Design, synthesis, and evaluation of an a-helix mimetic library targeting protein-protein interactions

Shaginian, Alex, Whitby, Landon R., Hong, Sukwon, Hwang, Inkyu, Farooqi, Bilal, Searcey, Mark, Chen, Jiandong, Vogt, Peter K. and Boger, Dale L. (2009) Design, synthesis, and evaluation of an a-helix mimetic library targeting protein-protein interactions. Journal of the American Chemical Society, 131 (15). pp. 5564-5572.

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Abstract

The design and solution-phase synthesis of an a-helix mimetic library as an integral component of a small-molecule library targeting protein - protein interactions are described. The iterative design, synthesis, and evaluation of the candidate a-helix mimetic was initiated from a precedented triaryl template and refined by screening the designs for inhibition of MDM2/p53 binding. Upon identifying a chemically and biologically satisfactory design and consistent with the screening capabilities of academic collaborators, the corresponding complete library was assembled as 400 mixtures of 20 compounds (20 × 20 × 20-mix), where the added subunits are designed to mimic all possible permutations of the naturally occurring i, i + 4, i + 7 amino acid side chains of an a-helix. The library (8000 compounds) was prepared using a solution-phase synthetic protocol enlisting acid/base liquid-liquid extractions for purification on a scale that insures its long-term availability for screening campaigns. Screening of the library for inhibition of MDM2/p53 binding not only identified the lead a-helix mimetic upon which the library was based, but also suggests that a digestion of the initial screening results that accompany the use of such a comprehensive library can provide insights into the nature of the interaction (e.g., an a-helix mediated protein-protein interaction) and define the key residues and their characteristics responsible for recognition. © 2009 American Chemical Society.

Item Type: Article
Uncontrolled Keywords: small,hdm2,iminodiacetic acid libraries,in-vivo,olefin metathesis,antagonists,phase combinatorial synthesis,small-molecule antagonists,reaction,parallel synthesis,p53-mdm2 interaction,terephthalamide derivatives,organic-molecules
Faculty \ School: Faculty of Science > School of Pharmacy
Related URLs:
Depositing User: Rachel Smith
Date Deposited: 17 Mar 2011 14:22
Last Modified: 17 Mar 2020 15:35
URI: https://ueaeprints.uea.ac.uk/id/eprint/26558
DOI: 10.1021/ja810025g

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