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Nucleic Acids Research Advance Access originally published online on February 6, 2007
Nucleic Acids Research 2007 35(5):1441-1451; doi:10.1093/nar/gkl1153
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Nucleic Acids Research, 2007, Vol. 35, No. 5 1441-1451
© 2007 The Author(s).
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Chemistry

2'-Fluoro-4'-thioarabino-modified oligonucleotides: conformational switches linked to siRNA activity

Jonathan K. Watts1, Niloufar Choubdar2, Kashinath Sadalapure2, Francis Robert3, Alexander S. Wahba1, Jerry Pelletier3, B. Mario Pinto2 and Masad J. Damha1,*

1Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC, Canada H3A 2K6, 2Department of Chemistry, Simon Fraser University, Burnaby, BC, Canada V5A 1S6 and 3Department of Biochemistry and McGill Cancer Center, McIntyre Medical Sciences Building, McGill University, Montreal, QC, Canada H3G 1Y6

*To whom correspondence should be addressed. Tel: +(514) 398-7552; Fax: +(514) 398-3797; Email: masad.damha{at}mcgill.ca Correspondence may also be addressed to B. Mario Pinto. Tel: +(604) 291-4152; Fax: +(604) 291-4860; Email: bpinto{at}sfu.ca

Received October 15, 2006. Revised December 15, 2006. Accepted December 18, 2006.

The synthesis of oligonucleotides containing 2'-deoxy-2'-fluoro-4'-thioarabinonucleotides is described. 2'-Deoxy-2'-fluoro-5-methyl-4'-thioarabinouridine (4'S-FMAU) was incorporated into 18-mer antisense oligonucleotides (AONs). 4'S-FMAU adopts a predominantly northern sugar conformation. Oligonucleotides containing 4'S-FMAU, unlike those containing FMAU, were unable to elicit E. coli or human RNase H activity, thus corroborating the hypothesis that RNase H prefers duplexes containing oligonucleotides that can adopt eastern conformations in the antisense strand. The duplex structure and stability of these oligonucleotides was also investigated via circular dichroism (CD)- and UV- binding studies. Replacement of the 4'-oxygen by a sulfur atom resulted in a marked decrease in melting temperature of AON:RNA as well as AON:DNA duplexes. 2'-Deoxy-2'-fluoro-4'-thioarabinouridine (4'S-FAU) was incorporated into 21-mer small interfering RNA (siRNA) and the resulting siRNA molecules were able to trigger RNA interference with good efficiency. Positional effects were explored, and synergy with 2'F-ANA, which has been previously established as a functional siRNA modification, was demonstrated.


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C. G. Peng and M. J. Damha
G-quadruplex induced stabilization by 2'-deoxy-2'-fluoro-D-arabinonucleic acids (2'F-ANA)
Nucleic Acids Res., August 1, 2007; 35(15): 4977 - 4988.
[Abstract] [Full Text] [PDF]


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