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Rational design of peptide inhibitor...

Sia, Samuel Kwok-ki.

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Rational design of peptide inhibitors of HIV-1 entry.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Rational design of peptide inhibitors of HIV-1 entry./
Author:	Sia, Samuel Kwok-ki.
Description:	124 p.
Notes:	Adviser: Peter S. Kim.
Contained By:	Dissertation Abstracts International63-04B.
Subject:	Biology, Molecular. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3051289
ISBN:	0493658637

Rational design of peptide inhibitors of HIV-1 entry.
Sia, Samuel Kwok-ki.

Rational design of peptide inhibitors of HIV-1 entry. - 124 p.

Adviser: Peter S. Kim.

Thesis (Ph.D.)--Harvard University, 2002.

A direct method for preventing infection of the human immunodeficiency virus (HIV) is to prevent the virus from entering the host cells. HIV entry is initiated by the binding of the HIV envelope glycoprotein to host receptors, which triggers a conformational change in the envelope glycoprotein that ultimately fuses the viral membrane with the host membrane (<italic>1–3</italic>). A key event in the conformational change of the envelope glycoprotein, which is composed of the gp 120 and gp41 subunits, is the formation of a six-helix bundle through the interaction of two gp41 domains: the “N-peptide” region and the “C-peptide” region.

ISBN: 0493658637Subjects--Topical Terms:

1017719
Biology, Molecular.

Rational design of peptide inhibitors of HIV-1 entry.
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035 $a (UnM)AAI3051289
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100 1 $a Sia, Samuel Kwok-ki. $3 1251335
245 1 0 $a Rational design of peptide inhibitors of HIV-1 entry.
300 $a 124 p.
500 $a Adviser: Peter S. Kim.
500 $a Source: Dissertation Abstracts International, Volume: 63-04, Section: B, page: 1745.
502 $a Thesis (Ph.D.)--Harvard University, 2002.
520 $a A direct method for preventing infection of the human immunodeficiency virus (HIV) is to prevent the virus from entering the host cells. HIV entry is initiated by the binding of the HIV envelope glycoprotein to host receptors, which triggers a conformational change in the envelope glycoprotein that ultimately fuses the viral membrane with the host membrane (<italic>1–3</italic>). A key event in the conformational change of the envelope glycoprotein, which is composed of the gp 120 and gp41 subunits, is the formation of a six-helix bundle through the interaction of two gp41 domains: the “N-peptide” region and the “C-peptide” region.
520 $a Peptides that block the formation of the six-helix bundle can prevent HIV entry into cells (<italic>1, 4–9</italic>). Remarkably, the most promising class of peptide inhibitors is peptides derived from the C-peptide region (C-peptides), which, when added exogenously, are potent inhibitors of HIV membrane fusion (<italic>4, 5</italic>). The C-peptides inhibit membrane fusion by binding in a helical conformation to the gp41 N-peptide region, thereby preventing its interaction with the endogenous C-peptide region and formation of the six-helix bundle.
520 $a Despite the efficacy of the C-peptides in blocking HIV entry, their practical use is limited by the lack of conformational structure when not bound to HIV gp41 (<italic>10, 11</italic>). This deficiency leads to two main problems: increased sensitivity to extracellular proteases in vivo, and a loss of binding affinity to their target. Consequently, large amounts of one C-peptide (T-20) are needed to achieve a significant reduction in plasma viral load in vivo (<italic>12</italic>).
520 $a This thesis explores strategies which stabilize the active three-dimensional conformation of the C-peptides, the α-helix. The effect of chemical cross-linkers and unnatural amino acid substitutions on the binding affinity and inhibitory potency of short C-peptides is described. In another experiment, the binding epitope of the C-peptide is transferred to a stable, helical protein scaffold. Finally, the potential of helical peptides containing D-amino acids as a means of protease resistance is explored with the design of a novel four-helix bundle. The overall goal of the thesis is to marshal the existing knowledge of protein stability and design for a direct and practical biomedical goal, the prevention of HIV-1 entry.
590 $a School code: 0084.
650 4 $a Biology, Molecular. $3 1017719
650 4 $a Biophysics, General. $3 1019105
650 4 $a Chemistry, Biochemistry. $3 1017722
690 $a 0307
690 $a 0487
690 $a 0786
710 2 0 $a Harvard University. $3 528741
773 0 $t Dissertation Abstracts International $g 63-04B.
790 $a 0084
790 1 0 $a Kim, Peter S., $e advisor
791 $a Ph.D.
792 $a 2002
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3051289