Bacterial RNase P RNA is a drug target for aminoglycoside-arginine conjugates

Bioconjugate Chemistry
Alexander Berchanski, Aviva Lapidot

Abstract

The ribonuclease P (RNase P) holoenzymes are RNPs composed of RNase P RNA (PRNA) and a variable number of P protein subunits. Primary differences in structure and function between bacterial and eukaryotic RNase P and its indispensability for cell viability make the bacterial enzyme an attractive drug target. On the basis of our previous studies, aminoglycoside-arginine conjugates (AACs) bind to HIV-1 TAR and Rev responsive element (RRE) RNAs significantly more efficiently than neomycin B. Their specific inhibition of bacterial rRNA as well as the findings that the hexa-arginine neomycin derivative (NeoR6) is 500-fold more potent than neomycin B in inhibiting bacterial RNase P, led us to explore the structure-function relationships of AACs in comparison to a new set of aminoglycoside-polyarginine conjugates (APACs). We here present predicted binding modes of AACs and APACs to PRNA. We used a multistep docking approach comprising rigid docking full scans and final refinement of the obtained complexes. Our docking results suggest three possible mechanisms of RNase P inhibition by AACs and APACs: competition with the P protein and pre-tRNA on binding to P1-P4 multihelix junction and to J19/4 region (probably including displacement ...Continue Reading

References

Jul 15, 1991·Proceedings of the National Academy of Sciences of the United States of America·U DellingN Sonenberg
Sep 14, 1990·Science·K M WeeksD M Crothers
Apr 15, 1993·Proceedings of the National Academy of Sciences of the United States of America·J D PuglisiJ R Williamson
Dec 19, 1995·Proceedings of the National Academy of Sciences of the United States of America·T PanK Zhong
May 26, 1999·Proceedings of the National Academy of Sciences of the United States of America·N E MikkelsenL A Kirsebom
Aug 26, 1999·Drug Discovery Today·D J Ecker, R H Griffey
Apr 5, 2000·The Journal of Biological Chemistry·C FaberP Rösch
Jan 10, 2001·The Journal of Organic Chemistry·T J BakerM Goodman
May 25, 2001·Nature Structural Biology·N E MikkelsenL A Kirsebom
Aug 10, 2001·Current Opinion in Structural Biology·A C ChengA D Frankel
Oct 5, 2001·Methods in Enzymology·T A Hall, J W Brown
Oct 17, 2001·Accounts of Chemical Research·J Gallego, G Varani
Feb 1, 2002·FEBS Letters·Timothy D EubankVenkat Gopalan
Feb 16, 2002·Protein Science : a Publication of the Protein Society·Alexander HeifetzMiriam Eisenstein
Oct 31, 2002·RNA·Marjolaine CarriereJerry Pelletier
Jan 1, 2003·Journal of Molecular Biology·Hsin-Yue TsaiVenkat Gopalan
Jun 12, 2003·Proceedings of the National Academy of Sciences of the United States of America·Alexei V KazantsevNorman R Pace
Oct 3, 2003·Chembiochem : a European Journal of Chemical Biology·Dagmar K WillkommRoland K Hartmann
Dec 4, 2003·Biochemical and Biophysical Research Communications·Gadi BorkowAviva Lapidot
May 27, 2004·Proteins·Alexander BerchanskiMiriam Eisenstein
Jan 13, 2005·Journal of Molecular Biology·Nathan H ZahlerMichael E Harris
Mar 22, 2005·Current Drug Targets. Infectious Disorders·G Borkow, A Lapidot
Aug 23, 2005·Nature·Alfredo Torres-LariosAlfonso Mondragón
Sep 15, 2005·Proceedings of the National Academy of Sciences of the United States of America·Alexei V KazantsevNorman R Pace
Sep 16, 2005·The EMBO Journal·Amy H BuckNorman R Pace
Apr 6, 2006·Critical Reviews in Biochemistry and Molecular Biology·Scott C Walker, David R Engelke

❮ Previous
Next ❯

Citations

Jan 1, 2010·Future Medicinal Chemistry·Fareed Aboul-ela
Dec 31, 2014·International Journal of Molecular Sciences·Shaileja Chopra, John Reader
Jan 23, 2015·Metallomics : Integrated Biometal Science·Annika GrossNils Metzler-Nolte
Oct 4, 2018·Acta Crystallographica. Section F, Structural Biology Communications·Lisha HaDaniel P Flaherty
Jul 4, 2012·Chembiochem : a European Journal of Chemical Biology·Shuang GaoZhen Xi
Jun 17, 2020·Chemistry : a European Journal·Klara AradiMaria Duca

❮ Previous
Next ❯

Related Concepts

Related Feeds

Aminoglycosides (ASM)

Aminoglycoside is a medicinal and bacteriologic category of traditional Gram-negative antibacterial medications that inhibit protein synthesis and contain as a portion of the molecule an amino-modified glycoside. Discover the latest research on aminoglycoside here.

Aminoglycosides

Aminoglycoside is a medicinal and bacteriologic category of traditional Gram-negative antibacterial medications that inhibit protein synthesis and contain as a portion of the molecule an amino-modified glycoside. Discover the latest research on aminoglycoside here.