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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">CROSS-LINKING TO AN INTERRUPTED POLYPURINE SEQUENCE WITH A PLATINUM-MODIFIED TRIPLEX-FORMING OLIGONUCLEOTIDE</title><author><name sortKey="Campbell, Meghan A" sort="Campbell, Meghan A" uniqKey="Campbell M" first="Meghan A." last="Campbell">Meghan A. Campbell</name></author><author><name sortKey="Miller, Paul S" sort="Miller, Paul S" uniqKey="Miller P" first="Paul S." last="Miller">Paul S. Miller</name></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">19350290</idno><idno type="pmc">2730491</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2730491</idno><idno type="RBID">PMC:2730491</idno><idno type="doi">10.1007/s00775-009-0499-3</idno><date when="2009">2009</date><idno type="wicri:Area/Pmc/Corpus">000114</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000114</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">CROSS-LINKING TO AN INTERRUPTED POLYPURINE SEQUENCE WITH A PLATINUM-MODIFIED TRIPLEX-FORMING OLIGONUCLEOTIDE</title><author><name sortKey="Campbell, Meghan A" sort="Campbell, Meghan A" uniqKey="Campbell M" first="Meghan A." last="Campbell">Meghan A. Campbell</name></author><author><name sortKey="Miller, Paul S" sort="Miller, Paul S" uniqKey="Miller P" first="Paul S." last="Miller">Paul S. Miller</name></author></analytic><series><title level="j">Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry</title><idno type="ISSN">0949-8257</idno><idno type="eISSN">1432-1327</idno><imprint><date when="2009">2009</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="P3">Triplex-forming oligonucleotides (TFOs) can bind specifically to polypurine sequences in double-stranded DNA. A single interruption of this polypurine tract can greatly destabilize triplex formation. The stability of triplexes can be significantly enhanced by covalently linking the TFO to its DNA target with reactive functional groups conjugated to the TFO. Covalently cross-linked TFOs are effective inhibitors of transcription of the target DNA sequence. We have designed a TFO with a platinum-modified base that can interact with and cross-link to a cytosine interruption in the polypurine tract of a target DNA duplex. The TFO contains an <italic>N</italic><sup>4</sup>-(aminoalkyl)cytosine derivatized with <italic>cis</italic>- or <italic>trans</italic>-diamminediaquaplatinum(II). When bound to its target, the tethered platinum of the TFO can reach across the major groove and form an adduct with the guanine N7 of the interrupting C·G base-pair. The optimal tether length is five methylene groups, and cross-linking is most efficient when the tether is modified with <italic>trans</italic>-diamminediaquaplatinum. Cross-linking requires that the TFO is bound to its designated DNA target. Addition of cyanide to the cross-linked TFO product reversed the cross-link, behavior that is consistent with the presence of a Pt-guanine adduct. The kinetics of the cross-linking reaction were studied and the half-life of the cross-linking reaction was approximately three hours. Our results demonstrate that platinum-conjugated TFOs can be designed to cross-link with DNA targets that contain a single pyrimidine interruption. Modifications of this type may prove useful for expanding the DNA sequences that can be targeted by TFOs and increasing the stability of the resulting triplexes.</p></div></front></TEI><pmc article-type="research-article" xml:lang="EN"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">9616326</journal-id><journal-id journal-id-type="pubmed-jr-id">21442</journal-id><journal-id journal-id-type="nlm-ta">J Biol Inorg Chem</journal-id><journal-title>Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry</journal-title><issn pub-type="ppub">0949-8257</issn><issn pub-type="epub">1432-1327</issn></journal-meta><article-meta><article-id pub-id-type="pmid">19350290</article-id><article-id pub-id-type="pmc">2730491</article-id><article-id pub-id-type="doi">10.1007/s00775-009-0499-3</article-id><article-id pub-id-type="manuscript">NIHMS105998</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>CROSS-LINKING TO AN INTERRUPTED POLYPURINE SEQUENCE WITH A PLATINUM-MODIFIED TRIPLEX-FORMING OLIGONUCLEOTIDE</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Campbell</surname><given-names>Meghan A.</given-names></name><xref ref-type="author-notes" rid="FN2">†</xref></contrib><contrib contrib-type="author"><name><surname>Miller</surname><given-names>Paul S.</given-names></name><xref ref-type="author-notes" rid="FN1">✉</xref></contrib><aff id="A1">Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, Baltimore, MD 21205</aff></contrib-group><author-notes><fn fn-type="corresp" id="FN1"><label>✉</label><p id="P1">Address correspondence to: Paul S. Miller, Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, Baltimore, MD 21205, phone: 410-955-3489, fax: 410-955-2926, e-mail: <email>pmiller@jhsph.edu</email></p></fn><fn id="FN2"><label>†</label><p id="P2">Present address: Nucleic Acid Center, Department of Physics and Chemistry, University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark</p></fn></author-notes><pub-date pub-type="nihms-submitted"><day>30</day><month>3</month><year>2009</year></pub-date><pub-date pub-type="epub"><day>7</day><month>4</month><year>2009</year></pub-date><pub-date pub-type="ppub"><month>8</month><year>2009</year></pub-date><pub-date pub-type="pmc-release"><day>1</day><month>8</month><year>2010</year></pub-date><volume>14</volume><issue>6</issue><fpage>873</fpage><lpage>881</lpage><abstract><p id="P3">Triplex-forming oligonucleotides (TFOs) can bind specifically to polypurine sequences in double-stranded DNA. A single interruption of this polypurine tract can greatly destabilize triplex formation. The stability of triplexes can be significantly enhanced by covalently linking the TFO to its DNA target with reactive functional groups conjugated to the TFO. Covalently cross-linked TFOs are effective inhibitors of transcription of the target DNA sequence. We have designed a TFO with a platinum-modified base that can interact with and cross-link to a cytosine interruption in the polypurine tract of a target DNA duplex. The TFO contains an <italic>N</italic><sup>4</sup>-(aminoalkyl)cytosine derivatized with <italic>cis</italic>- or <italic>trans</italic>-diamminediaquaplatinum(II). When bound to its target, the tethered platinum of the TFO can reach across the major groove and form an adduct with the guanine N7 of the interrupting C·G base-pair. The optimal tether length is five methylene groups, and cross-linking is most efficient when the tether is modified with <italic>trans</italic>-diamminediaquaplatinum. Cross-linking requires that the TFO is bound to its designated DNA target. Addition of cyanide to the cross-linked TFO product reversed the cross-link, behavior that is consistent with the presence of a Pt-guanine adduct. The kinetics of the cross-linking reaction were studied and the half-life of the cross-linking reaction was approximately three hours. Our results demonstrate that platinum-conjugated TFOs can be designed to cross-link with DNA targets that contain a single pyrimidine interruption. Modifications of this type may prove useful for expanding the DNA sequences that can be targeted by TFOs and increasing the stability of the resulting triplexes.</p></abstract><kwd-group><kwd>cisplatin</kwd><kwd>triplex-forming oligonucleotide</kwd><kwd>cross-link</kwd><kwd>pyrimidine interruption</kwd></kwd-group><contract-num rid="GM1">R01 GM057140-09</contract-num><contract-sponsor id="GM1">National Institute of General Medical Sciences : NIGMS</contract-sponsor></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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