Oligonucleotide N3'-->P5' phosphoramidates as potential therapeutic agents.
Identifieur interne : 003793 ( Main/Exploration ); précédent : 003792; suivant : 003794Oligonucleotide N3'-->P5' phosphoramidates as potential therapeutic agents.
Auteurs : S M Gryaznov [États-Unis]Source :
- Biochimica et biophysica acta [ 0006-3002 ] ; 1999.
Descripteurs français
- KwdFr :
- ADN (), ARN messager (antagonistes et inhibiteurs), Acides phosphoriques (), Amides (), Animaux, Conception de médicament, Conformation d'acide nucléique, Division cellulaire (), Expression des gènes (), Humains, Leucémie expérimentale (anatomopathologie), Leucémie expérimentale (traitement médicamenteux), Lignée cellulaire, Mimétisme moléculaire (génétique), Oligonucléotides antisens (), Oligonucléotides antisens (pharmacologie), Oligonucléotides antisens (usage thérapeutique), Protéines de fusion oncogènes (antagonistes et inhibiteurs), Protéines de fusion oncogènes (génétique), Protéines proto-oncogènes c-myc (antagonistes et inhibiteurs), Protéines proto-oncogènes c-myc (génétique), Relation dose-effet des médicaments, Souris, Spécificité du substrat (génétique), Taux de survie.
- MESH :
- anatomopathologie : Leucémie expérimentale.
- antagonistes et inhibiteurs : ARN messager, Protéines de fusion oncogènes, Protéines proto-oncogènes c-myc.
- génétique : Mimétisme moléculaire, Protéines de fusion oncogènes, Protéines proto-oncogènes c-myc, Spécificité du substrat.
- pharmacologie : Oligonucléotides antisens.
- traitement médicamenteux : Leucémie expérimentale.
- usage thérapeutique : Oligonucléotides antisens.
- ADN, Acides phosphoriques, Amides, Animaux, Conception de médicament, Conformation d'acide nucléique, Division cellulaire, Expression des gènes, Humains, Lignée cellulaire, Oligonucléotides antisens, Relation dose-effet des médicaments, Souris, Taux de survie.
English descriptors
- KwdEn :
- Amides (chemistry), Animals, Cell Division (drug effects), Cell Line, DNA (chemistry), Dose-Response Relationship, Drug, Drug Design, Gene Expression (drug effects), Humans, Leukemia, Experimental (drug therapy), Leukemia, Experimental (pathology), Mice, Molecular Mimicry (genetics), Nucleic Acid Conformation, Oligonucleotides, Antisense (chemistry), Oligonucleotides, Antisense (pharmacology), Oligonucleotides, Antisense (therapeutic use), Oncogene Proteins, Fusion (antagonists & inhibitors), Oncogene Proteins, Fusion (genetics), Phosphoric Acids (chemistry), Proto-Oncogene Proteins c-myc (antagonists & inhibitors), Proto-Oncogene Proteins c-myc (genetics), RNA, Messenger (antagonists & inhibitors), Substrate Specificity (genetics), Survival Rate.
- MESH :
- chemical , antagonists & inhibitors : Oncogene Proteins, Fusion, Proto-Oncogene Proteins c-myc, RNA, Messenger.
- chemical , chemistry : Amides, DNA, Oligonucleotides, Antisense, Phosphoric Acids.
- drug effects : Cell Division, Gene Expression.
- drug therapy : Leukemia, Experimental.
- genetics : Molecular Mimicry, Oncogene Proteins, Fusion, Proto-Oncogene Proteins c-myc, Substrate Specificity.
- pathology : Leukemia, Experimental.
- chemical , pharmacology : Oligonucleotides, Antisense.
- chemical , therapeutic use : Oligonucleotides, Antisense.
- Animals, Cell Line, Dose-Response Relationship, Drug, Drug Design, Humans, Mice, Nucleic Acid Conformation, Survival Rate.
