Terminally modified, short phosphorothioate oligonucleotides as inhibitors of gene expression in cells.
Identifieur interne : 001A61 ( Main/Exploration ); précédent : 001A60; suivant : 001A62Terminally modified, short phosphorothioate oligonucleotides as inhibitors of gene expression in cells.
Auteurs : Paul Marzenell [Allemagne] ; Helen Hagen [Allemagne] ; Jenny Blechinger [Allemagne] ; Holger Erfle [Allemagne] ; Andriy Mokhir [Allemagne]Source :
- Bioorganic & medicinal chemistry letters [ 1464-3405 ] ; 2014.
Descripteurs français
- KwdFr :
- ARN messager (antagonistes et inhibiteurs), ARN messager (génétique), Cellules HeLa, Expression des gènes (), Expression des gènes (génétique), Humains, Oligonucléotides phosphorothioates (), Oligonucléotides phosphorothioates (pharmacologie), Oligonucléotides phosphorothioates (synthèse chimique), Protéines luminescentes (antagonistes et inhibiteurs), Protéines luminescentes (génétique), Relation dose-effet des médicaments, Relation structure-activité, Structure moléculaire.
- MESH :
- antagonistes et inhibiteurs : ARN messager, Protéines luminescentes.
- génétique : ARN messager, Expression des gènes, Protéines luminescentes.
- pharmacologie : Oligonucléotides phosphorothioates.
- synthèse chimique : Oligonucléotides phosphorothioates.
- Cellules HeLa, Expression des gènes, Humains, Oligonucléotides phosphorothioates, Relation dose-effet des médicaments, Relation structure-activité, Structure moléculaire.
English descriptors
- KwdEn :
- Dose-Response Relationship, Drug, Gene Expression (drug effects), Gene Expression (genetics), HeLa Cells, Humans, Luminescent Proteins (antagonists & inhibitors), Luminescent Proteins (genetics), Molecular Structure, Phosphorothioate Oligonucleotides (chemical synthesis), Phosphorothioate Oligonucleotides (chemistry), Phosphorothioate Oligonucleotides (pharmacology), RNA, Messenger (antagonists & inhibitors), RNA, Messenger (genetics), Structure-Activity Relationship.
- MESH :
- chemical , antagonists & inhibitors : Luminescent Proteins, RNA, Messenger.
- chemical , chemical synthesis : Phosphorothioate Oligonucleotides.
- chemical , chemistry : Phosphorothioate Oligonucleotides.
- drug effects : Gene Expression.
- genetics : Gene Expression, Luminescent Proteins, RNA, Messenger.
- chemical , pharmacology : Phosphorothioate Oligonucleotides.
- Dose-Response Relationship, Drug, HeLa Cells, Humans, Molecular Structure, Structure-Activity Relationship.
Abstract
Phosphorothioates are excellent antisense inhibitors, which are active both in cells and in vivo. Since their affinity to complementary ribonucleic acids is rather low, long strands (⩾20-mers) are typically required to achieve the desired biological activity. However, mismatch discrimination of long inhibitors is reduced. In contrast, shorter phosphorothioates exhibit better sequence specificity, but have in most cases too low affinity for practical applications in cells. We screened a range of terminal modifiers of a 14-mer phosphorothioate sequence, which is complementary to mRNA of a representative gene, whose protein product is fluorescent (DsRed2) and easy to monitor in cells. We found that optimal combinations of 5'- and 3'-modifications include 5'-trimethoxystilbene with 3'-uracil(anthraquinone)-cap, 5'-chloic acid derivative with 3'-uracyl(anthraquinone)-cap and 5'-cholic acid derivative with three 3'-LNA moieties. In contrast to the LNA, stabilizing and activity-enhancing effects of other mentioned modifiers for PTO/RNA duplexes have not been previously reported. We observed that the 14-mer inhibitor carrying 5'-cholic acid derivative with three 3'-LNA moieties inhibits expression of DsRed2 in cells stronger than the unmodified 21-mer. Mismatch discrimination of this inhibitor was found to be comparable to that of the unmodified 14-mer.
