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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Kandimalla</name></author></analytic><series><title level="j">Journal of medicinal chemistry</title><idno type="eISSN">1520-4804</idno><imprint><date when="2010" type="published">2010</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Base Sequence</term><term>Cell Line</term><term>CpG Islands</term><term>Cross-Linking Reagents (chemistry)</term><term>Deoxyguanine Nucleotides</term><term>Glycols</term><term>Humans</term><term>Immunologic Factors (chemistry)</term><term>Mice</term><term>Oligodeoxyribonucleotides (chemistry)</term><term>Oligodeoxyribonucleotides (immunology)</term><term>Oligodeoxyribonucleotides (pharmacology)</term><term>Toll-Like Receptor 9 (agonists)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>Facteurs immunologiques ()</term><term>Glycols</term><term>Humains</term><term>Ilots CpG</term><term>Lignée cellulaire</term><term>Nucléotide désoxyguanylique</term><term>Oligodésoxyribonucléotides ()</term><term>Oligodésoxyribonucléotides (immunologie)</term><term>Oligodésoxyribonucléotides (pharmacologie)</term><term>Réactifs réticulants ()</term><term>Récepteur-9 de type Toll-like (agonistes)</term><term>Souris</term><term>Séquence nucléotidique</term></keywords><keywords scheme="MESH" type="chemical" qualifier="agonists" xml:lang="en"><term>Toll-Like Receptor 9</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Cross-Linking Reagents</term><term>Immunologic Factors</term><term>Oligodeoxyribonucleotides</term></keywords><keywords scheme="MESH" type="chemical" qualifier="immunology" xml:lang="en"><term>Oligodeoxyribonucleotides</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Oligodeoxyribonucleotides</term></keywords><keywords scheme="MESH" qualifier="agonistes" xml:lang="fr"><term>Récepteur-9 de type Toll-like</term></keywords><keywords scheme="MESH" qualifier="immunologie" xml:lang="fr"><term>Oligodésoxyribonucléotides</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Oligodésoxyribonucléotides</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Base Sequence</term><term>Cell Line</term><term>CpG Islands</term><term>Deoxyguanine Nucleotides</term><term>Glycols</term><term>Humans</term><term>Mice</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Facteurs immunologiques</term><term>Glycols</term><term>Humains</term><term>Ilots CpG</term><term>Lignée cellulaire</term><term>Nucléotide désoxyguanylique</term><term>Oligodésoxyribonucléotides</term><term>Réactifs réticulants</term><term>Souris</term><term>Séquence nucléotidique</term></keywords></textClass></profileDesc></teiHeader><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></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">20361743</PMID><DateCompleted><Year>2010</Year><Month>06</Month><Day>11</Day></DateCompleted><DateRevised><Year>2010</Year><Month>05</Month><Day>06</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Electronic">1520-4804</ISSN><JournalIssue CitedMedium="Internet"><Volume>53</Volume><Issue>9</Issue><PubDate><Year>2010</Year><Month>May</Month><Day>13</Day></PubDate></JournalIssue><Title>Journal of medicinal chemistry</Title><ISOAbbreviation>J. Med. Chem.</ISOAbbreviation></Journal><ArticleTitle>Impact of nature and length of linker incorporated in agonists on toll-like receptor 9-mediated immune responses.</ArticleTitle><Pagination><MedlinePgn>3730-8</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1021/jm100177p</ELocationID><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></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Putta</LastName><ForeName>Mallikarjuna Reddy</ForeName><Initials>MR</Initials><AffiliationInfo><Affiliation>Idera Pharmaceuticals, Inc., 167 Sidney Street, Cambridge, Massachusetts 02139, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Yu</LastName><ForeName>Dong</ForeName><Initials>D</Initials></Author><Author ValidYN="Y"><LastName>Bhagat</LastName><ForeName>Lakshmi</ForeName><Initials>L</Initials></Author><Author ValidYN="Y"><LastName>Wang</LastName><ForeName>Daqing</ForeName><Initials>D</Initials></Author><Author ValidYN="Y"><LastName>Zhu</LastName><ForeName>Fu-Gang</ForeName><Initials>FG</Initials></Author><Author ValidYN="Y"><LastName>Kandimalla</LastName><ForeName>Ekambar R</ForeName><Initials>ER</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>J Med Chem</MedlineTA><NlmUniqueID>9716531</NlmUniqueID><ISSNLinking>0022-2623</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D003432">Cross-Linking Reagents</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D003848">Deoxyguanine Nucleotides</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D006018">Glycols</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D007155">Immunologic Factors</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D009838">Oligodeoxyribonucleotides</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D051217">Toll-Like Receptor 9</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D001483" MajorTopicYN="N">Base Sequence</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D002460" MajorTopicYN="N">Cell Line</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D018899" MajorTopicYN="N">CpG Islands</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D003432" MajorTopicYN="N">Cross-Linking Reagents</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="Y">chemistry</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D003848" MajorTopicYN="N">Deoxyguanine Nucleotides</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006018" MajorTopicYN="N">Glycols</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D007155" MajorTopicYN="N">Immunologic Factors</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="Y">chemistry</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D051379" MajorTopicYN="N">Mice</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D009838" MajorTopicYN="N">Oligodeoxyribonucleotides</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000276" MajorTopicYN="N">immunology</QualifierName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D051217" MajorTopicYN="N">Toll-Like Receptor 9</DescriptorName><QualifierName UI="Q000819" MajorTopicYN="Y">agonists</QualifierName></MeshHeading></MeshHeadingList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="entrez"><Year>2010</Year><Month>4</Month><Day>6</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2010</Year><Month>4</Month><Day>7</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2010</Year><Month>6</Month><Day>12</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>ppublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">20361743</ArticleId><ArticleId IdType="doi">10.1021/jm100177p</ArticleId></ArticleIdList></PubmedData></pubmed></record>Pour manipuler ce document sous Unix (Dilib)
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