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Identification of insulin-sensitizing molecules acting by disrupting the interaction between the Insulin Receptor and
Anaïs Gondoin1,2, Cornelia Hampe1,2, Richard Eudes3
1Institut Cochin, Université Paris Descartes, CNRS (UMR8104), Paris, France.
Abstract:
Metabolic diseases are characterized by a decreased action of insulin. During the course of the disease, usual treatments frequently fail and patients are finally submitted to insulinotherapy. There is thus a need for innovative therapeutic strategies to improve insulin action. Growth factor receptor-bound protein 14 (Grb14) is a molecular adapter that specifically binds to the activated insulin receptor (IR) and inhibits its tyrosine kinase activity. Molecules disrupting Grb14-IR binding are therefore potential insulin-sensitizing agents. We used Structure-Based Virtual Ligand Screening to generate a list of 1000 molecules predicted to hinder Grb14-IR binding. Using an acellular bioluminescence resonance energy transfer (BRET) assay, we identified, out of these 1000 molecules, 3 compounds that inhibited Grb14-IR interaction. Their inhibitory effect on insulin-induced Grb14-IR interaction was confirmed in co-immunoprecipitation experiments. The more efficient molecule (C8) was further characterized. C8 increased downstream Ras-Raf and PI3-kinase insulin signaling, as shown by BRET experiments in living cells. Moreover, C8 regulated the expression of insulin target genes in mouse primary hepatocytes. These results indicate that C8, by reducing Grb14-IR interaction, increases insulin signalling. The use of C8 as a lead compound should allow for the development of new molecules of potential therapeutic interest for the treatment of diabetes.
Insights
Researchers identified a novel compound, C8, that enhances insulin signaling by disrupting the interaction between Growth factor receptor-bound protein 14 (Grb14) and the insulin receptor (IR). This discovery offers a potential new therapeutic strategy for metabolic diseases like diabetes.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Metabolic diseases are marked by reduced insulin action, often necessitating insulin therapy as conventional treatments fail.
- Growth factor receptor-bound protein 14 (Grb14) inhibits insulin receptor (IR) activity, presenting a target for improving insulin sensitivity.
Purpose of the Study:
- To identify novel molecules that disrupt the Grb14-IR interaction, thereby enhancing insulin signaling.
- To evaluate the therapeutic potential of identified compounds for metabolic diseases.
Main Methods:
- Structure-Based Virtual Ligand Screening was employed to generate a library of potential Grb14-IR binding inhibitors.
- A bioluminescence resonance energy transfer (BRET) assay and co-immunoprecipitation were used to validate compound efficacy.
- Downstream insulin signaling pathways (Ras-Raf, PI3-kinase) and gene expression were analyzed in vitro and in cellulo.
Main Results:
- Three compounds were identified that inhibited Grb14-IR interaction, with C8 showing the most significant effect.
- Compound C8 enhanced insulin-induced downstream signaling pathways, including Ras-Raf and PI3-kinase.
- C8 modulated the expression of insulin target genes in mouse primary hepatocytes, confirming its insulin-sensitizing effect.
Conclusions:
- Disrupting the Grb14-IR interaction with C8 effectively enhances insulin signaling.
- C8 serves as a promising lead compound for developing new therapeutic agents for diabetes and other metabolic disorders.
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