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" Characterization of Binding Interactions Between Heparin, and Peptides and Peptidomimetics "
Hamza, Mark
Rabenstein, Dallas L
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Latin Dissertation
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English
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905655
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TL5bk4z629
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Hamza, Mark
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Characterization of Binding Interactions Between Heparin, and Peptides and Peptidomimetics\ Hamza, MarkRabenstein, Dallas L
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UC Riverside
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2010
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2010
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| Abstract
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ABSTRACT OF THE DISSERTATIONCharacterization of Binding Interactions Between Heparin, and Peptides and PeptidomimeticsByMark HamzaDoctor of Philosophy, Graduate Program in ChemistryUniversity of California, Riverside, June 2010Dr. Dallas L. Rabenstein, Chairperson The aim of this work is to determine the feasibility of peptides and/or peptidomimetics, such as peptoids and peptide/peptoid hybrids, as suitable replacements for Protamine, a drug used to inactivate heparin's anticoagulant activity. Heparin is administered to prevent blood coagulation during certain medical procedures, such as cardiopulmonary bypass. Heparin prevents coagulation by forming a complex with antithrombin, a serine protease inhibitor, thereby accelerating antithrombin's activity. Protamine is then used to restore the coagulation cascade by displacing heparin from antithrombin forming a heparin-Protamine complex. As Protamine has exhibited detrimental side-effects during its administration, this work has endeavored to design a safer alternative. Several methods have been implemented to characterize the binding interaction between heparin, and the peptides and peptidomimetics developed in this work: (i) isothermal titration calorimetry was utilized to acquire a quantitative binding constant which demonstrated that some of the peptides and peptidomimetics exhibit a high heparin-binding affinity which is critical to displace heparin from antithrombin; (ii) heparin affinity chromatography was used to determine a relative heparin-binding affinity between peptides and peptidomimetics for which a quantitative binding constant could not be measured due to weak heparin-binding interactions; (iii) secondary structure of peptides and peptidomimetics was ascertained by circular dichroism. The compounds synthesized in this work were observed to conform to either a polyproline I-type or polyproline II-type helical secondary structure. Establishing secondary structure is a vital factor in the rational design of heparin-binding peptides and peptidomimetics. The results of this work show that peptides and peptidomimetics can be rationally designed so as to bind heparin with high affinity. This is an important step in demonstrating that the peptides and peptidomimetics designed in this work have the potential to replace Protamine as an antagonist to heparin.
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Rabenstein, Dallas L
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UC Riverside
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