A Novel Enediynyl Peptide Inhibitor of Furin That Blocks Processing of proPDGF-A, B and proVEGF-C
Identifieur interne : 000D84 ( Main/Exploration ); précédent : 000D83; suivant : 000D85A Novel Enediynyl Peptide Inhibitor of Furin That Blocks Processing of proPDGF-A, B and proVEGF-C
Auteurs : Ajoy Basak [Canada] ; Abdel-Majid Khatib [France] ; Dayani Mohottalage [Canada] ; Sarmistha Basak [Canada] ; Maria Kolajova [Canada] ; Subhendu Sekhar Bag [Inde] ; Amit Basak [Inde]Source :
- PLoS ONE [ 1932-6203 ] ; 2009.
Abstract
Furin represents a crucial member of secretory mammalian subtilase, the Proprotein Convertase (PC) or Proprotein Convertase Subtilisin/Kexin (PCSK) superfamily. It has been linked to cancer, tumorgenesis, viral and bacterial pathogenesis. As a result it is considered a major target for intervention of these diseases.
Herein, we report, for the first time, the synthesis and biological evaluation of a newly designed potent furin inhibitor that contains a highly reactive beta-turn inducing and radical generating “enediynyl amino acid” (Eda) moiety. “Eda” was inserted between P1 and P1′ residues of hfurin98–112 peptide, derived from the primary cleavage site of furin's own prodomain. The resulting hexadecapeptide derivative inhibited furin
These findings imply its potential as a therapeutic agent for intervention of cancer and other furin-associated diseases.
Url:
DOI: 10.1371/journal.pone.0007700
PubMed: 19956642
PubMed Central: 2778948
Affiliations:
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Diseases Program, Regional Protein Chemistry Center, Ottawa Hospital Research Institute, Department of Biochemistry, Microbiology and Immunology, University of Ottowa, Ottawa</wicri:regionArea><wicri:noRegion>Ottawa</wicri:noRegion></affiliation></author><author><name sortKey="Khatib, Abdel Majid" sort="Khatib, Abdel Majid" uniqKey="Khatib A" first="Abdel-Majid" last="Khatib">Abdel-Majid Khatib</name><affiliation wicri:level="3"><nlm:aff id="aff2"><addr-line>INSERM, UMRS940, Equipe AVENIR. Institut de Génétique Moléculaire, Hospital St-Louis, Paris, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>INSERM, UMRS940, Equipe AVENIR. 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It has been linked to cancer, tumorgenesis, viral and bacterial pathogenesis. As a result it is considered a major target for intervention of these diseases.</p></sec><sec><title>Methodology/Principal Findings</title><p>Herein, we report, for the first time, the synthesis and biological evaluation of a newly designed potent furin inhibitor that contains a highly reactive beta-turn inducing and radical generating “enediynyl amino acid” (Eda) moiety. “Eda” was inserted between P1 and P1′ residues of hfurin<sup>98–112</sup> peptide, derived from the primary cleavage site of furin's own prodomain. The resulting hexadecapeptide derivative inhibited furin <italic>in vitro</italic> with IC<sub>50</sub> ∼40 nM when measured against the fluorogenic substrate Boc-RVRR-MCA. It also inhibited furin-mediated cleavage of a fluorogenic peptide derived from hSARS-CoV spike protein with IC<sub>50</sub> ∼193 nM. Additionally it also blocked furin-processing of growth factors proPDGF-A, B and VEGF-C that are linked to tumor genesis and cancer. Circular dichroism study showed that this inhibitor displayed a predominantly beta-turn structure while western blots confirmed its ability to protect furin protein from self degradation.</p></sec><sec><title>Conclusion/Significance</title><p>These findings imply its potential as a therapeutic agent for intervention of cancer and other furin-associated diseases.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Seidah, Ng" uniqKey="Seidah N">NG Seidah</name></author><author><name sortKey="Mayer, G" uniqKey="Mayer G">G Mayer</name></author><author><name sortKey="Zaid, A" uniqKey="Zaid A">A Zaid</name></author><author><name sortKey="Rousselet, E" uniqKey="Rousselet E">E Rousselet</name></author><author><name sortKey="Nassoury, N" uniqKey="Nassoury N">N Nassoury</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Thomas, G" uniqKey="Thomas G">G 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sortKey="Cameron, A" uniqKey="Cameron A">A Cameron</name></author><author><name sortKey="Bourenkov, Gp" uniqKey="Bourenkov G">GP Bourenkov</name></author><author><name sortKey="Kiefersauer, R" uniqKey="Kiefersauer R">R Kiefersauer</name></author><author><name sortKey="Huber, R" uniqKey="Huber R">R Huber</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Holyoak, T" uniqKey="Holyoak T">T Holyoak</name></author><author><name sortKey="Kettner, Ca" uniqKey="Kettner C">CA Kettner</name></author><author><name sortKey="Petsko, Ga" uniqKey="Petsko G">GA Petsko</name></author><author><name sortKey="Fuller, Rs" uniqKey="Fuller R">RS Fuller</name></author><author><name sortKey="Ringe, D" uniqKey="Ringe D">D Ringe</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Siezen, Rj" uniqKey="Siezen R">RJ Siezen</name></author><author><name sortKey="Creemers, Jwm" uniqKey="Creemers J">JWM Creemers</name></author><author><name sortKey="Van De Ven, Wjm" uniqKey="Van De Ven W">WJM Van de ven</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>Canada</li><li>France</li><li>Inde</li></country><region><li>Île-de-France</li></region><settlement><li>Paris</li></settlement></list><tree><country name="Canada"><noRegion><name sortKey="Basak, Ajoy" sort="Basak, Ajoy" uniqKey="Basak A" first="Ajoy" last="Basak">Ajoy Basak</name></noRegion><name sortKey="Basak, Sarmistha" sort="Basak, Sarmistha" uniqKey="Basak S" first="Sarmistha" last="Basak">Sarmistha Basak</name><name sortKey="Kolajova, Maria" sort="Kolajova, Maria" uniqKey="Kolajova M" first="Maria" last="Kolajova">Maria Kolajova</name><name sortKey="Mohottalage, Dayani" sort="Mohottalage, Dayani" uniqKey="Mohottalage D" first="Dayani" last="Mohottalage">Dayani Mohottalage</name></country><country name="France"><region name="Île-de-France"><name sortKey="Khatib, Abdel Majid" sort="Khatib, Abdel Majid" uniqKey="Khatib A" first="Abdel-Majid" last="Khatib">Abdel-Majid Khatib</name></region><name sortKey="Khatib, Abdel Majid" sort="Khatib, Abdel Majid" uniqKey="Khatib A" first="Abdel-Majid" last="Khatib">Abdel-Majid Khatib</name></country><country name="Inde"><noRegion><name sortKey="Bag, Subhendu Sekhar" sort="Bag, Subhendu Sekhar" uniqKey="Bag S" first="Subhendu Sekhar" last="Bag">Subhendu Sekhar Bag</name></noRegion><name sortKey="Bag, Subhendu Sekhar" sort="Bag, Subhendu Sekhar" uniqKey="Bag S" first="Subhendu Sekhar" last="Bag">Subhendu Sekhar Bag</name><name sortKey="Basak, Amit" sort="Basak, Amit" uniqKey="Basak A" first="Amit" last="Basak">Amit Basak</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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