3Q61

3'-Fluoro Hexitol Nucleic Acid DNA Structure

Summary for 3Q61

• Entry DOI: 10.2210/pdb3q61/pdb
• Descriptor: DNA (5'-D(*GP*CP*GP*TP*AP*(F3H)P*AP*CP*GP*C)-3') (2 entities in total)
• Functional Keywords: a-form dna, 3'-fluoro hexitol nucleic acid, fhna, antisense oligonucleotides, dna
• Total number of polymer chains: 2
• Total formula weight: 6154.05

Authors

Seth, P.R.,Allerson, C.R.,Prakash, T.P.,Siwkowski, A.,Berdeja, A.,Yu, J.,Pallan, P.S.,Watt, A.T.,Gaus, H.,Bhat, B.,Egli, M.,Swayze, E.E. (deposition date: 2010-12-30, release date: 2012-01-18, Last modification date: 2023-09-13)

Primary citation

Egli, M.,Pallan, P.S.,Allerson, C.R.,Prakash, T.P.,Berdeja, A.,Yu, J.,Lee, S.,Watt, A.,Gaus, H.,Bhat, B.,Swayze, E.E.,Seth, P.P.
Synthesis, improved antisense activity and structural rationale for the divergent RNA affinities of 3'-fluoro hexitol nucleic acid (FHNA and Ara-FHNA) modified oligonucleotides.
J.Am.Chem.Soc., 133:16642-16649, 2011

PubMed Abstract: The synthesis, biophysical, structural, and biological properties of both isomers of 3'-fluoro hexitol nucleic acid (FHNA and Ara-FHNA) modified oligonucleotides are reported. Synthesis of the FHNA and Ara-FHNA thymine phosphoramidites was efficiently accomplished starting from known sugar precursors. Optimal RNA affinities were observed with a 3'-fluorine atom and nucleobase in a trans-diaxial orientation. The Ara-FHNA analog with an equatorial fluorine was found to be destabilizing. However, the magnitude of destabilization was sequence-dependent. Thus, the loss of stability is sharply reduced when Ara-FHNA residues were inserted at pyrimidine-purine (Py-Pu) steps compared to placement within a stretch of pyrimidines (Py-Py). Crystal structures of A-type DNA duplexes modified with either monomer provide a rationalization for the opposing stability effects and point to a steric origin of the destabilization caused by the Ara-FHNA analog. The sequence dependent effect can be explained by the formation of an internucleotide C-F···H-C pseudo hydrogen bond between F3' of Ara-FHNA and C8-H of the nucleobase from the 3'-adjacent adenosine that is absent at Py-Py steps. In animal experiments, FHNA-modified antisense oligonucleotides formulated in saline showed a potent downregulation of gene expression in liver tissue without producing hepatotoxicity. Our data establish FHNA as a useful modification for antisense therapeutics and also confirm the stabilizing influence of F(Py)···H-C(Pu) pseudo hydrogen bonds in nucleic acid structures.

PubMed: 21919455
DOI: 10.1021/ja207086x

Experimental method

X-RAY DIFFRACTION (1.56 Å)