Abstract
Uniformly modified nucleic acids analogues, oligonucleotide N3'-->P5' phosphoramidates, containing 3'-amino instead of 3'-hydroxyl nucleosides, were synthesized and studied. These compounds form very stable duplexes with complementary native phosphodiester DNA and exceptionally stable duplexes with RNA strands. Increases in duplex melting temperature, deltaTm, relatively to their phosphodiester counterparts, reaches 2.9-3.5 degrees C per modified nucleoside. Moreover, the phosphoramidate compounds form extremely stable triple stranded complexes with single or double stranded DNA oligomers under near physiological salt and pH conditions. Melting temperatures of these triplexes usually exceed that of the isosequential phosphodiester counterparts by up to 35 degrees C. For 11-15-mers 2'-deoxyphosphoramidates are structurally and functionally similar to the native RNA molecules and thus can be used as RNA decoys. They are resistant to enzymatic digestion by nucleases both in vitro and in vivo. Oligonucleotide phosphoramidates apparently are cell permeable, and they have a good bioavailability and biodistribution, while being non-toxic in mice at therapeutically relevant doses. Duplexes of the several studied phosphoramidates with complementary RNA strands apparently are not substrates for RNase H in vitro. Despite that, these compounds exerted high sequence-specific antisense activity in various cell lines and in SCID mice. The observed in vitro lack of RNase H recognition of the RNA:phosphoramidate duplexes may result in better specificity in biological activity of these compounds relative to RNase H inducing oligonucleotides. Experimental results also indicate that oligonucleotide phosphoramidates can be used as efficient and specific modulators of gene expression by an antigene mechanism of action. Finally, the oligo-2'-deoxyphosphoramidate double stranded complexes can structurally mimic native RNA complexes, which could be efficiently and specifically recognized by the RNA binding proteins, such as HIV-1 Rev and Tat.
DOI: 10.1016/s0167-4781(99)00151-7
PubMed: 10807003
Affiliations:
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Le document en format XML
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Amides (chemistry)</term>
<term>Animals</term>
<term>Cell Division (drug effects)</term>
<term>Cell Line</term>
<term>DNA (chemistry)</term>
<term>Dose-Response Relationship, Drug</term>
<term>Drug Design</term>
<term>Gene Expression (drug effects)</term>
<term>Humans</term>
<term>Leukemia, Experimental (drug therapy)</term>
<term>Leukemia, Experimental (pathology)</term>
<term>Mice</term>
<term>Molecular Mimicry (genetics)</term>
<term>Nucleic Acid Conformation</term>
<term>Oligonucleotides, Antisense (chemistry)</term>
<term>Oligonucleotides, Antisense (pharmacology)</term>
<term>Oligonucleotides, Antisense (therapeutic use)</term>
<term>Oncogene Proteins, Fusion (antagonists & inhibitors)</term>
<term>Oncogene Proteins, Fusion (genetics)</term>
<term>Phosphoric Acids (chemistry)</term>
<term>Proto-Oncogene Proteins c-myc (antagonists & inhibitors)</term>
<term>Proto-Oncogene Proteins c-myc (genetics)</term>
<term>RNA, Messenger (antagonists & inhibitors)</term>
<term>Substrate Specificity (genetics)</term>
<term>Survival Rate</term>
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<keywords scheme="KwdFr" xml:lang="fr"><term>ADN ()</term>
<term>ARN messager (antagonistes et inhibiteurs)</term>
<term>Acides phosphoriques ()</term>
<term>Amides ()</term>
<term>Animaux</term>
<term>Conception de médicament</term>
<term>Conformation d'acide nucléique</term>
<term>Division cellulaire ()</term>
<term>Expression des gènes ()</term>
<term>Humains</term>
<term>Leucémie expérimentale (anatomopathologie)</term>
<term>Leucémie expérimentale (traitement médicamenteux)</term>
<term>Lignée cellulaire</term>
<term>Mimétisme moléculaire (génétique)</term>
<term>Oligonucléotides antisens ()</term>
<term>Oligonucléotides antisens (pharmacologie)</term>
<term>Oligonucléotides antisens (usage thérapeutique)</term>
<term>Protéines de fusion oncogènes (antagonistes et inhibiteurs)</term>
<term>Protéines de fusion oncogènes (génétique)</term>
<term>Protéines proto-oncogènes c-myc (antagonistes et inhibiteurs)</term>
<term>Protéines proto-oncogènes c-myc (génétique)</term>
<term>Relation dose-effet des médicaments</term>
<term>Souris</term>
<term>Spécificité du substrat (génétique)</term>
<term>Taux de survie</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Oncogene Proteins, Fusion</term>
