Discovery of Small Molecule Ligands for MALAT1 by Tuning an RNA-Binding Scaffold.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Donlic, A; Morgan, BS; Xu, JL; Liu, A; Roble, C; Hargrove, AE

Published Date

  • October 2018

Published In

Volume / Issue

  • 57 / 40

Start / End Page

  • 13242 - 13247

PubMed ID

  • 30134013

Pubmed Central ID

  • PMC6589350

Electronic International Standard Serial Number (EISSN)

  • 1521-3773

International Standard Serial Number (ISSN)

  • 1433-7851

Digital Object Identifier (DOI)

  • 10.1002/anie.201808823


  • eng