Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 119, Issue 20, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2122660119
Keywords
RNA-targeted ligand discovery; SHAPE-MaP; cooperativity; fragment linking
Categories
Funding
- NIH [R01-EUREKA GM098662, R01 AI068462, R01 GM112940]
- Canadian Institutes of Health Research grant
- UNC Lineberger Comprehensive Cancer Center
- RNA Innovation Fellowship
- NIH NIGMS [1P30GM133893]
- DOE [BES-FWP-PS001]
- [BER-BO 070]
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In this study, a new technology was developed that utilizes fragment-based screening and RNA structure probing to discover small-molecule fragments that bind to a target RNA structure. Using structure-activity relationship information, a novel ligand was designed with high affinity for diverse RNA targets.
The transcriptome represents an attractive but underused set of targets for smallmolecule ligands. Here, we devise a technology that leverages fragment-based screening and SHAPE-MaP RNA structure probing to discover small-molecule fragments that bind an RNA structure of interest. We identified fragments and cooperatively binding fragment pairs that bind to the thiamine pyrophosphate (TPP) riboswitch with millimolar to micromolar affinities. We then used structure-activity relationship information to efficiently design a linked-fragment ligand, with no resemblance to the native ligand, with high ligand efficiency and druglikeness, that binds to the TPP thiM riboswitch with high nanomolar affinity and that modulates RNA conformation during cotranscriptional folding. Principles from this work are broadly applicable, leveraging cooperativity and multisite binding, for developing high-quality ligands for diverse RNA targets.
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