Polydeoxyguanine motifs in a 12-mer phosphorothioate oligodeoxynucleotide augment binding to the v3 loop of HIV-1 gp120 and potency of HIV-1 inhibition independency of G-tetrad formation.
Identifieur interne : 003E15 ( Main/Exploration ); précédent : 003E14; suivant : 003E16Polydeoxyguanine motifs in a 12-mer phosphorothioate oligodeoxynucleotide augment binding to the v3 loop of HIV-1 gp120 and potency of HIV-1 inhibition independency of G-tetrad formation.
Auteurs : S. Lederman [États-Unis] ; G. Sullivan ; L. Benimetskaya ; I. Lowy ; K. Land ; Z. Khaled ; A M Cleary ; L. Yakubov ; C A SteinSource :
- Antisense & nucleic acid drug development [ 1087-2906 ] ; 1996.
Descripteurs français
- KwdFr :
- Agents antiVIH (), Agents antiVIH (pharmacologie), Anticorps monoclonaux, Conformation d'acide nucléique, Liaison aux protéines, Oligodésoxyribonucléotides (), Oligodésoxyribonucléotides (pharmacologie), Poly G (), Protéine d'enveloppe gp120 du VIH (), Protéines de liaison à l'ADN (), Réplication virale (), Solutions, Structure tertiaire des protéines, Thionucléotides (), Thionucléotides (pharmacologie), VIH-1 (Virus de l'Immunodéficience Humaine de type 1) (pathogénicité).
- MESH :
- pathogénicité : VIH-1 (Virus de l'Immunodéficience Humaine de type 1).
- pharmacologie : Agents antiVIH, Oligodésoxyribonucléotides, Thionucléotides.
- Agents antiVIH, Anticorps monoclonaux, Conformation d'acide nucléique, Liaison aux protéines, Oligodésoxyribonucléotides, Poly G, Protéine d'enveloppe gp120 du VIH, Protéines de liaison à l'ADN, Réplication virale, Solutions, Structure tertiaire des protéines, Thionucléotides.
English descriptors
- KwdEn :
- Anti-HIV Agents (chemistry), Anti-HIV Agents (pharmacology), Antibodies, Monoclonal, DNA-Binding Proteins (chemistry), HIV Envelope Protein gp120 (chemistry), HIV-1 (pathogenicity), Nucleic Acid Conformation, Oligodeoxyribonucleotides (chemistry), Oligodeoxyribonucleotides (pharmacology), Poly G (chemistry), Protein Binding, Protein Structure, Tertiary, Solutions, Thionucleotides (chemistry), Thionucleotides (pharmacology), Virus Replication (drug effects).
- MESH :
- chemical , chemistry : Anti-HIV Agents, DNA-Binding Proteins, HIV Envelope Protein gp120, Oligodeoxyribonucleotides, Poly G, Thionucleotides.
- chemical , pharmacology : Anti-HIV Agents, Oligodeoxyribonucleotides, Thionucleotides.
- chemical : Antibodies, Monoclonal, Solutions.
- drug effects : Virus Replication.
- pathogenicity : HIV-1.
- Nucleic Acid Conformation, Protein Binding, Protein Structure, Tertiary.
