A BIVALENT METHODOLOGY FOR TARGETING PROTEIN KINASES: CONJUGATING PHAGE DISPLAY SELECTED CYCLIC PEPTIDES TO STAUROSPORINE

Persistent Link:
http://hdl.handle.net/10150/202950
Title:
A BIVALENT METHODOLOGY FOR TARGETING PROTEIN KINASES: CONJUGATING PHAGE DISPLAY SELECTED CYCLIC PEPTIDES TO STAUROSPORINE
Author:
Shomin, Carolyn
Issue Date:
2011
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
Protein kinases constitute essential biological and target class owing to the vital function of reversible phosphorylation catalyzed by these enzymes. With more than 500 kinases in the human genome, containing conserved structure and overlapping function, pose challenging targets for inhibition. Alternative methods for targeting protein kinases remain warranted as the traditional methods are biased toward ATP-competitive compounds. These methods have yielded successful therapeutics, however toxicity due to nonselectivity and limited development potential due to intense drug discovery efforts renders alternative modes of action attractive as new goals for protein kinase inhibition.Herein is presented a bivalent methodology for targeting protein kinases comprising staurosporine tethered a phage display cyclic peptide library such that the cyclic peptide is directed to areas on the kinase surface distinct from the ATP-site where staurosporine is bound. Presented in detail is this strategy as it was successfully applied to Protein Kinase A and the subsequent analysis of bivalent ligands. Since this initial study several kinases have been targeted with this methodology and Application to Aurora Kinase A will be explored in detail. An essential analysis of results to date is included as it applies to the redesign, construction, and application of new cyclic phage libraries. Finally, to complete the first successful application against Protein Kinase A, we explore kinase expression for structural studies.
Type:
text; Electronic Dissertation
Keywords:
surface targeting; Pharmaceutical Sciences; inhibitor; protein kinases
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Pharmaceutical Sciences
Degree Grantor:
University of Arizona
Advisor:
Ghosh, Indraneel

Full metadata record

DC FieldValue Language
dc.language.isoenen_US
dc.titleA BIVALENT METHODOLOGY FOR TARGETING PROTEIN KINASES: CONJUGATING PHAGE DISPLAY SELECTED CYCLIC PEPTIDES TO STAUROSPORINEen_US
dc.creatorShomin, Carolynen_US
dc.contributor.authorShomin, Carolynen_US
dc.date.issued2011-
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractProtein kinases constitute essential biological and target class owing to the vital function of reversible phosphorylation catalyzed by these enzymes. With more than 500 kinases in the human genome, containing conserved structure and overlapping function, pose challenging targets for inhibition. Alternative methods for targeting protein kinases remain warranted as the traditional methods are biased toward ATP-competitive compounds. These methods have yielded successful therapeutics, however toxicity due to nonselectivity and limited development potential due to intense drug discovery efforts renders alternative modes of action attractive as new goals for protein kinase inhibition.Herein is presented a bivalent methodology for targeting protein kinases comprising staurosporine tethered a phage display cyclic peptide library such that the cyclic peptide is directed to areas on the kinase surface distinct from the ATP-site where staurosporine is bound. Presented in detail is this strategy as it was successfully applied to Protein Kinase A and the subsequent analysis of bivalent ligands. Since this initial study several kinases have been targeted with this methodology and Application to Aurora Kinase A will be explored in detail. An essential analysis of results to date is included as it applies to the redesign, construction, and application of new cyclic phage libraries. Finally, to complete the first successful application against Protein Kinase A, we explore kinase expression for structural studies.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectsurface targetingen_US
dc.subjectPharmaceutical Sciencesen_US
dc.subjectinhibitoren_US
dc.subjectprotein kinasesen_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplinePharmaceutical Sciencesen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorGhosh, Indraneelen_US
dc.contributor.committeememberHulme, Christopheren_US
dc.contributor.committeememberHurley, Laurenceen_US
dc.contributor.committeememberWondrak, Georgen_US
dc.contributor.committeememberVaillancourt, Richarden_US
dc.contributor.committeememberGhosh, Indraneelen_US
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