EGF Receptor-Targeting Peptide Conjugate Incorporating a Near-IR Fluorescent Dye and a Novel 1,4,7-Triazacyclononane-Based ^sup 64^Cu(II) Chelator Assembled via Click Chemistry
A new Boc-protected 1,4,7-triazacyclononane (TACN)-based pro-chelator compound featuring a "clickable" azidomethylpyridine pendant has been developed as a building block for the construction of multimodal imaging agents. Conjugation to a model alkyne (propargyl alcohol), followed by deprot...
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| Veröffentlicht in: | Bioconjugate chemistry 2014-05, Vol.25 (5), p.1011 |
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| creator | Viehweger, Katrin Barbaro, Lisa García, Karina Pombo Joshi, Tanmaya Geipel, Gerhard Steinbach, Jörg Stephan, Holger Spiccia, Leone Graham, Bim |
| description | A new Boc-protected 1,4,7-triazacyclononane (TACN)-based pro-chelator compound featuring a "clickable" azidomethylpyridine pendant has been developed as a building block for the construction of multimodal imaging agents. Conjugation to a model alkyne (propargyl alcohol), followed by deprotection, generates a pentadentate ligand, as confirmed by X-ray crystallographic analysis of the corresponding distorted square-pyramidal Cu(II) complex. The ligand exhibits rapid 64Cu(II)-binding kinetics (>95% radiochemical yield in |
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Conjugation to a model alkyne (propargyl alcohol), followed by deprotection, generates a pentadentate ligand, as confirmed by X-ray crystallographic analysis of the corresponding distorted square-pyramidal Cu(II) complex. The ligand exhibits rapid 64Cu(II)-binding kinetics (>95% radiochemical yield in <5 min) and a high resistance to demetalation. It may thus prove suitable for use in 64Cu(II)-based in vivo positron emission tomography (PET). The new chelating building block has been applied to the construction of a bimodal (PET/fluorescence) peptide-based imaging probe targeting the epidermal growth factor (EGF) receptor, which is highly overexpressed on the surface of several types of cancer cells. The probe consists of a hexapeptide sequence, Leu-Ala-Arg-Leu-Leu-Thr (designated "D4"), followed by a Cys-β-Ala-β-Ala spacer, then a β-homopropargylglycine residue with the TACN-based chelator "clicked" to its side chain. A sulfonated near-infrared (NIR) fluorescent cyanine dye (sulfo-Cy5) was introduced at the N-terminus to study the EGF receptor-binding ability of the probe by laser-fluorescence spectroscopy. Binding was also confirmed by coimmunoprecipitation methods, and an apparent dissociation constant (Kd) of ca. 10 nM was determined from radioactivity-based measurements of probe binding to two EGF receptor-expressing cell lines (FaDu and A431). The probe is shown to be a biased or partial allosteric agonist of the EGF receptor, inducing phosphorylation of Thr669 and Tyr992, but not the Tyr845, Tyr998, Tyr1045, Tyr1068, or Tyr1148 residues of the receptor, in the absence of the orthosteric EGF ligand. Additionally, the probe was found to suppress the EGF-stimulated autophosphorylation of these latter residues, indicating that it is also a noncompetitive antagonist.</description><identifier>ISSN: 1043-1802</identifier><identifier>EISSN: 1520-4812</identifier><language>eng</language><publisher>Washington: American Chemical Society</publisher><subject>Cancer ; Crystallography ; Fluorescence ; Phosphorylation ; Radioactivity ; Tomography</subject><ispartof>Bioconjugate chemistry, 2014-05, Vol.25 (5), p.1011</ispartof><rights>Copyright American Chemical Society May 21, 2014</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780</link.rule.ids></links><search><creatorcontrib>Viehweger, Katrin</creatorcontrib><creatorcontrib>Barbaro, Lisa</creatorcontrib><creatorcontrib>García, Karina Pombo</creatorcontrib><creatorcontrib>Joshi, Tanmaya</creatorcontrib><creatorcontrib>Geipel, Gerhard</creatorcontrib><creatorcontrib>Steinbach, Jörg</creatorcontrib><creatorcontrib>Stephan, Holger</creatorcontrib><creatorcontrib>Spiccia, Leone</creatorcontrib><creatorcontrib>Graham, Bim</creatorcontrib><title>EGF