Abstract
Phosphorothioate oligodeoxynucleotides belong to a class of polyanions that bind to the third variable domain (v3) of HIV-1 gp120 and inhibit infectivity of a wide variety of HIV-1 isolates. This potent v3 binding of phosphorothioate oligodeoxynucleotides, which is relatively independent of the nucleotide sequence of the oligodeoxynucleotides, decreases with chain length (below 18-mers) and is low for 8-mers. However, recent studies have observed a nucleotide sequence-dependent augmentation of phosphorothioate oligodeoxynucleotide binding to v3 for 8-mers that contain the S-dG4 motif (e.g., SdT2G4T2) and have suggested that formation of quadruple helical tetraplexes (G-tetrads) is associated with the acquisition of v3 binding ability by small phosphorothioate oligodeoxynucleotides. In the current study, a series of SdG4-containing oligodeoxynucleotides were synthesized with varying tandem length (including the 8-mer SdT2G4T2, the 12-mer SdG4T4G4, and the 28-mer SdG4(T4G4)3) and compared with phosphorothioate oligodeoxynucleotides (with similar lengths or related sequences) for (1) their inhibition of the binding of mAb 9284, which binds to the N-terminal portion of the v3 loop, (2) the values of Kc when these compounds are used as competitors of the rgp120-binding of an alkylating phosphodiester oligodeoxynucleotide probe, and (3) inhibition of HIV-1 infectivity in a cell-cell transmission model. The presence of S-dG4 motifs and the number of tandem motifs augmented v3 binding and anti-HIV-1 infectivity for small (8-mer or 12-mer oligodeoxynucleotides) but did not significantly augment the potency of 28-mers. Whereas tetraplex formation of SdT2G4T2 may contribute to its v3 binding, the 12-mer SdG4T4G4 does not migrate as the tetraplex on nonreducing gels, suggesting that S-dG4 motifs may augment anti-HIV activity by multiple mechanisms.
DOI: 10.1089/oli.1.1996.6.281
PubMed: 9012864
Affiliations:
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Lowy</name></author><author><name sortKey="Land, K" sort="Land, K" uniqKey="Land K" first="K" last="Land">K. Land</name></author><author><name sortKey="Khaled, Z" sort="Khaled, Z" uniqKey="Khaled Z" first="Z" last="Khaled">Z. Khaled</name></author><author><name sortKey="Cleary, A M" sort="Cleary, A M" uniqKey="Cleary A" first="A M" last="Cleary">A M Cleary</name></author><author><name sortKey="Yakubov, L" sort="Yakubov, L" uniqKey="Yakubov L" first="L" last="Yakubov">L. Yakubov</name></author><author><name sortKey="Stein, C A" sort="Stein, C A" uniqKey="Stein C" first="C A" last="Stein">C A Stein</name></author></analytic><series><title level="j">Antisense & nucleic acid drug development</title><idno type="ISSN">1087-2906</idno><imprint><date when="1996" type="published">1996</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Anti-HIV Agents (chemistry)</term><term>Anti-HIV Agents (pharmacology)</term><term>Antibodies, Monoclonal</term><term>DNA-Binding Proteins (chemistry)</term><term>HIV Envelope Protein gp120 (chemistry)</term><term>HIV-1 (pathogenicity)</term><term>Nucleic Acid Conformation</term><term>Oligodeoxyribonucleotides (chemistry)</term><term>Oligodeoxyribonucleotides (pharmacology)</term><term>Poly G (chemistry)</term><term>Protein Binding</term><term>Protein Structure, Tertiary</term><term>Solutions</term><term>Thionucleotides (chemistry)</term><term>Thionucleotides (pharmacology)</term><term>Virus Replication (drug effects)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Agents antiVIH ()</term><term>Agents antiVIH (pharmacologie)</term><term>Anticorps monoclonaux</term><term>Conformation d'acide nucléique</term><term>Liaison aux protéines</term><term>Oligodésoxyribonucléotides ()</term><term>Oligodésoxyribonucléotides (pharmacologie)</term><term>Poly G ()</term><term>Protéine d'enveloppe gp120 du VIH ()</term><term>Protéines de liaison à l'ADN ()</term><term>Réplication virale ()</term><term>Solutions</term><term>Structure tertiaire des protéines</term><term>Thionucléotides ()</term><term>Thionucléotides (pharmacologie)</term><term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1) (pathogénicité)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Anti-HIV Agents</term><term>DNA-Binding Proteins</term><term>HIV Envelope Protein gp120</term><term>Oligodeoxyribonucleotides</term><term>Poly G</term><term>Thionucleotides</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Anti-HIV