Functionalized Double Strain-Promoted Stapled Peptides for Inhibiting the p53-MDM2 Interaction
| Autor: | Krishna Sharma, Hannah F. Sore, Warren R. J. D. Galloway, Laura S. Itzhaki, Yu Heng Lau, Ben G. N. Chappell, Matthew N. Grayson, David R. Spring, Wenshu Xu, Elaine Fowler, Alexander V. Strizhak |
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| Přispěvatelé: | Sore, Hannah [0000-0002-6542-0394], Itzhaki, Laura [0000-0001-6504-2576], Spring, David [0000-0001-7355-2824], Apollo - University of Cambridge Repository |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Strain (chemistry)
34 Chemical Sciences 010405 organic chemistry Chemistry General Chemical Engineering Substituent 3405 Organic Chemistry General Chemistry 010402 general chemistry 01 natural sciences Combinatorial chemistry Article P53 mdm2 0104 chemical sciences 3. Good health chemistry.chemical_compound 5.1 Pharmaceuticals Biological property Stapled peptide Reactivity (chemistry) 5 Development of treatments and therapeutic interventions QD1-999 |
| Zdroj: | ACS Omega, Vol 5, Iss 2, Pp 1157-1169 (2020) ACS Omega Sharma, K, Strizhak, A V, Fowler, E, Xu, W, Chappell, B, Sore, H F, Galloway, W R J D, Grayson, M N, Lau, Y H, Itzhaki, L S & Spring, D R 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 |
| ISSN: | 2470-1343 |
| DOI: | 10.1021/acsomega.9b03459 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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