Rationally Targeted, Conformationally Constrained, Oxetane‐Modified Oligonucleotides Demonstrate Efficient Gene‐Silencing Activity in a Cellular System
Identifieur interne : 000F22 ( Istex/Corpus ); précédent : 000F21; suivant : 000F23Rationally Targeted, Conformationally Constrained, Oxetane‐Modified Oligonucleotides Demonstrate Efficient Gene‐Silencing Activity in a Cellular System
Auteurs : J B Opalinska ; A M GewirtzSource :
- Annals of the New York Academy of Sciences [ 0077-8923 ] ; 2005-11.
English descriptors
- Teeft :
- Antisense, Antisense oligodeoxynucleotides, Antisense oligonucleotides, Biologic activity, Cell lysates, Cellular system, Control cells, Dppz moiety, Duplex, Gene expression, Gewirtz, Hamster fibroblast cells, Hybrid duplex, Hybridization, Identical sequence, Invitrogen corporation, Large decrease, Mapping procedure, Modification, Molecule, Mrna, Mrna levels, Mrna target, Nuclease stability, Nucleic, Nucleic acid, Nucleic acids, Nucleoporation, Nucleoside, Oligonucleotides, Opalinska, Opalinska gewirtz, Oxetane, Oxetane molecules, Phosphorothioate, Protein expression, Pvdf membrane, Real time detection, Rnase, Same extent, Slot blot, Sqrm, Sqrm molecules, Thermodynamic stability, Transfected cells, York academy.
Abstract
Antisense oligodeoxynucleotides (AS ODN) have been employed as gene‐silencing agents in the laboratory and, in the clinic. The in vivo use of these molecules has been facilitated by chemical modifications to the DNA backbone which augment their nuclease stability. Attempts to further improve the efficacy of AS ODN have largely focused on 2′ alterations of the ribose sugar that make the molecules more RNA like in structure. This increases the Tm of formed DNA/RNA hybrids but simultaneously prevents binding of RNaseH which is important for ODN effectiveness. Herein, we demonstrate the use of AS ODN containing nucleosides with a novel oxetane (OXE) modification [oxetane, 1‐(1′, 3′‐O‐anhydro‐β‐D‐psicofuranosyl nucleosides)] which augments Tm, enhances nuclease stability, and is permissive of RNaseH activation. We also illustrate herein the value of rational targeting of OXE modified, and by analogy, AS ODN of any chemical modification.
Url:
DOI: 10.1196/annals.1359.007
Links to Exploration step
ISTEX:253B5542758C9179DA639680BFF5321715D693A7Le document en format XML
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Antisense and siRNA: Chemistry, Sequence Specificity, and Target Validation</title></titleGroup><eventGroup><event type="firstOnline" date="2006-01-22"></event><event type="publishedOnlineFinalForm" date="2006-01-22"></event><event type="xmlConverted" agent="Converter:BPG_TO_WML3G version:2.3.2 mode:FullText source:FullText result:FullText" date="2010-02-27"></event><event type="xmlConverted" agent="Converter:WILEY_ML3G_TO_WILEY_ML3GV2 version:4.0.1" date="2014-03-19"></event><event type="xmlConverted" agent="Converter:WML3G_To_WML3G version:4.1.7 mode:FullText,remove_FC" date="2014-10-14"></event></eventGroup><numberingGroup><numbering type="pageFirst" number="39">39</numbering><numbering type="pageLast" number="51">51</numbering></numberingGroup><correspondenceTo>Address for correspondence: J. B. Opalinska, Department of Hematology, Pomeranian Medical University, Konopnickiej 76/3, Unii Lubelskiej 1, Szczecin, Poland. Voice: 0048‐91‐4253349; fax: 0048‐91‐4253357; E‐mail: !<email>jopal@poczta.onet.pl</email></correspondenceTo><linkGroup><link type="toTypesetVersion" href="file:NYAS.NYAS39.pdf"></link></linkGroup></publicationMeta><contentMeta><countGroup><count type="figureTotal" number="7"></count><count type="tableTotal" number="0"></count><count type="formulaTotal" number="0"></count><count type="referenceTotal" number="28"></count><count type="linksCrossRef" number="40"></count></countGroup><titleGroup><title type="main">Rationally Targeted, Conformationally Constrained, Oxetane‐Modified Oligonucleotides Demonstrate Efficient Gene‐Silencing Activity in a Cellular System</title></titleGroup><creators><creator creatorRole="author" xml:id="cr1" affiliationRef="#a1" corresponding="yes"><personName><givenNames>J B</givenNames><familyName>OPALINSKA</familyName></personName></creator><creator creatorRole="author" xml:id="cr2" affiliationRef="#a2"><personName><givenNames>A