Polycationic Peptides That Bind T-Box Riboswitch Antiterminator RNA and Inhibit Riboswitch Function

Area of Science:

• Molecular Biology
• RNA Biology
• Drug Discovery

Background:

• Antibiotic resistance poses a significant global health threat, driving the need for novel antibacterial targets.
• Noncoding regulatory RNAs, such as the T-box riboswitch, represent a promising class of novel antibacterial targets.
• The antiterminator RNA element of the T-box riboswitch is a specific target for therapeutic intervention.

Purpose of the Study:

• To investigate a spatially dispersed polycationic pharmacophore model for targeting the T-box antiterminator RNA.
• To design decapeptides based on known alkyl polyamine agonists of the T-box riboswitch.
• To assess the binding and functional modulation of the T-box antiterminator RNA by designed peptides.

Main Methods:

• Design of decapeptides mimicking biogenic polyamines.
• Assessment of antiterminator RNA binding using native mass spectrometry.
• Determination of T-box riboswitch function modulation via a fluorescence-based assay.

Main Results:

• One designed polycationic peptide demonstrated complex formation with the antiterminator model RNA.
• This peptide selectively inhibited T-box riboswitch transcription readthrough, independent of tRNA induction.
• The peptide's inhibitory activity suggests its potential as a therapeutic agent.

Conclusions:

• A novel polycationic peptide effectively targets and inhibits the T-box antiterminator RNA.
• This finding supports the T-box riboswitch as a viable drug target for combating antibiotic resistance.
• The study highlights the potential of targeting noncoding regulatory RNAs for future antibacterial drug discovery efforts.