Is irrelevant cleavage the price of antisense efficacy?
Identifieur interne : 000530 ( Istex/Corpus ); précédent : 000529; suivant : 000531Is irrelevant cleavage the price of antisense efficacy?
Auteurs : C. A SteinSource :
- Pharmacology and Therapeutics [ 0163-7258 ] ; 2000.
English descriptors
- Teeft :
- Acid drug, Antisense, Antisense effect, Antisense oligomer, Antisense oligonucleotide, Antisense oligonucleotide technology, Antisense oligonucleotides, Biol chem, Cationic, Cationic lipids, Cleavage, Competency, Complementarity, Contiguous, Duplex, Gene expression, Globin, Globin mrna, Harlow, Harlow sequence, Intact cells, Irrelevant cleavage, Isis, Kinase, Methylphosphonate, Methylphosphonate linkages, Mrna, Mrna expression, Nucleic, Nucleic acids, Oligodeoxynucleotides, Oligomer, Oligonucleotide, Oligonucleotides, Pharmacology, Phosphodiester, Phosphorothioate, Proc natl acad, Protein kinase, Rnase, Stein pharmacology therapeutics, Tidd, Wheat germ, Xenopus oocytes.
Abstract
Abstract: Antisense oligonucleotides are useful reagents for the suppression of gene expression. Their mechanism of action in eukaryotic cells appears to depend heavily on the activity of RNase H, a ubiquitous enzyme that cleaves the mRNA strand of an RNA-DNA duplex. However, the stringency requirements of RNase H are very low, and as little as a 5-base complementary region of oligomer to target may be sufficient to elicit RNase H activity. This would result in scission of nontargeted mRNAs, or what is known as “irrelevant cleavage.” One strategy to reduce RNase H competency that has been employed is modification of the oligonucleotide backbone, replacing phosphodiester linkages with uncharged methylphosphonates, which are not RNase H competent. Another strategy involves replacement of deoxyribonucleic acid with 2′-O-alkylribonucleic acid. A third strategy, eliminating RNase H dependency entirely, requires activation of RNase P. The relative merits of these strategies will be discussed in the context of selective inhibition of gene function.
Url:
DOI: 10.1016/S0163-7258(99)00053-4
Links to Exploration step
ISTEX:C0170D2A7FD2FFAF32FE134230B031C38BB09102Le document en format XML
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A Stein</name><affiliation><mods:affiliation>Departments of Medicine and Pharmacology, Columbia University, College of Physicians and Surgeons, 630 W. 168 Street, New York, NY 10032, USA</mods:affiliation></affiliation><affiliation><mods:affiliation>Tel.: 212-305-3606; fax: 212-305-7348.(C.A. 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Their mechanism of action in eukaryotic cells appears to depend heavily on the activity of RNase H, a ubiquitous enzyme that cleaves the mRNA strand of an RNA-DNA duplex. However, the stringency requirements of RNase H are very low, and as little as a 5-base complementary region of oligomer to target may be sufficient to elicit RNase H activity. This would result in scission of nontargeted mRNAs, or what is known as “irrelevant cleavage.” One strategy to reduce RNase H competency that has been employed is modification of the oligonucleotide backbone, replacing phosphodiester linkages with uncharged methylphosphonates, which are not RNase H competent. Another strategy involves replacement of deoxyribonucleic acid with 2′-O-alkylribonucleic acid. A third strategy, eliminating RNase H dependency entirely, requires activation of RNase P. 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Their mechanism of action in eukaryotic cells appears to depend heavily on the activity of RNase H, a ubiquitous enzyme that cleaves the mRNA strand of an RNA-DNA duplex. However, the stringency requirements of RNase H are very low, and as little as a 5-base complementary region of oligomer to target may be sufficient to elicit RNase H activity. This would result in scission of nontargeted mRNAs, or what is known as “irrelevant cleavage.” One strategy to reduce RNase H competency that has been employed is modification of the oligonucleotide backbone, replacing phosphodiester linkages with uncharged methylphosphonates, which are not RNase H competent. Another strategy involves replacement of deoxyribonucleic acid with 2′-O-alkylribonucleic acid. A third strategy, eliminating RNase H dependency entirely, requires activation of RNase P. The relative merits of these strategies will be discussed in the context of selective inhibition of gene function.