SHAPE-enabled fragment-based ligand discovery for RNA

Author:

Zeller Meredith J.1,Favorov Oleg2ORCID,Li Kelin3ORCID,Nuthanakanti Ashok4ORCID,Hussein Dina5ORCID,Michaud Auréliane5ORCID,Lafontaine Daniel A.5ORCID,Busan Steven1,Serganov Alexander4,Aubé Jeffrey13,Weeks Kevin M.1ORCID

Affiliation:

1. Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599

2. Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599

3. Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599

4. Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016

5. Department of Biology, Faculty of Science, RNA Group, Université de Sherbrooke, Sherbrooke, J1K 2R1, QC, Canada

Abstract

Significance RNA molecules encode proteins and play numerous regulatory roles in cells. Targeting RNA with small molecules, as is routine with proteins, would create broad opportunities for modulating biology and creating new drugs. However, this opportunity has been difficult to realize because creating novel small molecules that bind RNA, especially using modest resources, is challenging. This study integrates two widely used technologies, SHAPE chemical probing of RNA and fragment-based ligand discovery, to craft an innovative strategy for creating small molecules that bind to and modulate the activity of a structured RNA. The anticipated impact is high because the methods are simple, can be implemented in diverse research and discovery contexts, and lead to realistic druglike molecules.

Funder

HHS | National Institutes of Health

Gouvernement du Canada | Canadian Institutes of Health Research

Lineberger Comprehensive Cancer Center, UNC

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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