Targeting RNA with small molecules: lessons learned from Xist RNA.

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Most of the human genome is noncoding, yet drugs primarily target proteins.
• Noncoding RNAs are increasingly implicated in disease, presenting a vast, largely untapped therapeutic target space.
• Targeting noncoding RNA could significantly expand opportunities for novel drug development.

Purpose of the Study:

• To develop a strategy for identifying bioactive compounds targeting noncoding RNAs.
• To demonstrate proof-of-concept for targeting the Xist noncoding RNA with small molecules.
• To explore the potential of small molecules to disrupt RNA structure and function for therapeutic benefit.

Main Methods:

• Affinity-selection mass spectrometry screening strategy.
• In vitro and in vivo binding assays for compound specificity.
• Small-angle X-ray scattering (SAXS) for structural analysis.

Main Results:

• Identification of a drug-like compound, X1, targeting the noncoding RNA Xist.
• X1 specifically binds to the RepA motif of Xist.
• X1 alters RepA conformation, displacing protein factors (PRC2, SPEN) and inhibiting X-chromosome inactivation.

Conclusions:

• Noncoding RNAs can be effectively targeted by drug-like small molecules.
• Disruption of RNA structure and function by small molecules is a viable therapeutic strategy.
• This work opens new possibilities for drug development against noncoding RNA-associated diseases.