DNA-encoded library versus RNA-encoded library selection enables design of an oncogenic noncoding RNA inhibitor

Raphael I. Benhamou, Blessy M. Suresh, Yuquan Tong, Wesley G. Cochrane, Valerie Cavett, Simon Vezina-Dawod, Daniel Abegg, Jessica L. Childs-Disney, Alexander Adibekian, Brian M. Paegel*, Matthew D. Disney*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Nature evolves molecular interaction networks through persistent perturbation and selection, in stark contrast to drug discovery, which evaluates candidates one at a time by screening. Here, nature's highly parallel ligand-target search paradigm is recapitulated in a screen of a DNA-encoded library (DEL; 73,728 ligands) against a library of RNA structures (4,096 targets). In total, the screen evaluated ∼300 million interactions and identified numerous bona fide ligand-RNA three-dimensional fold target pairs. One of the discovered ligands bound a 50GAG/30CCC internal loop that is present in primary microRNA-27a (pri-miR-27a), the oncogenic precursor of microRNA-27a. The DEL-derived pri-miR-27a ligand was cell active, potently and selectively inhibiting pri-miR-27a processing to reprogram gene expression and halt an otherwise invasive phenotype in triple-negative breast cancer cells. By exploiting evolutionary principles at the earliest stages of drug discovery, it is possible to identify high-affinity and selective target-ligand interactions and predict engagements in cells that short circuit disease pathways in preclinical disease models.

Original languageAmerican English
Article numbere2114971119
JournalProceedings of the National Academy of Sciences of the United States of America
Volume119
Issue number6
DOIs
StatePublished - 8 Feb 2022
Externally publishedYes

Bibliographical note

Publisher Copyright:
© This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).

Keywords

  • Drug design
  • Nucleic acids
  • RNA
  • RNA folding

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