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Chem. 2018 Oct 11;4(10):2384-2404. doi: 10.1016/j.chempr.2018.08.003. Epub 2018 Sep 13.

A Massively Parallel Selection of Small Molecule-RNA Motif Binding Partners Informs Design of an Antiviral from Sequence.

Author information

1
Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458, USA.
2
Mitsubishi Tanabe Pharma Corporation, 3-2-10, Dosho-machi, Chuo-ku, Osaka 541-8505, Japan.
3
Informatics Core, The Scripps Research Institute, Jupiter, FL 33458, USA.
4
Department of Immunology & Infectious Diseases, The Scripps Research Institute, Jupiter, FL 33458, USA.
5
Present address: Department of Virology, Roche Pharmaceutical Research and Early Development (pRED), F. Hoffmann-La Roche, Basel, Switzerland.
6
Lead Contact.

Abstract

Many RNAs cause disease; however, RNA is rarely exploited as a small-molecule drug target. Our programmatic focus is to define privileged RNA motif small-molecule interactions to enable the rational design of compounds that modulate RNA biology starting from only sequence. We completed a massive, library-versus-library screen that probed over 50 million binding events between RNA motifs and small molecules. The resulting data provide a rich encyclopedia of small-molecule RNA recognition patterns, defining chemotypes and RNA motifs that confer selective, avid binding. The resulting interaction maps were mined against the entire viral genome of hepatitis C virus (HCV). A small molecule was identified that avidly bound RNA motifs present in the HCV 30 UTR and inhibited viral replication while having no effect on host cells. Collectively, this study represents the first whole-genome pattern recognition between small molecules and RNA folds.

PMID:
30719503
PMCID:
PMC6358276
[Available on 2019-10-11]
DOI:
10.1016/j.chempr.2018.08.003

Conflict of interest statement

DECLARATION OF INTERESTS Y.M. is an employee of Mitsubishi Tanabe Pharma Corporation, 3-2-10 Dosho-ma-chi, Chuo-ku, Osaka 541-8505, Japan. The other authors declare no competing interests.

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