Peptide nucleic acids can form hairpins and bind RNA-binding proteins

Area of Science:

• Molecular Biology
• Drug Discovery
• Biochemistry

Background:

• RNA-binding proteins (RBPs) are crucial for cellular processes, and their unique interactions in prokaryotes and viruses make them potential drug targets.
• Developing small molecule drugs targeting RBPs is challenging due to the extended, shallow, and dynamic nature of RNA-binding sites.

Purpose of the Study:

• To investigate the potential of peptide nucleic acids (PNAs) as a novel strategy for targeting RNA-binding proteins (RBPs).
• To design and validate PNAs that mimic RNA structures to inhibit RBP function, focusing on prokaryotic signal recognition particle (SRP) assembly and SARS-CoV-2 Nsp9.

Main Methods:

• Design of PNAs to mimic specific RNA stem-loop sequences.
• Utilized biophysical and biochemical assays to assess PNA structure, protein binding, and functional inhibition.
• Tested PNA efficacy against prokaryotic SRP assembly and SARS-CoV-2 Nsp9.

Main Results:

• Designed PNAs successfully folded into hairpin structures and bound to target RBPs.
• PNAs inhibited prokaryotic SRP assembly by competing with the native RNA hairpin.
• A PNA demonstrated binding to SARS-CoV-2 Nsp9, highlighting potential against non-sequence-specific RNA binders.

Conclusions:

• Peptide nucleic acids (PNAs) represent a promising class of compounds for targeting RNA-binding activities of RBPs.
• This PNA-based strategy offers a potential new avenue for developing antibiotics and antiviral therapeutics.