Discovery of Small Molecule Ligands for MALAT1 by Tuning an RNA‐Binding Scaffold. Issue 40 (10th September 2018)

• Record Type: Journal Article
• Authors: Donlic, Anita; Morgan, Brittany S.; Xu, Jason L.; Liu, Anqi; Roble, Carlos; Hargrove, Amanda E.
• Is Part Of: Angewandte Chemie international edition. Volume 57:Issue 40(2018)
• Page Start: 13242
• Page End: 13247
• Publication Date: 2018-09-10
• Subjects: long noncoding RNA -- molecular recognition -- principal moment of inertia -- RNA recognition -- small molecule ligands; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201808823
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: Structural studies of the 3′‐end of the oncogenic long non‐coding RNA metastasis‐associated lung adenocarcinoma transcript 1 (MALAT1) confirmed a unique triple‐helix structure. This structure enables accumulation of the transcript, and high levels of MALAT1 are found in several cancers. Here, we synthesize a small molecule library based on an RNA‐binding scaffold, diphenylfuran (DPF), screen it against a variety of nucleic acid constructs, and demonstrate for the first time that the MALAT1 triple helix can be selectively targeted with small molecules. Computational analysis revealed a trend between subunit positioning and composition on DPF shape and intramolecular interactions, which in turn generally correlated with selectivity and binding strengths. This work thus provides design strategies toward chemical probe development for the MALAT1 triple helix and suggests that comprehensive analyses of RNA‐focused libraries can generate insights into selective RNA recognition. Abstract : DPF shapes up as MALAT1 triplex threat : The synthesis and evaluation of a scaffold‐based small molecule library led to the discovery of first ligands for the MALAT1 triple helix. Computational analysis revealed the role of ligand shape for selective recognition, thereby providing design strategies toward future probe development for this unique target.