Molecular Glue for RNA: Regulating RNA Structure and Function through Synthetic RNA Binding Molecules

Abstract

We introduce the concept of molecular glues for RNA, in which specific RNA‐binding small molecules induce designed structural changes in target functional RNAs, resulting in modulation of the functions. (Z)‐NCTS is an RNA‐mismatch‐binding small molecule that recognizes 5′‐r(XGG)‐3′/5′‐r(XGG)‐3′ sequences (X=U or A) and acts as a molecular glue for RNA. The binding of (Z)‐NCTS brings two distinct 5′‐r(XGG)‐3′ domains into contact with each other, and this can result in higher‐order structural changes of target RNAs. We applied (Z)‐NCTS to induce the formation of a proposed tertiary structure of a ribozyme together with activation of RNA‐cleaving ability. The concept of a molecular glue could inspire new small‐molecule‐based strategies for regulating biological functions: a synthetic small molecule targeting functional RNAs could regulate the RNA structure and function.

Rational design of a photoswitchable DNA glue enabling high regulatory function and supramolecular chirality transfer

“…Development of photoswitchable MBLs with precisely tuned photoisomerization properties would pave the way toward regulation of biological processes by targeting endogenous DNAs and RNAs. 62 Here, we focus on tuning the photochemical properties of the azobenzene core structure to adjust them to the requirements of the system (cf. Figure 1A and B), which enabled fast dynamic control of DNA double helix formation and real-time studies.…”

Versatile Target-Guided Screen for Discovering Bidirectional Transcription Inhibitors of a Trinucleotide Repeat Disease

“…32 Hargrove has demonstrated the importance of amiloride and its analogues as RNA binding scaffolds, 33 and Nakatani has used naphthyridine derivatives for recognition of GG mismatches. 34 Thus, 11 and 12 were also included to explore new potential binding roles for these ligands. As can be seen in Figure 2, the binding scaffolds were modified with either one or two azide or alkyne groups for potential proximity-induced, template-assisted click (see the Supporting Information for synthesis and characterization).…”

“…The heterocyclic nucleus in 10 was found in a high-throughput screen to selectively bind to d­(CTG) exp . Hargrove has demonstrated the importance of amiloride and its analogues as RNA binding scaffolds, and Nakatani has used naphthyridine derivatives for recognition of GG mismatches . Thus, 11 and 12 were also included to explore new potential binding roles for these ligands.…”