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Studies toward design of an oligosaccharide scaffold to targetp53-MDM2.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Studies toward design of an oligosaccharide scaffold to targetp53-MDM2.
Author:	Sakurai, Kaori.
Description:	238 p.
Notes:	Adviser: Dan Kahne.
Notes:	Source: Dissertation Abstracts International, Volume: 64-01, Section: B, page: 0218.
Contained By:	Dissertation Abstracts International64-01B.
Subject:	Chemistry, Organic.
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3078637
ISBN:	0493995137

Studies toward design of an oligosaccharide scaffold to targetp53-MDM2.
Sakurai, Kaori.

Studies toward design of an oligosaccharide scaffold to targetp53-MDM2. [electronic resource] - 238 p.

Adviser: Dan Kahne.

Thesis (Ph.D.)--Princeton University, 2003.

A co-complex between MDM2 and an 8-residue p53 peptide analogue developed at Novartis is described. The 8 mer peptide binds MDM2 in short helical turns, similar to the wild type p53 peptide. Notably, the orientations of the key hydrophobic side chains were almost superimposable at the binding interface.

ISBN: 0493995137Subjects--Topical Terms:

193634
Chemistry, Organic.

Studies toward design of an oligosaccharide scaffold to targetp53-MDM2.
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500 $a Source: Dissertation Abstracts International, Volume: 64-01, Section: B, page: 0218.
502 $a Thesis (Ph.D.)--Princeton University, 2003.
520 # $a A co-complex between MDM2 and an 8-residue p53 peptide analogue developed at Novartis is described. The 8 mer peptide binds MDM2 in short helical turns, similar to the wild type p53 peptide. Notably, the orientations of the key hydrophobic side chains were almost superimposable at the binding interface.
520 # $a Overexpression of MDM2 inhibits p53 function and has been implicated in many human cancers. Molecules that target the p53-MDM2 interface are, therefore, anticipated to be therapeutic agents.
520 # $a To further explore if the peptide backbone can be replaced by a preorganized, non-peptidic scaffold to achieve the required side chain presentation for the binding, oligosaccharide scaffold was designed. A synthetic route for the functionalized oligosaccharide scaffold was developed using the sulfoxide glycosylation reaction as a key coupling method. The functionalized oligosaccharide scaffold aggregated, making it difficult to evaluate their MDM2 binding activity. However, a modular and convergent synthesis of functionalized oligosaccharides may potentially be utilized to target other protein-protein interfaces that involve similar helical recognition motifs as in the p53-MDM2 interaction.
520 # $a Two approaches toward the design of small molecule scaffolds that target p53-MDM2 are presented. In one, we probed the role of the peptide backbone of the p53 peptide in MDM2 binding, using a retro and a retroinverso peptide. The conformational behavior and the activity of these backbone modified peptides are described. We found that specific side chain presentation is important for binding but the peptide backbone structure is not. Our results demonstrate the utility of retroinverso peptides for probing the nature of peptide-protein interactions.
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