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Crystal structure and improved antisense properties of 2'-O-(2-methoxyethyl)-RNA

Nature Structural Biology volume 6, pages 535–539 (1999)Cite this article

Abstract

2'-O-(2-Methoxyethyl)-RNA (MOE-RNA) is a nucleic acid analog with promising features for antisense applications. Compared with phosphorothioate DNA (PS-DNA), the MOE modification offers improved nuclease resistance, enhanced RNA affinity, improved cellular uptake and intestinal absorption, reduced toxicity and immune stimulation. The crystal structure of a fully modified MOE-RNA dodecamer duplex (CGCGAAUUCGCG) was determined at 1.7 Å resolution. In the majority of the MOE substituents, the torsion angle around the ethylene alkyl chain assumes a gauche conformation. The conformational preorganization of the MOE groups is consistent with the improved RNA affinity and the extensive hydration of the substituents could play a role in the improved cellular uptake of MOE-RNA. A specific hydration pattern that bridges substituent and phosphate oxygen atoms in the minor groove of MOE-RNA may explain its high nuclease resistance.

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Figure 1: Structure and stability of MOE-RNA and quality of the electron density.
Figure 2: Geometry and topology of the MOE-RNA duplex.
Figure 3: Conformational properties of the MOE substituents.
Figure 4: MOE-mediated hydration of residues with gauche and trans conformations around the ethyl bond of the 2'-O-substituent.

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Acknowledgements

This work was supported through a grant by the National Institutes of Health to M.E. We are indebted to Northwestern University Medical School for supporting structural research through the Macromolecular Crystallography and Biochemical Computation Resource and to the Northwestern Drug Discovery Program. We thank B. Ross and his group at Isis Pharmaceuticals Inc. for providing the phosphoramidites for the dodecamer synthesis and S.T. Wallace for technical assistance. Part of the data collections were performed at the DuPont-Northwestern-Dow Collaborative Access Team (DND-CAT) Synchrotron Research Center located at Sector 5 of the Advanced Photon Source at Argonne National Laboratory, Argonne, Illinois. DND-CAT is supported by the E.I. DuPont de Nemours & Co., The Dow Chemical Company, the U.S. National Science Foundation and the State of Illinois.

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Authors and Affiliations

  1. Department of Molecular Pharmacology and Biological Chemistry and The Drug Discovery Program, Northwestern University Medical School, Chicago, 60611, Illinois, USA

    Marianna Teplova, George Minasov, Valentina Tereshko & Martin Egli

  2. Department of Medicinal Chemistry, Isis Pharmaceuticals Inc., Carlsbad, 92008, California, USA

    Gopal B. Inamati, P. Dan Cook & Muthiah Manoharan

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  1. Marianna Teplova
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  2. George Minasov
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  7. Martin Egli
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Correspondence to Muthiah Manoharan or Martin Egli.

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Teplova, M., Minasov, G., Tereshko, V. et al. Crystal structure and improved antisense properties of 2'-O-(2-methoxyethyl)-RNA. Nat Struct Mol Biol 6, 535–539 (1999). https://doi.org/10.1038/9304

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