Abstract

In the past year, two lines of research yielded publications. In collaboration with Dr. Piszczek (NHLBI Biophysics Core) we have determined best-practice methods for the analysis of riboswitch-small molecule interactions with the first-principles method isothermal calorimetry. In collaboration with Dr. Schneekloth (NCI) we have combined high-throughput small molecule screening, X-ray crystallography, and structure-guided design to create synthetic ligands for the bacterial PreQ1 riboswitch. This study produced lead compounds with biochemical activity to be elaborated further, and also yielded insights into the mechanism of action of this important bacterial gene-regulatory RNA.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAHL006150-08
Application #
10008813
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2019
Total Cost
Indirect Cost

  Institution

Name
National Heart, Lung, and Blood Institute
Department
Type
DUNS #
City
State
Country
Zip Code

  Publications

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