver fibrosis in vivo, and compound 841 was identified as a selective CELF1 inhibitor.
Conclusions:
- Targeting the RNA-binding activity of CELF1 with small molecules is achievable.
- This strategy offers a novel therapeutic approach for liver fibrosis and other CELF1-associated diseases.
