Impact of nature and length of linker incorporated in agonists on toll-like receptor 9-mediated immune responses.
Identifieur interne : 001F56 ( PubMed/Curation ); précédent : 001F55; suivant : 001F57Impact of nature and length of linker incorporated in agonists on toll-like receptor 9-mediated immune responses.
Auteurs : Mallikarjuna Reddy Putta [États-Unis] ; Dong Yu ; Lakshmi Bhagat ; Daqing Wang ; Fu-Gang Zhu ; Ekambar R. KandimallaSource :
- Journal of medicinal chemistry [ 1520-4804 ] ; 2010.
Descripteurs français
- KwdFr :
- Animaux, Facteurs immunologiques (), Glycols, Humains, Ilots CpG, Lignée cellulaire, Nucléotide désoxyguanylique, Oligodésoxyribonucléotides (), Oligodésoxyribonucléotides (immunologie), Oligodésoxyribonucléotides (pharmacologie), Réactifs réticulants (), Récepteur-9 de type Toll-like (agonistes), Souris, Séquence nucléotidique.
- MESH :
- agonistes : Récepteur-9 de type Toll-like.
- immunologie : Oligodésoxyribonucléotides.
- pharmacologie : Oligodésoxyribonucléotides.
- Animaux, Facteurs immunologiques, Glycols, Humains, Ilots CpG, Lignée cellulaire, Nucléotide désoxyguanylique, Oligodésoxyribonucléotides, Réactifs réticulants, Souris, Séquence nucléotidique.
English descriptors
- KwdEn :
- Animals, Base Sequence, Cell Line, CpG Islands, Cross-Linking Reagents (chemistry), Deoxyguanine Nucleotides, Glycols, Humans, Immunologic Factors (chemistry), Mice, Oligodeoxyribonucleotides (chemistry), Oligodeoxyribonucleotides (immunology), Oligodeoxyribonucleotides (pharmacology), Toll-Like Receptor 9 (agonists).
- MESH :
- chemical , agonists : Toll-Like Receptor 9.
- chemical , chemistry : Cross-Linking Reagents, Immunologic Factors, Oligodeoxyribonucleotides.
- chemical , immunology : Oligodeoxyribonucleotides.
- chemical , pharmacology : Oligodeoxyribonucleotides.
- Animals, Base Sequence, Cell Line, CpG Islands, Deoxyguanine Nucleotides, Glycols, Humans, Mice.
Abstract
Oligodeoxynucleotides containing unmethylated CpG motifs act as ligands of Toll-like receptor 9 (TLR9). We previously reported a novel class of TLR9 agonists, referred to as immune-modulatory oligonucleotides (IMOs), in which two 11-mers of the same sequence are attached via their 3'-ends through a 1,2,3-propanetriol linker and contain a synthetic immune-stimulatory motif, Cp7-deaza-dG. In the present study, we have examined the impact of length, nature, and stereochemistry of the linker incorporated in agonists for TLR9 activation. The new linkers studied include (S)-(-)-1,2,4-butanetriol, 1,3,5-pentanetriol, cis,cis-1,3,5-cyclohexanetriol, cis,trans-1,3,5-cyclohexanetriol, 1,3,5-tris(2-hydroxyethyl)isocyanurate, tetraethyleneglycol, and hexaethyleneglycol in place of 1,2,3-propanetriol linker. Agonists with various linkers are studied for TLR9-mediated immune responses in HEK293 cells, human cell-based assays, and in vivo in mice. Results of these studies suggest that C3-C5 linkers, 1,2,3-propanetriol, (S)-(-)-1,2,4-butanetriol, or 1,3,5-pentanetriol, are optimal for stimulation of TLR9-mediated immune responses. Rigid C3 linkers with different stereochemistry have little effect on immune stimulation, while linkers longer than C5 reduced TLR9-mediated immune stimulation.
DOI: 10.1021/jm100177p
PubMed: 20361743
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pubmed:20361743Le document en format XML
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<term>Deoxyguanine Nucleotides</term>
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<term>Oligodeoxyribonucleotides (chemistry)</term>
<term>Oligodeoxyribonucleotides (immunology)</term>
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<term>Oligodésoxyribonucléotides (immunologie)</term>
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<term>Lignée cellulaire</term>
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<front><div type="abstract" xml:lang="en">Oligodeoxynucleotides containing unmethylated CpG motifs act as ligands of Toll-like receptor 9 (TLR9). We previously reported a novel class of TLR9 agonists, referred to as immune-modulatory oligonucleotides (IMOs), in which two 11-mers of the same sequence are attached via their 3'-ends through a 1,2,3-propanetriol linker and contain a synthetic immune-stimulatory motif, Cp7-deaza-dG. In the present study, we have examined the impact of length, nature, and stereochemistry of the linker incorporated in agonists for TLR9 activation. The new linkers studied include (S)-(-)-1,2,4-butanetriol, 1,3,5-pentanetriol, cis,cis-1,3,5-cyclohexanetriol, cis,trans-1,3,5-cyclohexanetriol, 1,3,5-tris(2-hydroxyethyl)isocyanurate, tetraethyleneglycol, and hexaethyleneglycol in place of 1,2,3-propanetriol linker. Agonists with various linkers are studied for TLR9-mediated immune responses in HEK293 cells, human cell-based assays, and in vivo in mice. Results of these studies suggest that C3-C5 linkers, 1,2,3-propanetriol, (S)-(-)-1,2,4-butanetriol, or 1,3,5-pentanetriol, are optimal for stimulation of TLR9-mediated immune responses. Rigid C3 linkers with different stereochemistry have little effect on immune stimulation, while linkers longer than C5 reduced TLR9-mediated immune stimulation.</div>
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<Abstract><AbstractText>Oligodeoxynucleotides containing unmethylated CpG motifs act as ligands of Toll-like receptor 9 (TLR9). We previously reported a novel class of TLR9 agonists, referred to as immune-modulatory oligonucleotides (IMOs), in which two 11-mers of the same sequence are attached via their 3'-ends through a 1,2,3-propanetriol linker and contain a synthetic immune-stimulatory motif, Cp7-deaza-dG. In the present study, we have examined the impact of length, nature, and stereochemistry of the linker incorporated in agonists for TLR9 activation. The new linkers studied include (S)-(-)-1,2,4-butanetriol, 1,3,5-pentanetriol, cis,cis-1,3,5-cyclohexanetriol, cis,trans-1,3,5-cyclohexanetriol, 1,3,5-tris(2-hydroxyethyl)isocyanurate, tetraethyleneglycol, and hexaethyleneglycol in place of 1,2,3-propanetriol linker. Agonists with various linkers are studied for TLR9-mediated immune responses in HEK293 cells, human cell-based assays, and in vivo in mice. Results of these studies suggest that C3-C5 linkers, 1,2,3-propanetriol, (S)-(-)-1,2,4-butanetriol, or 1,3,5-pentanetriol, are optimal for stimulation of TLR9-mediated immune responses. Rigid C3 linkers with different stereochemistry have little effect on immune stimulation, while linkers longer than C5 reduced TLR9-mediated immune stimulation.</AbstractText>
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