Premium
Discovery of Small Molecule Ligands for MALAT1 by Tuning an RNA‐Binding Scaffold
Author(s) -
Donlic Anita,
Morgan Brittany S.,
Xu Jason L.,
Liu Anqi,
Roble Carlos,
Hargrove Amanda E.
Publication year - 2018
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201808823
Subject(s) - rna , triple helix , small molecule , malat1 , nucleic acid , chemistry , nucleic acid structure , scaffold , computational biology , biochemistry , biophysics , biology , gene , stereochemistry , long non coding rna , computer science , database
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.