The RNA binding protein Human Antigen R (HuR) has been identified as a main regulator of the innate immune response and its inhibition can lead to beneficial anti-inflammatory effects. To this aim, we previously synthesized a novel class of small molecules named Tanshinone Mimics (TMs) able to interfere with HuR-RNA binding, and that dampen the LPS-induced immune response. Herein, we present a novel series of TMs, encompassing thiophene 3/TM9 and 4/TM10, furan 5/TM11 and 6/TM12, pyrrole 7b/TM13, and pyrazole 8. The furan-containing 5(TM11) showed the greatest inhibitory effect of the series on HuR-RNA complex formation, as suggested by RNA Electromobility Shift Assay and Time-Resolved FRET. Molecular Dynamics Calculation of HuR - 5/TM11 interaction, quantum mechanics approaches and Surface Plasmon Resonance data, all indicates that, within the novel heteroaryl substituents, the furan ring better recapitulates the chemical features of the RNA bound to HuR. Compound 5/TM11 also showed improved aqueous solubility compared to previously reported TMs. Real-time monitoring of cell growth and flow cytometry analyses showed that 5/TM11 preferentially reduced cell proliferation rather than apoptosis in murine macrophages at immunomodulatory doses. We observed its effects on the innate immune response triggered by lipopolysaccharide (LPS) in macrophages, showing that 5/TM11 significantly reduced the expression of proinflammatory cytokines as Cxcl10 and Il1b.

• Keywords
• Anti-inflammatory agents, ELAVL1, HuR, HuR inhibitors, LPS, Tanshinone mimics,
• MeSH
• Anti-Inflammatory Agents pharmacology   chemistry   MeSH
• Apoptosis drug effects   MeSH
• Chemokine CXCL10 metabolism   MeSH
• Abietanes * pharmacology   chemistry   MeSH
• Furans pharmacology   chemistry   MeSH
• ELAV-Like Protein 1 metabolism   MeSH
• Humans MeSH
• Lipopolysaccharides pharmacology   MeSH
• Macrophages * drug effects   metabolism   MeSH
• Mice MeSH
• RAW 264.7 Cells MeSH
• Solubility MeSH
• Molecular Dynamics Simulation MeSH
• Inflammation drug therapy   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Anti-Inflammatory Agents MeSH
• Chemokine CXCL10 MeSH
• Abietanes * MeSH
• Furans MeSH
• ELAV-Like Protein 1 MeSH
• Lipopolysaccharides MeSH
• tanshinone MeSH Browser