</p></abstract><textClass><keywords scheme="keyword"><list><head>Keywords</head><item><term>Antisense oligonucleotides</term></item><item><term>RNase H</term></item><item><term>Irrelevant cleavage</term></item><item><term>Backbone modifications</term></item></list></keywords></textClass><textClass><keywords scheme="keyword"><list><head>Abbreviations</head><item><term>EGS, external guide sequence</term></item><item><term>PKC, protein kinase C</term></item><item><term>Tm, melting temperature</term></item><item><term>tRNA, transfer RNA</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2000">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/ark:/67375/6H6-4H2NLQN8-9/fulltext.txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Elsevier, elements deleted: body; tail"><istex:xmlDeclaration>version="1.0" encoding="utf-8"</istex:xmlDeclaration><istex:docType PUBLIC="-//ES//DTD journal article DTD version 4.5.2//EN//XML" URI="art452.dtd" name="istex:docType"></istex:docType><istex:document><converted-article version="4.5.2" docsubtype="rev"><item-info><jid>JPT</jid><aid>5272</aid><ce:pii>S0163-7258(99)00053-4</ce:pii><ce:doi>10.1016/S0163-7258(99)00053-4</ce:doi><ce:copyright type="full-transfer" year="2000">Elsevier Science Inc.</ce:copyright></item-info><head><ce:dochead><ce:textfn>Review article</ce:textfn></ce:dochead><ce:title>Is irrelevant cleavage the price of antisense efficacy?</ce:title><ce:author-group><ce:author><ce:given-name>C.A</ce:given-name><ce:surname>Stein</ce:surname><ce:cross-ref refid="AFF1"><ce:sup>a</ce:sup></ce:cross-ref><ce:cross-ref refid="CORR1">*</ce:cross-ref><ce:e-address>stein@cuccfa.ccc.columbia.edu</ce:e-address></ce:author><ce:affiliation id="AFF1"><ce:label>a</ce:label><ce:textfn>Departments of Medicine and Pharmacology, Columbia University, College of Physicians and Surgeons, 630 W. 168 Street, New York, NY 10032, USA</ce:textfn></ce:affiliation><ce:correspondence id="CORR1"><ce:label>*</ce:label><ce:text>Tel.: 212-305-3606; fax: 212-305-7348.(C.A. Stein)</ce:text></ce:correspondence></ce:author-group><ce:abstract><ce:section-title>Abstract</ce:section-title><ce:abstract-sec><ce:simple-para>Antisense oligonucleotides are useful reagents for the suppression of gene expression. Their mechanism of action in eukaryotic cells appears to depend heavily on the activity of RNase H, a ubiquitous enzyme that cleaves the mRNA strand of an RNA-DNA duplex. However, the stringency requirements of RNase H are very low, and as little as a 5-base complementary region of oligomer to target may be sufficient to elicit RNase H activity. This would result in scission of nontargeted mRNAs, or what is known as “irrelevant cleavage.” One strategy to reduce RNase H competency that has been employed is modification of the oligonucleotide backbone, replacing phosphodiester linkages with uncharged methylphosphonates, which are not RNase H competent. Another strategy involves replacement of deoxyribonucleic acid with 2′-O-alkylribonucleic acid. A third strategy, eliminating RNase H dependency entirely, requires activation of RNase P. The relative merits of these strategies will be discussed in the context of selective inhibition of gene function.</ce:simple-para></ce:abstract-sec></ce:abstract><ce:keywords><ce:section-title>Keywords</ce:section-title><ce:keyword><ce:text>Antisense oligonucleotides</ce:text></ce:keyword><ce:keyword><ce:text>RNase H</ce:text></ce:keyword><ce:keyword><ce:text>Irrelevant cleavage</ce:text></ce:keyword><ce:keyword><ce:text>Backbone modifications</ce:text></ce:keyword></ce:keywords><ce:keywords class="abr"><ce:section-title>Abbreviations</ce:section-title><ce:keyword><ce:text>EGS, external guide sequence</ce:text></ce:keyword><ce:keyword><ce:text>PKC, protein kinase C</ce:text></ce:keyword><ce:keyword><ce:text><ce:italic>T</ce:italic><ce:inf>m</ce:inf>, melting temperature</ce:text></ce:keyword><ce:keyword><ce:text>tRNA, transfer RNA</ce:text></ce:keyword></ce:keywords></head></converted-article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Is irrelevant cleavage the price of antisense efficacy?