Functionalized Double Strain-Promoted Stapled Peptides for Inhibiting the p53-MDM2 Interaction

Krishna Sharma, Alexander V. Strizhak, Elaine Fowler, Wenshu Xu, Ben Chappell, Hannah F. Sore, Warren R. J. D. Galloway, Matthew N. Grayson, Yu Heng Lau, Laura S. Itzhaki, David R. Spring

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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.
Original languageEnglish
Pages (from-to)1157-1169
JournalACS OMEGA
Volume5
Issue number2
Early online date7 Jan 2020
DOIs
Publication statusPublished - 21 Jan 2020

Cite this

Sharma, K., Strizhak, A. V., Fowler, E., Xu, W., Chappell, B., Sore, H. F., ... Spring, D. R. (2020). Functionalized Double Strain-Promoted Stapled Peptides for Inhibiting the p53-MDM2 Interaction. ACS OMEGA, 5(2), 1157-1169. https://doi.org/10.1021/acsomega.9b03459

Functionalized Double Strain-Promoted Stapled Peptides for Inhibiting the p53-MDM2 Interaction. / Sharma, Krishna; Strizhak, Alexander V.; Fowler, Elaine; Xu, Wenshu; Chappell, Ben; Sore, Hannah F.; Galloway, Warren R. J. D.; Grayson, Matthew N.; Lau, Yu Heng; Itzhaki, Laura S.; Spring, David R.

In: ACS OMEGA, Vol. 5, No. 2, 21.01.2020, p. 1157-1169.

Research output: Contribution to journalArticle

Sharma, K, Strizhak, AV, Fowler, E, Xu, W, Chappell, B, Sore, HF, Galloway, WRJD, Grayson, MN, Lau, YH, Itzhaki, LS & Spring, DR 2020, 'Functionalized Double Strain-Promoted Stapled Peptides for Inhibiting the p53-MDM2 Interaction', ACS OMEGA, vol. 5, no. 2, pp. 1157-1169. https://doi.org/10.1021/acsomega.9b03459
Sharma K, Strizhak AV, Fowler E, Xu W, Chappell B, Sore HF et al. Functionalized Double Strain-Promoted Stapled Peptides for Inhibiting the p53-MDM2 Interaction. ACS OMEGA. 2020 Jan 21;5(2):1157-1169. https://doi.org/10.1021/acsomega.9b03459
Sharma, Krishna ; Strizhak, Alexander V. ; Fowler, Elaine ; Xu, Wenshu ; Chappell, Ben ; Sore, Hannah F. ; Galloway, Warren R. J. D. ; Grayson, Matthew N. ; Lau, Yu Heng ; Itzhaki, Laura S. ; Spring, David R. / Functionalized Double Strain-Promoted Stapled Peptides for Inhibiting the p53-MDM2 Interaction. In: ACS OMEGA. 2020 ; Vol. 5, No. 2. pp. 1157-1169.
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