Crystal structure and improved antisense properties of 2'- O -(2-methoxyethyl)-RNA
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, re...
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| Veröffentlicht in: | Nature Structural Biology 1999-06, Vol.6 (6), p.535-539 |
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| container_title | Nature Structural Biology |
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| creator | Manoharan, Muthiah Egli, Martin Teplova, Marianna Minasov, George Tereshko, Valentina Inamati, Gopal B Cook, P. Dan |
| description | 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. |
| doi_str_mv | 10.1038/9304 |
| format | Article |
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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.</description><identifier>ISSN: 1072-8368</identifier><identifier>EISSN: 2331-365X</identifier><identifier>EISSN: 1545-9985</identifier><identifier>DOI: 10.1038/9304</identifier><identifier>PMID: 10360355</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>Base Pairing ; Base Sequence ; Biochemistry ; Biological Microscopy ; Biomedical and Life Sciences ; Crystallization ; Crystallography, X-Ray ; Drug Design ; Ethylenes - chemistry ; Ethylenes - metabolism ; Hydrogen Bonding ; letter ; Life Sciences ; Membrane Biology ; Models, Molecular ; Nucleic Acid Conformation ; Oligoribonucleotides ; Oxygen - metabolism ; Phosphates - metabolism ; Protein Structure ; RNA, Antisense - chemistry ; RNA, Antisense - genetics ; RNA, Antisense - metabolism ; RNA, Antisense - therapeutic use ; Structure-Activity Relationship ; Water - metabolism</subject><ispartof>Nature Structural Biology, 1999-06, Vol.6 (6), p.535-539</ispartof><rights>Nature America Inc. 1999</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c395t-8c4484d0e29af307a43b0be3973f3fecf2edf63721784a5c29395647a00520f3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/9304$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/9304$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,778,782,27907,27908,41471,42540,51302</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10360355$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Manoharan, Muthiah</creatorcontrib><creatorcontrib>Egli, Martin</creatorcontrib><creatorcontrib>Teplova, Marianna</creatorcontrib><creatorcontrib>Minasov, George</creatorcontrib><creatorcontrib>Tereshko, Valentina</creatorcontrib><creatorcontrib>Inamati, Gopal B</creatorcontrib><creatorcontrib>Cook, P. Dan</creatorcontrib><title>Crystal structure and improved antisense properties of 2'- O -(2-methoxyethyl)-RNA</title><title>Nature Structural Biology</title><addtitle>Nat Struct Mol Biol</addtitle><addtitle>Nat Struct Biol</addtitle><description>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.</description><subject>Base Pairing</subject><subject>Base Sequence</subject><subject>Biochemistry</subject><subject>Biological Microscopy</subject><subject>Biomedical and Life Sciences</subject><subject>Crystallization</subject><subject>Crystallography, X-Ray</subject><subject>Drug Design</subject><subject>Ethylenes - chemistry</subject><subject>Ethylenes - metabolism</subject><subject>Hydrogen Bonding</subject><subject>letter</subject><subject>Life Sciences</subject><subject>Membrane Biology</subject><subject>Models, Molecular</subject><subject>Nucleic Acid Conformation</subject><subject>Oligoribonucleotides</subject><subject>Oxygen - metabolism</subject><subject>Phosphates - metabolism</subject><subject>Protein Structure</subject><subject>RNA, Antisense - chemistry</subject><subject>RNA, Antisense - genetics</subject><subject>RNA, Antisense - metabolism</subject><subject>RNA, Antisense - therapeutic use</subject><subject>Structure-Activity Relationship</subject><subject>Water - metabolism</subject><issn>1072-8368</issn><issn>2331-365X</issn><issn>1545-9985</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1999</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kMtOwzAQRS0EoqXlF1BY8FoYHI-dxMuq4iVVVKq6YBc5yQRS5VFsB5G_x1ULmxnNzJmrq0vINGT3IYPkQQETR2TMAUIKkXw_JuOQxZwmECUjcmbthrFQCKZOycg_RAykHJPV3AzW6TqwzvS56w0Gui2Cqtma7hsLP7jKYmsx8IstGlehDboy4Dc0WAb0ltMG3Wf3M_g61Hd09TabkpNS1xbPD31C1k-P6_kLXSyfX-ezBc1BSUeTXIhEFAy50iWwWAvIWIagYiihxLzkWJQRxDyME6FlzpV_i0SsGZOclTAh13tZb-yrR-vSprI51rVusettGsZcqkSEHrw4gH3WYJFuTdVoM6R_IXjgag9Yf2o_0KSbrjet9-6ZHZaku3A9d7nnWr0L6l-otRmLlEolSPgF84xyJQ</recordid><startdate>19990601</startdate><enddate>19990601</enddate><creator>Manoharan, Muthiah</creator><creator>Egli, Martin</creator><creator>Teplova, Marianna</creator><creator>Minasov, George</creator><creator>Tereshko, Valentina</creator><creator>Inamati, Gopal B</creator><creator>Cook, P. 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Dan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Crystal structure and improved antisense properties of 2'- O -(2-methoxyethyl)-RNA</atitle><jtitle>Nature Structural Biology</jtitle><stitle>Nat Struct Mol Biol</stitle><addtitle>Nat Struct Biol</addtitle><date>1999-06-01</date><risdate>1999</risdate><volume>6</volume><issue>6</issue><spage>535</spage><epage>539</epage><pages>535-539</pages><issn>1072-8368</issn><eissn>2331-365X</eissn><eissn>1545-9985</eissn><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.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>10360355</pmid><doi>10.1038/9304</doi><tpages>5</tpages></addata></record> |
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| subjects | Base Pairing Base Sequence Biochemistry Biological Microscopy Biomedical and Life Sciences Crystallization Crystallography, X-Ray Drug Design Ethylenes - chemistry Ethylenes - metabolism Hydrogen Bonding letter Life Sciences Membrane Biology Models, Molecular Nucleic Acid Conformation Oligoribonucleotides Oxygen - metabolism Phosphates - metabolism Protein Structure RNA, Antisense - chemistry RNA, Antisense - genetics RNA, Antisense - metabolism RNA, Antisense - therapeutic use Structure-Activity Relationship Water - metabolism |
| title | Crystal structure and improved antisense properties of 2'- O -(2-methoxyethyl)-RNA |
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