Directed Evolution of a Beta-Sheet Scaffold for Targeting Proteins Involved in Human Disease - Thrombin and the Vascular Endothelial Growth Factor (VEGF)

Persistent Link:
http://hdl.handle.net/10150/194401
Title:
Directed Evolution of a Beta-Sheet Scaffold for Targeting Proteins Involved in Human Disease - Thrombin and the Vascular Endothelial Growth Factor (VEGF)
Author:
Rajagopal, Srivats
Issue Date:
2007
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:
Aberrant protein-protein interactions have been implicated in numerous human diseases. Hence it becomes important to understand the physicochemical basis of these interactions as well as to develop methods to selectively target these protein surfaces. However, it is difficult to target such protein surfaces by small molecules as these surfaces (≥ 600 Ų) are large and flat. We demonstrate the feasibility of utilizing a small beta-sheet scaffold for targeting thrombin as proof of principle. Thrombin is a trypsinlike serine protease generated in the penultimate step of the blood coagulation cascade. Thrombin has numerous potential interaction sites to test our methodology. This strategy was further extended to target the Vascular Endothelial Growth Factor (VEGF). VEGF is a disulfide-linked cytokine that exerts its activity by binding to two high affinity receptors. VEGF has been implicated in angiogenesis where the growth of new blood capillaries provides nourishment to tumor cells and damage delicate retinal tissues. This will help us to develop a new scaffold and provide essential chemical and structural information necessary for binding these discrete protein surfaces. Furthermore, this facilitates the subsequent transfer of minimal epitope information to a small molecule.
Type:
text; Electronic Dissertation
Keywords:
Chemistry
Degree Name:
PhD
Degree Level:
doctoral
Degree Program:
Chemistry; Graduate College
Degree Grantor:
University of Arizona
Advisor:
Ghosh, Indraneel
Committee Chair:
Ghosh, Indraneel

Full metadata record

DC FieldValue Language
dc.language.isoENen_US
dc.titleDirected Evolution of a Beta-Sheet Scaffold for Targeting Proteins Involved in Human Disease - Thrombin and the Vascular Endothelial Growth Factor (VEGF)en_US
dc.creatorRajagopal, Srivatsen_US
dc.contributor.authorRajagopal, Srivatsen_US
dc.date.issued2007en_US
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.abstractAberrant protein-protein interactions have been implicated in numerous human diseases. Hence it becomes important to understand the physicochemical basis of these interactions as well as to develop methods to selectively target these protein surfaces. However, it is difficult to target such protein surfaces by small molecules as these surfaces (≥ 600 Ų) are large and flat. We demonstrate the feasibility of utilizing a small beta-sheet scaffold for targeting thrombin as proof of principle. Thrombin is a trypsinlike serine protease generated in the penultimate step of the blood coagulation cascade. Thrombin has numerous potential interaction sites to test our methodology. This strategy was further extended to target the Vascular Endothelial Growth Factor (VEGF). VEGF is a disulfide-linked cytokine that exerts its activity by binding to two high affinity receptors. VEGF has been implicated in angiogenesis where the growth of new blood capillaries provides nourishment to tumor cells and damage delicate retinal tissues. This will help us to develop a new scaffold and provide essential chemical and structural information necessary for binding these discrete protein surfaces. Furthermore, this facilitates the subsequent transfer of minimal epitope information to a small molecule.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectChemistryen_US
thesis.degree.namePhDen_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineChemistryen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorGhosh, Indraneelen_US
dc.contributor.chairGhosh, Indraneelen_US
dc.contributor.committeememberPolt, Robin L.en_US
dc.contributor.committeememberMash, Eugene A.en_US
dc.contributor.committeememberOlenyuk, Bogdan Z.en_US
dc.contributor.committeememberEnemark, John H.en_US
dc.contributor.committeememberMiranda, Katrina M.en_US
dc.identifier.proquest2469en_US
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