M</givenNames><familyName>GEWIRTZ</familyName></personName></creator></creators><affiliationGroup><affiliation xml:id="a1" countryCode="PL"><unparsedAffiliation><sup>a</sup>Department of Hematology, Pomeranian Medical University, Szczecin, Poland</unparsedAffiliation></affiliation><affiliation xml:id="a2" countryCode="US"><unparsedAffiliation><sup>b</sup>Divison of Hematology/Oncology, Department of Medicine, and Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA</unparsedAffiliation></affiliation></affiliationGroup><keywordGroup xml:lang="en"><keyword xml:id="k1">antisense oligodeoxynucleotides</keyword><keyword xml:id="k2">oxetane</keyword><keyword xml:id="k3">c‐myb</keyword><keyword xml:id="k4">gene silencing</keyword><keyword xml:id="k5">rational targeting</keyword></keywordGroup><abstractGroup><abstract type="main" xml:lang="en"><p>Antisense oligodeoxynucleotides (AS ODN) have been employed as gene‐silencing agents in the laboratory and, in the clinic. The <i>in vivo</i> use of these molecules has been facilitated by chemical modifications to the DNA backbone which augment their nuclease stability. Attempts to further improve the efficacy of AS ODN have largely focused on 2′ alterations of the ribose sugar that make the molecules more RNA like in structure. This increases the T<sub>m</sub> of formed DNA/RNA hybrids but simultaneously prevents binding of RNaseH which is important for ODN effectiveness. Herein, we demonstrate the use of AS ODN containing nucleosides with a novel oxetane (OXE) modification [oxetane, 1‐(1′, 3′‐<i>O</i>‐anhydro‐β‐D‐psicofuranosyl nucleosides)] which augments Tm, enhances nuclease stability, and is permissive of RNaseH activation. We also illustrate herein the value of rational targeting of OXE modified, and by analogy, AS ODN of any chemical modification.</p></abstract></abstractGroup></contentMeta></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Rationally Targeted, Conformationally Constrained, Oxetane‐Modified Oligonucleotides Demonstrate Efficient Gene‐Silencing Activity in a Cellular System</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Rationally Targeted, Conformationally Constrained, Oxetane‐Modified Oligonucleotides Demonstrate Efficient Gene‐Silencing Activity in a Cellular System</title></titleInfo><name type="personal"><namePart type="given">J B</namePart><namePart type="family">OPALINSKA</namePart><affiliation>aDepartment of Hematology, Pomeranian Medical University, Szczecin, Poland</affiliation><affiliation>E-mail: jopal@poczta.onet.pl</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">A M</namePart><namePart type="family">GEWIRTZ</namePart><affiliation>bDivison of Hematology/Oncology, Department of Medicine, and Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="article" displayLabel="article" authority="ISTEX" authorityURI="https://content-type.data.istex.fr" valueURI="https://content-type.data.istex.fr/ark:/67375/XTP-6N5SZHKN-D">article</genre><originInfo><publisher>Blackwell Publishing Ltd</publisher><place><placeTerm type="text">Oxford, UK</placeTerm></place><dateIssued encoding="w3cdtf">2005-11</dateIssued><copyrightDate encoding="w3cdtf">2005</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><physicalDescription><extent unit="figures">7</extent><extent unit="tables">0</extent><extent unit="formulas">0</extent><extent unit="references">28</extent><extent unit="linksCrossRef">40</extent></physicalDescription><abstract lang="en">Antisense oligodeoxynucleotides (AS ODN) have been employed as gene‐silencing agents in the laboratory and, in the clinic. The in vivo use of these molecules has been facilitated by chemical modifications to the DNA backbone which augment their nuclease stability. Attempts to further improve the efficacy of AS ODN have largely focused on 2′ alterations of the ribose sugar that make the molecules more RNA like in structure. This increases the Tm of formed DNA/RNA hybrids but simultaneously prevents binding of RNaseH which is important for ODN effectiveness. Herein, we demonstrate the use of AS ODN containing nucleosides with a novel oxetane (OXE) modification [oxetane, 1‐(1′, 3′‐O‐anhydro‐β‐D‐psicofuranosyl nucleosides)] which augments Tm, enhances nuclease stability, and is permissive of RNaseH activation. 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