Unique gene-silencing and structural properties of 2'-fluoro-modified siRNAs - PubMed (original) (raw)

. 2011 Mar 1;50(10):2284-8.

doi: 10.1002/anie.201006519. Epub 2011 Jan 31.

Akin Akinc, Rajendra K Pandey, June Qin, Philipp Hadwiger, Matthias John, Kathy Mills, Klaus Charisse, Martin A Maier, Lubomir Nechev, Emily M Greene, Pradeep S Pallan, Eriks Rozners, Kallanthottathil G Rajeev, Martin Egli

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Unique gene-silencing and structural properties of 2'-fluoro-modified siRNAs

Muthiah Manoharan et al. Angew Chem Int Ed Engl. 2011.

No abstract available

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Figures

Figure 1

Figure 1

In vivo activities of 2′-F-modified siRNA and comparison relative to native RNA and other modifications. a) 2′-F-modified siRNA is approximately twice as potent as the unmodified siRNA in vivo. Mice (n = 5) received a single i.v. dose of LNP01-formulated siRNA A or siRNA B or PBS. FVII protein levels were measured from serum collected at the indicated time points post administration using a chromogenic assay (Coaset Factor VII, DiaPharma Group or Biophen FVII, Aniara Corp.). b) In vivo FVII gene silencing as a function of chemistries using siRNA sequences and chemical modifications described in Table 1.

Figure 2

Figure 2

In vitro activity of 2′-F- and 2′-_O_Me-modified and unmodified siRNAs in the FVII assay.

Figure 3

Figure 3

Differences in the minor groove hydration of a) RNA and b) 2′-F-RNA illustrated by the water structure at individual base-pair steps in the crystal structures of r(CCCCGGGG)]2[20] and [f(CGAAUUCG)]2 (this work). 2′-F atoms are colored in green, water molecules are gray spheres, and hydrogen bonds are thin solid lines.

Figure 4

Figure 4

Interactions between antisense RNA (magenta):mRNA (green) duplexes and Piwi protein. The models of the Piwi complexes with a) 2′-_O_-MOE RNA:RNA and b) 2′-F-RNA:RNA are based on the crystal structure of the protein from Archaeoglobus fulgidus (AfPiwi) bound to an siRNA-like duplex that mimics the 5′-end of a guide RNA strand bound to an overhanging target mRNA (PDB ID 2bgg).[25] The models were built by superimposing crystal structures of either 2′-_O_-MOE-RNA[22] or 2′-F-RNA (this work) onto the RNA duplex in the experimental crystal structure. Carbon atoms of 2′-_O_-MOE substituents are yellow, 2′-F atoms are green, 2′-oxygen atoms are red, and selected Piwi residues are labeled. A metal ion that anchors the 5′-nucleotide of the guide RNA is depicted as a red sphere. There are clashes between 2′-_O_-MOE substituents and protein atoms.

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