</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Is irrelevant cleavage the price of antisense efficacy?</title></titleInfo><name type="personal"><namePart type="given">C.A</namePart><namePart type="family">Stein</namePart><affiliation>Departments of Medicine and Pharmacology, Columbia University, College of Physicians and Surgeons, 630 W. 168 Street, New York, NY 10032, USA</affiliation><affiliation>Tel.: 212-305-3606; fax: 212-305-7348.(C.A. Stein)</affiliation><affiliation>E-mail: stein@cuccfa.ccc.columbia.edu</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="review-article" displayLabel="Review article" authority="ISTEX" authorityURI="https://content-type.data.istex.fr" valueURI="https://content-type.data.istex.fr/ark:/67375/XTP-L5L7X3NF-P">review-article</genre><originInfo><publisher>ELSEVIER</publisher><dateIssued encoding="w3cdtf">2000</dateIssued><copyrightDate encoding="w3cdtf">2000</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><abstract lang="en">Abstract: Antisense oligonucleotides are useful reagents for the suppression of gene expression. Their mechanism of action in eukaryotic cells appears to depend heavily on the activity of RNase H, a ubiquitous enzyme that cleaves the mRNA strand of an RNA-DNA duplex. However, the stringency requirements of RNase H are very low, and as little as a 5-base complementary region of oligomer to target may be sufficient to elicit RNase H activity. This would result in scission of nontargeted mRNAs, or what is known as “irrelevant cleavage.” One strategy to reduce RNase H competency that has been employed is modification of the oligonucleotide backbone, replacing phosphodiester linkages with uncharged methylphosphonates, which are not RNase H competent. Another strategy involves replacement of deoxyribonucleic acid with 2′-O-alkylribonucleic acid. A third strategy, eliminating RNase H dependency entirely, requires activation of RNase P. The relative merits of these strategies will be discussed in the context of selective inhibition of gene function.</abstract><note type="content">Section title: Review article</note><subject><genre>Keywords</genre><topic>Antisense oligonucleotides</topic><topic>RNase H</topic><topic>Irrelevant cleavage</topic><topic>Backbone modifications</topic></subject><subject><genre>Abbreviations</genre><topic>EGS, external guide sequence</topic><topic>PKC, protein kinase C</topic><topic>Tm, melting temperature</topic><topic>tRNA, transfer RNA</topic></subject><relatedItem type="host"><titleInfo><title>Pharmacology and Therapeutics</title></titleInfo><titleInfo type="abbreviated"><title>JPT</title></titleInfo><genre type="journal" authority="ISTEX" authorityURI="https://publication-type.data.istex.fr" valueURI="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</genre><originInfo><publisher>ELSEVIER</publisher><dateIssued encoding="w3cdtf">2000</dateIssued></originInfo><identifier type="ISSN">0163-7258</identifier><identifier type="PII">S0163-7258(00)X0058-7</identifier><part><date>2000</date><detail type="volume"><number>85</number><caption>vol.</caption></detail><detail type="issue"><number>3</number><caption>no.</caption></detail><extent unit="issue-pages"><start>111</start><end>276</end></extent><extent unit="pages"><start>231</start><end>236</end></extent></part></relatedItem><identifier type="istex">C0170D2A7FD2FFAF32FE134230B031C38BB09102</identifier><identifier type="ark">ark:/67375/6H6-4H2NLQN8-9</identifier><identifier type="DOI">10.1016/S0163-7258(99)00053-4</identifier><identifier type="PII">S0163-7258(99)00053-4</identifier><accessCondition type="use and reproduction" contentType="copyright">©2000 Elsevier Science Inc.</accessCondition><recordInfo><recordContentSource authority="ISTEX" authorityURI="https://loaded-corpus.data.istex.fr" valueURI="https://loaded-corpus.data.istex.fr/ark:/67375/XBH-HKKZVM7B-M">elsevier</recordContentSource><recordOrigin>Elsevier Science Inc., ©2000</recordOrigin></recordInfo></mods><json:item><extension>json</extension><original>false</original><mimetype>application/json</mimetype><uri>https://api.istex.fr/ark:/67375/6H6-4H2NLQN8-9/record.json</uri></json:item></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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