Receptor-Targeting Peptide Conjugate Incorporating a Near-IR Fluorescent Dye and a Novel 1,4,7-Triazacyclononane-Based ^sup 64^Cu(II) Chelator Assembled via Click Chemistry</title><title>Bioconjugate chemistry</title><description>A new Boc-protected 1,4,7-triazacyclononane (TACN)-based pro-chelator compound featuring a "clickable" azidomethylpyridine pendant has been developed as a building block for the construction of multimodal imaging agents. Conjugation to a model alkyne (propargyl alcohol), followed by deprotection, generates a pentadentate ligand, as confirmed by X-ray crystallographic analysis of the corresponding distorted square-pyramidal Cu(II) complex. The ligand exhibits rapid 64Cu(II)-binding kinetics (>95% radiochemical yield in <5 min) and a high resistance to demetalation. It may thus prove suitable for use in 64Cu(II)-based in vivo positron emission tomography (PET). The new chelating building block has been applied to the construction of a bimodal (PET/fluorescence) peptide-based imaging probe targeting the epidermal growth factor (EGF) receptor, which is highly overexpressed on the surface of several types of cancer cells. The probe consists of a hexapeptide sequence, Leu-Ala-Arg-Leu-Leu-Thr (designated "D4"), followed by a Cys-β-Ala-β-Ala spacer, then a β-homopropargylglycine residue with the TACN-based chelator "clicked" to its side chain. A sulfonated near-infrared (NIR) fluorescent cyanine dye (sulfo-Cy5) was introduced at the N-terminus to study the EGF receptor-binding ability of the probe by laser-fluorescence spectroscopy. Binding was also confirmed by coimmunoprecipitation methods, and an apparent dissociation constant (Kd) of ca. 10 nM was determined from radioactivity-based measurements of probe binding to two EGF receptor-expressing cell lines (FaDu and A431). The probe is shown to be a biased or partial allosteric agonist of the EGF receptor, inducing phosphorylation of Thr669 and Tyr992, but not the Tyr845, Tyr998, Tyr1045, Tyr1068, or Tyr1148 residues of the receptor, in the absence of the orthosteric EGF ligand. Additionally, the probe was found to suppress the EGF-stimulated autophosphorylation of these latter residues, indicating that it is also a noncompetitive antagonist.</description><subject>Cancer</subject><subject>Crystallography</subject><subject>Fluorescence</subject><subject>Phosphorylation</subject><subject>Radioactivity</subject><subject>Tomography</subject><issn>1043-1802</issn><issn>1520-4812</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><recordid>eNqNjs1Kw0AUhYMoWH_e4YIbhQ7MTJKaLjU2mo1Iybrlmlxj4nQmzk8hPpWPaCo-gKtzON-3OEfRTKSSsyQT8njqPImZyLg8jc6c6znnS5HJWfS9eixgTTUN3lhWoW3Jd7qFl2noGoLc6D606AlKXRs7GIu_HOGZ0LJyDYUKxpKrSXt4GAlQNwdq9qRAzJP5Latsh19Yj7Uy2mjUxO7RUQMbFwZYJJs8XJflDeTvpHB6AXfO0e5VTca-Q8hVV38c4K5z3o4X0ckbKkeXf3keXRWrKn9igzWfgZzf9iZYPaGtSGMp02UWL-L_WT-aWmCq</recordid><startdate>20140521</startdate><enddate>20140521</enddate><creator>Viehweger, Katrin</creator><creator>Barbaro, Lisa</creator><creator>García, Karina Pombo</creator><creator>Joshi, Tanmaya</creator><creator>Geipel, Gerhard</creator><creator>Steinbach, Jörg</creator><creator>Stephan, Holger</creator><creator>Spiccia, Leone</creator><creator>Graham, Bim</creator><general>American Chemical Society</general><scope>7QO</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20140521</creationdate><title>EGF Receptor-Targeting Peptide Conjugate Incorporating a Near-IR Fluorescent Dye and a Novel 1,4,7-Triazacyclononane-Based ^sup 64^Cu(II) Chelator Assembled via Click Chemistry</title><author>Viehweger, Katrin ; Barbaro, Lisa ; García, Karina Pombo ; Joshi, Tanmaya ; Geipel, Gerhard ; Steinbach, Jörg ; Stephan, Holger ; Spiccia, Leone ; Graham, Bim</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-proquest_journals_15322598363</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Cancer</topic><topic>Crystallography</topic><topic>Fluorescence</topic><topic>Phosphorylation</topic><topic>Radioactivity</topic><topic>Tomography</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Viehweger, Katrin</creatorcontrib><creatorcontrib>Barbaro, Lisa</creatorcontrib><creatorcontrib>García, Karina Pombo</creatorcontrib><creatorcontrib>Joshi, Tanmaya</creatorcontrib><creatorcontrib>Geipel, Gerhard</creatorcontrib><creatorcontrib>Steinbach, Jörg</creatorcontrib><creatorcontrib>Stephan, Holger</creatorcontrib><creatorcontrib>Spiccia, Leone</creatorcontrib><creatorcontrib>Graham, Bim</creatorcontrib><collection>Biotechnology Research Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Bioconjugate chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Viehweger, Katrin</au><au>Barbaro, Lisa</au><au>García, Karina Pombo</au><au>Joshi, Tanmaya</au><au>Geipel, Gerhard</au><au>Steinbach, Jörg</au><au>Stephan, Holger</au><au>Spiccia, Leone</au><au>Graham, Bim</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>EGF Receptor-Targeting Peptide Conjugate Incorporating a Near-IR Fluorescent Dye and a Novel 1,4,7-Triazacyclononane-Based ^sup 64^Cu(II) Chelator Assembled via Click Chemistry</atitle><jtitle>Bioconjugate chemistry</jtitle><date>2014-05-21</date><risdate>2014</risdate><volume>25</volume><issue>5</issue><spage>1011</spage><pages>1011-</pages><issn>1043-1802</issn><eissn>1520-4812</eissn><abstract>A new Boc-protected 1,4,7-triazacyclononane (TACN)-based pro-chelator compound featuring a "clickable" azidomethylpyridine pendant has been developed as a building block for the construction of multimodal imaging agents. Conjugation to a model alkyne (propargyl alcohol), followed by deprotection, generates a pentadentate ligand, as confirmed by X-ray crystallographic analysis of the corresponding distorted square-pyramidal Cu(II) complex. The ligand exhibits rapid 64Cu(II)-binding kinetics (>95% radiochemical yield in <5 min) and a high resistance to demetalation. It may thus prove suitable for use in 64Cu(II)-based in vivo positron emission tomography (PET). The new chelating building block has been applied to the construction of a bimodal (PET/fluorescence) peptide-based imaging probe targeting the epidermal growth factor (EGF) receptor, which is highly overexpressed on the surface of several types of cancer cells. The probe consists of a hexapeptide sequence, Leu-Ala-Arg-Leu-Leu-Thr (designated "D4"), followed by a Cys-β-Ala-β-Ala spacer, then a β-homopropargylglycine residue with the TACN-based chelator "clicked" to its side chain. A sulfonated near-infrared (NIR) fluorescent cyanine dye (sulfo-Cy5) was introduced at the N-terminus to study the EGF receptor-binding ability of the probe by laser-fluorescence spectroscopy. Binding was also confirmed by coimmunoprecipitation methods, and an apparent dissociation constant (Kd) of ca. 10 nM was determined from radioactivity-based measurements of probe binding to two EGF receptor-expressing cell lines (FaDu and A431). The probe is shown to be a biased or partial allosteric agonist of the EGF receptor, inducing phosphorylation of Thr669 and Tyr992, but not the Tyr845, Tyr998, Tyr1045, Tyr1068, or Tyr1148 residues of the receptor, in the absence of the orthosteric EGF ligand. Additionally, the probe was found to suppress the EGF-stimulated autophosphorylation of these latter residues, indicating that it is also a noncompetitive antagonist.</abstract><cop>Washington</cop><pub>American Chemical Society</pub></addata></record> |
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| ispartof | Bioconjugate chemistry, 2014-05, Vol.25 (5), p.1011 |
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| source | American Chemical Society Journals |
| subjects | Cancer Crystallography Fluorescence Phosphorylation Radioactivity Tomography |
| title | EGF Receptor-Targeting Peptide Conjugate Incorporating a Near-IR Fluorescent Dye and a Novel 1,4,7-Triazacyclononane-Based ^sup 64^Cu(II) Chelator Assembled via Click Chemistry |
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