Sharma, K orcid.org/0000-0001-5220-5823, Strizhak, AV, Fowler, E et al. (8 more authors) (2020) Functionalized Double Strain-Promoted Stapled Peptides for Inhibiting the p53-MDM2 Interaction. ACS Omega, 5 (2). pp. 1157-1169. ISSN 2470-1343
Abstract
The Sondheimer dialkyne reagent has previously been employed in strain-promoted double-click cycloadditions with bis-azide peptides to generate stapled peptide inhibitors of protein–protein interactions. The substituted variants of the Sondheimer dialkyne can be used to generate functionalized stapled peptide inhibitors with improved biological properties; however, this remains a relatively underdeveloped field. Herein, we report the synthesis of new substituted variants of Sondheimer dialkyne and their application in the stapling of p53-based diazido peptides to generate potent stapled peptide-based inhibitors of the oncogenic p53-MDM2 interaction. The functionalized stapled peptide formed from a meta-fluoro-substituted Sondheimer dialkyne was found to be the most potent inhibitor. Furthermore, through experimental studies and density functional theory calculations, we investigated the impact of the substituent on the strain-promoted double-click reactivity of Sondheimer dialkyne.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2020 American Chemical Society. ACS AuthorChoice - This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes. (https://pubs.acs.org/page/policy/authorchoice_termsofuse.html) |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Engineering & Physical Sciences (Leeds) > School of Chemistry (Leeds) > Organic Chemistry (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 23 Mar 2020 17:05 |
Last Modified: | 23 Mar 2020 17:05 |
Status: | Published |
Publisher: | American Chemical Society (ACS) |
Identification Number: | 10.1021/acsomega.9b03459 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:158648 |