DOI: 10.1016/j.bmcl.2014.08.027
PubMed: 25176331
Affiliations:
- Allemagne
- Bade-Wurtemberg, Bavière, District de Karlsruhe, District de Moyenne-Franconie
- Erlangen, Heidelberg
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Le document en format XML
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xml:lang="fr">Allemagne</country><wicri:regionArea>Friedrich-Alexander University of Erlangen-Nürnberg, Department of Chemistry and Pharmacy, Organic Chemistry II, Henkestr. 42, 91054 Erlangen, Germany; Ruprecht-Karls University of Heidelberg, Institute of Inorganic Chemistry, Im Neuenheimer Feld 270, 69120 Heidelberg</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Karlsruhe</region><settlement type="city">Heidelberg</settlement></placeName></affiliation></author><author><name sortKey="Hagen, Helen" sort="Hagen, Helen" uniqKey="Hagen H" first="Helen" last="Hagen">Helen Hagen</name><affiliation wicri:level="3"><nlm:affiliation>Ruprecht-Karls University of Heidelberg, Institute of Inorganic Chemistry, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Ruprecht-Karls University of Heidelberg, Institute of Inorganic Chemistry, Im 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University of Erlangen-Nürnberg, Department of Chemistry and Pharmacy, Organic Chemistry II, Henkestr. 42, 91054 Erlangen, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Friedrich-Alexander University of Erlangen-Nürnberg, Department of Chemistry and Pharmacy, Organic Chemistry II, Henkestr. 42, 91054 Erlangen</wicri:regionArea><wicri:noRegion>91054 Erlangen</wicri:noRegion><placeName><settlement type="city">Erlangen</settlement><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Moyenne-Franconie</region></placeName></affiliation></author></analytic><series><title level="j">Bioorganic & medicinal chemistry letters</title><idno type="eISSN">1464-3405</idno><imprint><date when="2014" type="published">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Dose-Response Relationship, Drug</term><term>Gene Expression (drug effects)</term><term>Gene Expression (genetics)</term><term>HeLa Cells</term><term>Humans</term><term>Luminescent Proteins (antagonists & inhibitors)</term><term>Luminescent Proteins (genetics)</term><term>Molecular Structure</term><term>Phosphorothioate Oligonucleotides (chemical synthesis)</term><term>Phosphorothioate Oligonucleotides (chemistry)</term><term>Phosphorothioate Oligonucleotides (pharmacology)</term><term>RNA, Messenger (antagonists & inhibitors)</term><term>RNA, Messenger (genetics)</term><term>Structure-Activity Relationship</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>ARN messager (antagonistes et inhibiteurs)</term><term>ARN messager (génétique)</term><term>Cellules HeLa</term><term>Expression des gènes ()</term><term>Expression des gènes (génétique)</term><term>Humains</term><term>Oligonucléotides phosphorothioates ()</term><term>Oligonucléotides phosphorothioates (pharmacologie)</term><term>Oligonucléotides phosphorothioates (synthèse chimique)</term><term>Protéines luminescentes (antagonistes et inhibiteurs)</term><term>Protéines luminescentes (génétique)</term><term>Relation dose-effet des médicaments</term><term>Relation structure-activité</term><term>Structure moléculaire</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Luminescent Proteins</term><term>RNA, Messenger</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemical synthesis" xml:lang="en"><term>Phosphorothioate Oligonucleotides</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Phosphorothioate Oligonucleotides</term></keywords><keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>ARN messager</term><term>Protéines luminescentes</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Gene Expression</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Gene Expression</term><term>Luminescent Proteins</term><term>RNA, Messenger</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>ARN messager</term><term>Expression des gènes</term><term>Protéines luminescentes</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Oligonucléotides phosphorothioates</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Phosphorothioate Oligonucleotides</term></keywords><keywords scheme="MESH" qualifier="synthèse chimique" xml:lang="fr"><term>Oligonucléotides phosphorothioates</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Dose-Response Relationship, Drug</term><term>HeLa Cells</term><term>Humans</term><term>Molecular Structure</term><term>Structure-Activity Relationship</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Cellules HeLa</term><term>Expression des gènes</term><term>Humains</term><term>Oligonucléotides phosphorothioates</term><term>Relation dose-effet des médicaments</term><term>Relation structure-activité</term><term>Structure moléculaire</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Phosphorothioates are excellent antisense inhibitors, which are active both in cells and in vivo. Since their affinity to complementary ribonucleic acids is rather low, long strands (⩾20-mers) are typically required to achieve the desired biological activity. However, mismatch discrimination of long inhibitors is reduced. In contrast, shorter phosphorothioates exhibit better sequence specificity, but have in most cases too low affinity for practical applications in cells. We screened a range of terminal modifiers of a 14-mer phosphorothioate sequence, which is complementary to mRNA of a representative gene, whose protein product is fluorescent (DsRed2) and easy to monitor in cells. We found that optimal combinations of 5'- and 3'-modifications include 5'-trimethoxystilbene with 3'-uracil(anthraquinone)-cap, 5'-chloic acid derivative with 3'-uracyl(anthraquinone)-cap and 5'-cholic acid derivative with three 3'-LNA moieties. In contrast to the LNA, stabilizing and activity-enhancing effects of other mentioned modifiers for PTO/RNA duplexes have not been previously reported. We observed that the 14-mer inhibitor carrying 5'-cholic acid derivative with three 3'-LNA moieties inhibits expression of DsRed2 in cells stronger than the unmodified 21-mer. Mismatch discrimination of this inhibitor was found to be comparable to that of the unmodified 14-mer. </div></front></TEI><affiliations><list><country><li>Allemagne</li></country><region><li>Bade-Wurtemberg</li><li>Bavière</li><li>District de Karlsruhe</li><li>District de Moyenne-Franconie</li></region><settlement><li>Erlangen</li><li>Heidelberg</li></settlement></list><tree><country name="Allemagne"><region name="Bade-Wurtemberg"><name sortKey="Marzenell, Paul" sort="Marzenell, Paul" uniqKey="Marzenell P" first="Paul" last="Marzenell">Paul Marzenell</name></region><name sortKey="Blechinger, Jenny" sort="Blechinger, Jenny" uniqKey="Blechinger J" first="Jenny" last="Blechinger">Jenny Blechinger</name><name sortKey="Erfle, Holger" sort="Erfle, Holger" uniqKey="Erfle H" first="Holger" last="Erfle">Holger Erfle</name><name sortKey="Hagen, Helen" sort="Hagen, Helen" uniqKey="Hagen H" first="Helen" last="Hagen">Helen Hagen</name><name sortKey="Mokhir, Andriy" sort="Mokhir, Andriy" uniqKey="Mokhir A" first="Andriy" last="Mokhir">Andriy Mokhir</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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