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    Design and synthesis of conformationally constrained glucagon analogues to study the conformational features important for glucagon bioactivity.

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    Author
    Lin, Ying.
    Issue Date
    1993
    Keywords
    Dissertations, Academic.
    Biochemistry.
    Chemistry, Organic.
    Committee Chair
    Hruby, Victor J.
    
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    Show full item record
    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
    We have synthesized ten glucagon analogues that are either conformationally constrained systematically in the middle portion of the molecule, or modified from the known superagonist analogue [Lys¹⁷,¹⁸, Glu²¹]glucagon to study the structure-activity relationships of glucagon. The analogues were prepared using the solid-phase peptide synthesis method. Cyclizations were accomplished by forming the side chain lactam (amide) bridges on the resin. All peptide analogues were cleaved from the solid support, deprotected by the low-high HF procedure, and purified by a combination of gel filtration chromatography and dialysis followed by reverse-phase high performance liquid chromatography. A new characterization method for cyclic glucagon analogues using fast atom bombardment mass spectrometry with endoproteinase Asp-N peptide mapping has been developed that has provided unequivocal confirmation of the presence and site of the rings as well as the amino acid compositions. Receptor binding and adenylate cyclase activity assays and circular dichroism spectroscopy have been used to reveal the role of the structure and conformation of the middle portion of the molecule. The effects of the modification of the 17, 18 and 21 positions on the superagonist activity have also been examined. Several key features of the peptide backbone conformation responsible for binding and transduction have been further studied by theoretical calculations and computer modeling (energy minimization) using the Sybyl program.
    Type
    text
    Dissertation-Reproduction (electronic)
    Degree Name
    Ph.D.
    Degree Level
    doctoral
    Degree Program
    Chemistry
    Graduate College
    Degree Grantor
    University of Arizona
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    Dissertations

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