A synthetic antibody-mimetic approach to protein surface receptors [electronic resource] / Qing Lin

Lin, Qing
Bib ID
vtls000568973
稽核項
179 p.
電子版
附註項
數位化論文典藏聯盟
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$a A synthetic antibody-mimetic approach to protein surface receptors $h [electronic resource] / $c Qing Lin
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$a 179 p.
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$a Source: Dissertation Abstracts International, Volume: 61-05, Section: B, page: 2521.
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$a Director:  Andrew D. Hamilton.
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$a Thesis (Ph.D.)--Yale University, 2000.
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$a The design, synthesis and evaluation of synthetic receptors for protein surface recognition is described. The receptors are based on a design in which four peptide loops are arrayed around a central calix[4]arene core, in an analog to antibody Fab structures. A receptor library with differently functionalized receptor surfaces approximately 450&Aring;<super>2</super> was thus prepared. In a model study with cytochrome <italic>c</italic>, some members of the library were shown to inhibit the reduction activity of Fe(III)cytochrome <italic> c</italic> through binding to the heme region. One receptor (<bold>26</bold>) was able to disrupt a native Cc-CcP protein complex in aqueous buffer.
520
$a We have identified several potent inhibitors of &alpha;-chymotrypsin from this receptor library that function by binding to the surface of the protein. The most potent of these (<bold>26</bold>) shows slow binding kinetics in an analogous manner to several of the natural proteinaceous inhibitors (<italic>K</italic><sub>i</sub> and <italic>K</italic><sub>i</sub>* values of 0.81 and 0.11&mu;M, respectively). In addition, receptor <bold>26</bold> is able to displace a proteinaceous inhibitor, STI, from the native ChT-STI complex via a ternary complex intermediate in a time-dependent manner.
520
$a An antagonist for protein-protein interactions, GFB-111 (<bold>27</bold>), was also identified from our receptor library. GFB-111 is able to bind to PDGF, prevent it from binding to its receptor, block PDGF-induced receptor autophosphorylation, activation of Erk1 and Erk2 kinases and DNA synthesis. GFB-111 is also shown to be a highly potent (IC<sub>50</sub> = 250nM) and selective antagonist for PDGF over EGF, IGF-1, aFGF, bFGF and HRG&beta; (IC<sub> 50</sub> values > 100&mu;M).
520
$a A series of hybrids that combine a protein surface receptor with a protein active site inhibitor were constructed via variable-length linkers with the aim to modulate protein function. One linked hybrid molecule (<bold>80</bold>) was found to increase the inhibitory activity of the active site inhibitor for thrombin by over 12 fold.
520
$a An efficient route for the stepwise functionalizations of calix[4]arene upper rim was described. A series of A3B- and A2B2-type unsymmetrical receptors (<bold>91-99</bold>) based on the partially protected calix[4]arene tetracarboxylic acids were thus synthesized in a parallel fashion. A solution phase receptor library (<bold>100</bold>) containing over 170 members was prepared and characterized.
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$a 數位化論文典藏聯盟 $b PQDT $c 中山大學(2001~2002)
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$a Chemistry, Biochemistry.
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$a Hamilton, Andrew D., $e advisor
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$a Yale University.
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The design, synthesis and evaluation of synthetic receptors for protein surface recognition is described. The receptors are based on a design in which four peptide loops are arrayed around a central calix[4]arene core, in an analog to antibody Fab structures. A receptor library with differently functionalized receptor surfaces approximately 450&Aring;<super>2</super> was thus prepared. In a model study with cytochrome <italic>c</italic>, some members of the library were shown to inhibit the reduction activity of Fe(III)cytochrome <italic> c</italic> through binding to the heme region. One receptor (<bold>26</bold>) was able to disrupt a native Cc-CcP protein complex in aqueous buffer.
We have identified several potent inhibitors of &alpha;-chymotrypsin from this receptor library that function by binding to the surface of the protein. The most potent of these (<bold>26</bold>) shows slow binding kinetics in an analogous manner to several of the natural proteinaceous inhibitors (<italic>K</italic><sub>i</sub> and <italic>K</italic><sub>i</sub>* values of 0.81 and 0.11&mu;M, respectively). In addition, receptor <bold>26</bold> is able to displace a proteinaceous inhibitor, STI, from the native ChT-STI complex via a ternary complex intermediate in a time-dependent manner.
An antagonist for protein-protein interactions, GFB-111 (<bold>27</bold>), was also identified from our receptor library. GFB-111 is able to bind to PDGF, prevent it from binding to its receptor, block PDGF-induced receptor autophosphorylation, activation of Erk1 and Erk2 kinases and DNA synthesis. GFB-111 is also shown to be a highly potent (IC<sub>50</sub> = 250nM) and selective antagonist for PDGF over EGF, IGF-1, aFGF, bFGF and HRG&beta; (IC<sub> 50</sub> values > 100&mu;M).
A series of hybrids that combine a protein surface receptor with a protein active site inhibitor were constructed via variable-length linkers with the aim to modulate protein function. One linked hybrid molecule (<bold>80</bold>) was found to increase the inhibitory activity of the active site inhibitor for thrombin by over 12 fold.
An efficient route for the stepwise functionalizations of calix[4]arene upper rim was described. A series of A3B- and A2B2-type unsymmetrical receptors (<bold>91-99</bold>) based on the partially protected calix[4]arene tetracarboxylic acids were thus synthesized in a parallel fashion. A solution phase receptor library (<bold>100</bold>) containing over 170 members was prepared and characterized.
附註
Source: Dissertation Abstracts International, Volume: 61-05, Section: B, page: 2521.
Director: Andrew D. Hamilton.
Thesis (Ph.D.)--Yale University, 2000.
數位化論文典藏聯盟
合著者
ISBN/ISSN
0599791306