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Nucleic Acids Research 2006 34(5):1305-1316; doi:10.1093/nar/gkl004
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Published online 6 March 2006

© The Author 2006. Published by Oxford University Press. All rights reserved
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org

Article

Inhibitory effects of archetypical nucleic acid ligands on the interactions of HIV-1 nucleocapsid protein with elements of {Psi}-RNA

Kevin B. Turner, Nathan A. Hagan and Daniele Fabris*

Department of Chemistry and Biochemistry, University of Maryland Baltimore County 1000 Hilltop Circle, Baltimore, MD 21228 USA

*To whom correspondence should be addressed. Tel: +1 410 455 3053; Fax: +1 410 455 2608; Email: fabris{at}umbc.edu

Received January 24, 2006. Revised February 10, 2006. Accepted February 10, 2006.

Disrupting the interactions between human immunodeficiency virus type 1 (HIV-1) nucleocapsid (NC) protein and structural elements of the packaging signal ({Psi}-RNA) could constitute an ideal strategy to inhibit the functions of this region of the genome leader in the virus life cycle. We have employed electrospray ionization (ESI) Fourier transform mass spectrometry (FTMS) to assess the ability of a series of nucleic acid ligands to bind selected structures of {Psi}-RNA and inhibit their specific interactions with NC in vitro. We found that the majority of the ligands included in the study were able to form stable non-covalent complexes with stem–loop 2, 3 and 4 (SL2–4), consistent with their characteristic nucleic acid binding modes. However, only aminoglycosidic antibiotics were capable of dissociating preformed NC•SL3 and NC•SL4 complexes, but not NC•SL2. The apparent specificity of these inhibitory effects is closely dependent on distinctive structural features of the different NC•RNA complexes. The trends observed for the IC50 values correlate very well with those provided by the ligand binding affinities and the dissociation constants of target NC•RNA complexes. This systematic investigation of archetypical nucleic acid ligands provides a valid framework to support the design of novel ligand inhibitors for HIV-1 treatment.


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K. B. Turner, R. G. Brinson, H. Y. Yi-Brunozzi, J. W. Rausch, J. T. Miller, S. F.J. Le Grice, J. P. Marino, and D. Fabris
Structural probing of the HIV-1 polypurine tract RNA:DNA hybrid using classic nucleic acid ligands
Nucleic Acids Res., May 1, 2008; 36(8): 2799 - 2810.
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