Novel Compounds Targeting the RNA-Binding Protein HuR. Structure-Based Design, Synthesis, and Interaction Studies

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• RNA-binding proteins (RBPs) regulate gene expression post-transcriptionally.
• Dysregulation of RBPs is implicated in diseases such as cancer and neurodegeneration.
• Hu proteins (ELAV/HuR) and their mRNA complexes are key players in these pathologies.

Purpose of the Study:

• To design and synthesize novel small molecules targeting the HuR protein.
• To investigate compounds that can interfere with HuR-mRNA complex stability.
• To provide a basis for developing new therapeutic agents against HuR-related diseases.

Main Methods:

• Rational drug design and chemical synthesis of new HuR ligands.
• Structural analysis of ligand-HuR interactions using Saturation-Transfer Difference (STD) NMR.
• Computational modeling and in silico studies to assess binding interactions.

Main Results:

• Successful design and synthesis of structurally novel HuR ligands.
• Characterization of the interaction modes between the designed ligands and HuR.
• Identification of key structural features for modulating HuR-RNA complex stability.

Conclusions:

• Novel HuR ligands were developed with potential as HuR-RNA interferers.
• STD NMR and in silico studies elucidated critical interaction details.
• This research provides a foundation for developing innovative therapeutics targeting HuR-mediated diseases.