Selective small-molecule inhibition of an RNA structural element

Area of Science:

• Molecular Biology
• RNA Biology
• Drug Discovery

Background:

• Riboswitches are regulatory RNA elements controlling gene expression by binding ligands.
• Targeting riboswitches for drug development is challenging due to limited chemical diversity of inhibitors.
• Existing inhibitors are often restricted to antimetabolites or ligand analogues.

Purpose of the Study:

• To discover and characterize novel chemical modulators of bacterial riboflavin riboswitches.
• To explore the potential of targeting non-coding RNA structures with synthetic small molecules.
• To identify inhibitors with distinct chemical structures for improved selectivity.

Main Methods:

• Phenotypic screening to identify potential modulators.
• Characterization of ribocil's interaction with riboflavin riboswitches.
• Assessing ribocil's effect on ribB gene expression and bacterial growth.

Main Results:

• Discovery of ribocil, a selective chemical modulator of bacterial riboflavin riboswitches.
• Ribocil acts as a synthetic mimic of flavin mononucleotide.
• Ribocil represses riboswitch-mediated ribB gene expression and inhibits bacterial growth.

Conclusions:

• Non-coding RNA structural elements can be targeted by a broader range of synthetic small molecules than previously thought.
• Ribocil represents a new class of inhibitors for bacterial riboflavin riboswitches.
• This study expands the chemical space for riboswitch-targeted drug discovery.