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Discovery of Small Molecules that Target a Tertiary-Structured RNA

Menichelli, Elena, Lam, Bianca J., Wang, Yu, Wang, Vivian S., Shaffer, Jennifer, Tjhung, Katrina F., Bursulaya, Badry, Nguyen, Truc, Vo, Michael, Alper, Phillip, McAllister, Christopher, Jones, David, Spraggon, Glen, Michellys, Pierre-Yves, Joslin, John, Joyce, Gerald F. and Rogers, Jeff (2022) Discovery of Small Molecules that Target a Tertiary-Structured RNA. Proceedings of the National Academy of Sciences of the United States of America PNAS., 119 (48). ISSN 0027-8424


There is growing interest in therapeutic intervention that targets disease-relevant RNAs using
small molecules. While there have been some successes in RNA-targeted small molecule
discovery, a deeper understanding of structure-activity relationships in pursuing these targets has
remained elusive. One of the best studied tertiary-structured RNAs is the theophylline aptamer,
which binds theophylline with high affinity and selectivity. Although not a drug target, this
aptamer has had many applications, especially pertaining to genetic control circuits. Heretofore,
no compound has been shown to bind the theophylline aptamer with greater affinity than
theophylline itself. However, by carrying out a high-throughput screen of low molecular weight
compounds, several unique hits were identified that are chemically distinct from theophylline
and bind with up to 340-fold greater affinity. Multiple atomic-resolution X-ray crystal structures
were determined to investigate the binding mode of theophylline and four of the best hits. These
structures reveal both the rigidity of the theophylline aptamer binding pocket and the opportunity
for other ligands to bind more tightly in this pocket by forming additional hydrogen bonding
interactions. These results give encouragement that the same approaches to drug discovery that
have been applied so successfully to proteins can also be applied to RNAs.

Item Type: Article
Keywords: theophylline, aptamer, RNA structure, x-ray crystallography
Date Deposited: 10 Dec 2022 00:45
Last Modified: 10 Dec 2022 00:45


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