RNA-targeted therapeutics: prospects and promise

Swayze, Eric E.; Griffey, Richard H.

doi:10.1517/13543776.12.9.1367

Cited by 4 publications

(1 citation statement)

References 34 publications

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“…The increasing realization of the essential roles of RNA in many biological processes and in the progression of diseases makes RNA an attractive target in drug discovery. The search for small organic molecules that interact with RNA is therefore drawing growing interest for drug discovery. − There are many potential RNA targets, including RNA that is involved in cellular protein interactions such as transcription, splicing, and translation, and RNA that is involved in viral infection such as human immunodeficiency virus (HIV) Rev response element (RRE), the trans-activation responsive element (Tar), and the hepatitis C-virus internal ribosome entry site (IRES) RNA . The recently solved crystal structures of the ribosome − and other cellular and viral RNA motifs open up numerous opportunities for the discovery of small molecules that modulate RNA functions.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Aminoglycoside Mimetics by NMR-Based Screening of Escherichia coli A-site RNA

Oost

Schkeryantz

et al. 2003

J. Am. Chem. Soc.

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A method is described for the NMR-based screening for the discovery of aminoglycoside mimetics that bind to Escherichia coli A-site RNA. Although aminoglycosides are clinically useful, they exhibit high nephrotoxicity and ototoxicity, and their overuse has led to the development of resistance to important microbial pathogens. To identify a new series of aminoglycoside mimetics that could potentially overcome the problems associated with toxicities and resistance development observed with the aminoglycosides, we have prepared large quantities of E. coli 16 S A-site RNA and conducted an NMR-based screening of our compound library in search for small-molecule RNA binders against this RNA target. From these studies, several classes of compounds were identified as initial hits with binding affinities in the range of 70 microM to 3 mM. Lead optimization through synthetic modifications of these initial hits led to the discovery of several small-molecule aminoglycoside mimetics that are structurally very different from the known aminoglycosides. Structural models of the A-site RNA/ligand complexes were prepared and compared to the three-dimensional structures of the RNA/aminoglycoside complexes.

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