Agents</term><term>Oligodeoxyribonucleotides</term><term>Thionucleotides</term></keywords><keywords scheme="MESH" type="chemical" xml:lang="en"><term>Antibodies, Monoclonal</term><term>Solutions</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Virus Replication</term></keywords><keywords scheme="MESH" qualifier="pathogenicity" xml:lang="en"><term>HIV-1</term></keywords><keywords scheme="MESH" qualifier="pathogénicité" xml:lang="fr"><term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1)</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Agents antiVIH</term><term>Oligodésoxyribonucléotides</term><term>Thionucléotides</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Nucleic Acid Conformation</term><term>Protein Binding</term><term>Protein Structure, Tertiary</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Agents antiVIH</term><term>Anticorps monoclonaux</term><term>Conformation d'acide nucléique</term><term>Liaison aux protéines</term><term>Oligodésoxyribonucléotides</term><term>Poly G</term><term>Protéine d'enveloppe gp120 du VIH</term><term>Protéines de liaison à l'ADN</term><term>Réplication virale</term><term>Solutions</term><term>Structure tertiaire des protéines</term><term>Thionucléotides</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Phosphorothioate oligodeoxynucleotides belong to a class of polyanions that bind to the third variable domain (v3) of HIV-1 gp120 and inhibit infectivity of a wide variety of HIV-1 isolates. This potent v3 binding of phosphorothioate oligodeoxynucleotides, which is relatively independent of the nucleotide sequence of the oligodeoxynucleotides, decreases with chain length (below 18-mers) and is low for 8-mers. However, recent studies have observed a nucleotide sequence-dependent augmentation of phosphorothioate oligodeoxynucleotide binding to v3 for 8-mers that contain the S-dG4 motif (e.g., SdT2G4T2) and have suggested that formation of quadruple helical tetraplexes (G-tetrads) is associated with the acquisition of v3 binding ability by small phosphorothioate oligodeoxynucleotides. In the current study, a series of SdG4-containing oligodeoxynucleotides were synthesized with varying tandem length (including the 8-mer SdT2G4T2, the 12-mer SdG4T4G4, and the 28-mer SdG4(T4G4)3) and compared with phosphorothioate oligodeoxynucleotides (with similar lengths or related sequences) for (1) their inhibition of the binding of mAb 9284, which binds to the N-terminal portion of the v3 loop, (2) the values of Kc when these compounds are used as competitors of the rgp120-binding of an alkylating phosphodiester oligodeoxynucleotide probe, and (3) inhibition of HIV-1 infectivity in a cell-cell transmission model. The presence of S-dG4 motifs and the number of tandem motifs augmented v3 binding and anti-HIV-1 infectivity for small (8-mer or 12-mer oligodeoxynucleotides) but did not significantly augment the potency of 28-mers. Whereas tetraplex formation of SdT2G4T2 may contribute to its v3 binding, the 12-mer SdG4T4G4 does not migrate as the tetraplex on nonreducing gels, suggesting that S-dG4 motifs may augment anti-HIV activity by multiple mechanisms.</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><noCountry><name sortKey="Benimetskaya, L" sort="Benimetskaya, L" uniqKey="Benimetskaya L" first="L" last="Benimetskaya">L. Benimetskaya</name><name sortKey="Cleary, A M" sort="Cleary, A M" uniqKey="Cleary A" first="A M" last="Cleary">A M Cleary</name><name sortKey="Khaled, Z" sort="Khaled, Z" uniqKey="Khaled Z" first="Z" last="Khaled">Z. Khaled</name><name sortKey="Land, K" sort="Land, K" uniqKey="Land K" first="K" last="Land">K. Land</name><name sortKey="Lowy, I" sort="Lowy, I" uniqKey="Lowy I" first="I" last="Lowy">I. Lowy</name><name sortKey="Stein, C A" sort="Stein, C A" uniqKey="Stein C" first="C A" last="Stein">C A Stein</name><name sortKey="Sullivan, G" sort="Sullivan, G" uniqKey="Sullivan G" first="G" last="Sullivan">G. Sullivan</name><name sortKey="Yakubov, L" sort="Yakubov, L" uniqKey="Yakubov L" first="L" last="Yakubov">L. Yakubov</name></noCountry><country name="États-Unis"><region name="État de New York"><name sortKey="Lederman, S" sort="Lederman, S" uniqKey="Lederman S" first="S" last="Lederman">S. Lederman</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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