In collaboration with J. Schneekloth (NCI) we have subjected a number of riboswitches to high-throughput screening employing a library of immobilized compounds. This methodology has revealed several lead compounds that bind specifically to particular bacterial riboswitches. We determined co-crystal structures of these leads bound to the RNAs, and using the structures, designed second-generation compounds. Functional and structural analyses of these compounds in turn demonstrated how small perturbations in the structures of ligands can affect their mode of interaction with regulatory RNAs. Publications describing this work are in preparation.

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Budget End
Support Year
7
Fiscal Year
2018
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Indirect Cost
Name
U.S. National Heart Lung and Blood Inst
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Stagno, J R; Liu, Y; Bhandari, Y R et al. (2017) Structures of riboswitch RNA reaction states by mix-and-inject XFEL serial crystallography. Nature 541:242-246
Baird, Nathan J; Inglese, James; Ferré-D'Amaré, Adrian R (2015) Rapid RNA-ligand interaction analysis through high-information content conformational and stability landscapes. Nat Commun 6:8898
Warner, Katherine Deigan; Homan, Philip; Weeks, Kevin M et al. (2014) Validating fragment-based drug discovery for biological RNAs: lead fragments bind and remodel the TPP riboswitch specifically. Chem Biol 21:591-5
Baird, Nathan J; Ferré-D'Amaré, Adrian R (2014) Analysis of riboswitch structure and ligand binding using small-angle X-ray scattering (SAXS). Methods Mol Biol 1103:211-25
Posakony, Jeffrey J; Ferré-D'Amaré, Adrian R (2013) Glucosamine and glucosamine-6-phosphate derivatives: catalytic cofactor analogues for the glmS ribozyme. J Org Chem 78:4730-43
Ferre-D'Amare, Adrian R (2011) Use of a coenzyme by the glmS ribozyme-riboswitch suggests primordial expansion of RNA chemistry by small molecules. Philos Trans R Soc Lond B Biol Sci 366:2942-8
Deigan, Katherine E; Ferré-D'Amaré, Adrian R (2011) Riboswitches: discovery of drugs that target bacterial gene-regulatory RNAs. Acc Chem Res 44:1329-38