RNP interfaces as regulatory "active sites": a repurposing strategy for small molecules targeting viral...

Area of Science:

• Molecular Biology
• Drug Discovery
• Structural Biology

Background:

• RNA-protein (RNP) complexes are crucial in gene expression, viral infections, and diseases.
• Targeting RNPs with small molecules (SMs) is difficult due to the lack of defined binding pockets.
• RNP interfaces, where RNA structure meets protein recognition, act as regulatory 'active sites'.

Purpose of the Study:

• To propose an integrative framework for identifying and targeting RNP interfaces for therapeutic development.
• To overcome the challenge of targeting dynamic RNP structures within complex regulatory networks.
• To enable the rational repurposing of FDA-approved SMs for RNP-targeted therapies.

Main Methods:

• Integrative discovery framework combining structure prediction, molecular dynamics simulations, and ensemble-based virtual screening.
• Focus on minimal RNP fragments and recurrent structural motifs (e.g., bulge loops) for ensemble sampling.
• Utilizing viral 5'-untranslated regions (5'-UTRs) as model systems, exemplified by Enterovirus A-71 5'-UTR.

Main Results:

• The proposed framework identifies transient pockets in RNP interfaces suitable for SM virtual docking.
• Interface-guided modeling prioritizes SMs for modulating specific RNP interactions.
• Demonstrated the potential of focusing on conserved RNP interfaces within viral 5'-UTRs.

Conclusions:

• The ensemble-guided RNP interface framework accelerates the discovery of SMs targeting RNP complexes.
• This strategy offers a generalizable approach for developing RNP-targeted therapies for viral infections and human diseases.
• Highlights the potential of repurposing existing drugs for novel therapeutic applications against RNP-mediated conditions.