Is irrelevant cleavage the price of antisense efficacy?
Identifieur interne : 003654 ( Main/Exploration ); précédent : 003653; suivant : 003655Is irrelevant cleavage the price of antisense efficacy?
Auteurs : C. A Stein [États-Unis]Source :
- 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
Affiliations:
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A" last="Stein">C. A Stein</name><affiliation wicri:level="4"><country xml:lang="fr">États-Unis</country><wicri:regionArea>Departments of Medicine and Pharmacology, Columbia University, College of Physicians and Surgeons, 630 W. 168 Street, New York, NY 10032</wicri:regionArea><orgName type="university">Université Columbia</orgName><placeName><settlement type="city">New York</settlement><region type="state">État de New York</region></placeName></affiliation><affiliation></affiliation><affiliation wicri:level="1"><country wicri:rule="url">États-Unis</country></affiliation></author></analytic><monogr></monogr><series><title level="j">Pharmacology and Therapeutics</title><title level="j" type="abbrev">JPT</title><idno type="ISSN">0163-7258</idno><imprint><publisher>ELSEVIER</publisher><date type="published" when="2000">2000</date><biblScope unit="volume">85</biblScope><biblScope unit="issue">3</biblScope><biblScope unit="page" from="231">231</biblScope><biblScope unit="page" to="236">236</biblScope></imprint><idno type="ISSN">0163-7258</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0163-7258</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="Teeft" xml:lang="en"><term>Acid drug</term><term>Antisense</term><term>Antisense effect</term><term>Antisense oligomer</term><term>Antisense oligonucleotide</term><term>Antisense oligonucleotide technology</term><term>Antisense oligonucleotides</term><term>Biol chem</term><term>Cationic</term><term>Cationic lipids</term><term>Cleavage</term><term>Competency</term><term>Complementarity</term><term>Contiguous</term><term>Duplex</term><term>Gene expression</term><term>Globin</term><term>Globin mrna</term><term>Harlow</term><term>Harlow sequence</term><term>Intact cells</term><term>Irrelevant cleavage</term><term>Isis</term><term>Kinase</term><term>Methylphosphonate</term><term>Methylphosphonate linkages</term><term>Mrna</term><term>Mrna expression</term><term>Nucleic</term><term>Nucleic acids</term><term>Oligodeoxynucleotides</term><term>Oligomer</term><term>Oligonucleotide</term><term>Oligonucleotides</term><term>Pharmacology</term><term>Phosphodiester</term><term>Phosphorothioate</term><term>Proc natl acad</term><term>Protein kinase</term><term>Rnase</term><term>Stein pharmacology therapeutics</term><term>Tidd</term><term>Wheat germ</term><term>Xenopus oocytes</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml: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.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>État de New York</li></region><settlement><li>New York</li></settlement><orgName><li>Université Columbia</li></orgName></list><tree><country name="États-Unis"><region name="État de New York"><name sortKey="Stein, C A" sort="Stein, C A" uniqKey="Stein C" first="C. A" last="Stein">C. A Stein</name></region><name sortKey="Stein, C A" sort="Stein, C A" uniqKey="Stein C" first="C. A" last="Stein">C. A Stein</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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