<term>Proto-Oncogene Proteins c-myc</term>
<term>RNA, Messenger</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Amides</term>
<term>DNA</term>
<term>Oligonucleotides, Antisense</term>
<term>Phosphoric Acids</term>
</keywords>
<keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Leucémie expérimentale</term>
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<keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>ARN messager</term>
<term>Protéines de fusion oncogènes</term>
<term>Protéines proto-oncogènes c-myc</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Cell Division</term>
<term>Gene Expression</term>
</keywords>
<keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Leukemia, Experimental</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Molecular Mimicry</term>
<term>Oncogene Proteins, Fusion</term>
<term>Proto-Oncogene Proteins c-myc</term>
<term>Substrate Specificity</term>
</keywords>
<keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Mimétisme moléculaire</term>
<term>Protéines de fusion oncogènes</term>
<term>Protéines proto-oncogènes c-myc</term>
<term>Spécificité du substrat</term>
</keywords>
<keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Leukemia, Experimental</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Oligonucléotides antisens</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Oligonucleotides, Antisense</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Oligonucleotides, Antisense</term>
</keywords>
<keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Leucémie expérimentale</term>
</keywords>
<keywords scheme="MESH" qualifier="usage thérapeutique" xml:lang="fr"><term>Oligonucléotides antisens</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Cell Line</term>
<term>Dose-Response Relationship, Drug</term>
<term>Drug Design</term>
<term>Humans</term>
<term>Mice</term>
<term>Nucleic Acid Conformation</term>
<term>Survival Rate</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>ADN</term>
<term>Acides phosphoriques</term>
<term>Amides</term>
<term>Animaux</term>
<term>Conception de médicament</term>
<term>Conformation d'acide nucléique</term>
<term>Division cellulaire</term>
<term>Expression des gènes</term>
<term>Humains</term>
<term>Lignée cellulaire</term>
<term>Oligonucléotides antisens</term>
<term>Relation dose-effet des médicaments</term>
<term>Souris</term>
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<front><div type="abstract" xml:lang="en">Uniformly modified nucleic acids analogues, oligonucleotide N3'-->P5' phosphoramidates, containing 3'-amino instead of 3'-hydroxyl nucleosides, were synthesized and studied. These compounds form very stable duplexes with complementary native phosphodiester DNA and exceptionally stable duplexes with RNA strands. Increases in duplex melting temperature, deltaTm, relatively to their phosphodiester counterparts, reaches 2.9-3.5 degrees C per modified nucleoside. Moreover, the phosphoramidate compounds form extremely stable triple stranded complexes with single or double stranded DNA oligomers under near physiological salt and pH conditions. Melting temperatures of these triplexes usually exceed that of the isosequential phosphodiester counterparts by up to 35 degrees C. For 11-15-mers 2'-deoxyphosphoramidates are structurally and functionally similar to the native RNA molecules and thus can be used as RNA decoys. They are resistant to enzymatic digestion by nucleases both in vitro and in vivo. Oligonucleotide phosphoramidates apparently are cell permeable, and they have a good bioavailability and biodistribution, while being non-toxic in mice at therapeutically relevant doses. Duplexes of the several studied phosphoramidates with complementary RNA strands apparently are not substrates for RNase H in vitro. Despite that, these compounds exerted high sequence-specific antisense activity in various cell lines and in SCID mice. The observed in vitro lack of RNase H recognition of the RNA:phosphoramidate duplexes may result in better specificity in biological activity of these compounds relative to RNase H inducing oligonucleotides. Experimental results also indicate that oligonucleotide phosphoramidates can be used as efficient and specific modulators of gene expression by an antigene mechanism of action. Finally, the oligo-2'-deoxyphosphoramidate double stranded complexes can structurally mimic native RNA complexes, which could be efficiently and specifically recognized by the RNA binding proteins, such as HIV-1 Rev and Tat.</div>
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