Peptide stapling by late-stage Suzuki-Miyaura cross-coupling

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Date

2022-01-01

Author

Gruss, Hendrik
Feiner, Rebecca C.
Mseya, Ridhiwan
Schroeder, David C.
Jewginski, Michat
Mueller, Kristian M.
Latajka, Rafat
Marıon, Antoıne
Sewald, Norbert

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The development of peptide stapling techniques to stabilise alpha-helical secondary structure motifs of peptides led to the design of modulators of protein-protein interactions, which had been considered undruggable for a long time. We disclose a novel approach towards peptide stapling utilising macrocyclisation by late-stage Suzuki-Miyaura cross-coupling of bromotryptophan-containing peptides of the catenin-binding domain of axin. Optimisation of the linker length in order to find a compromise between both sufficient linker rigidity and flexibility resulted in a peptide with an increased alpha-helicity and enhanced binding affinity to its native binding partner beta-catenin. An increased proteolytic stability against proteinase K has been demonstrated.

Subject Keywords

accelerated molecular dynamics, halotryptophan, intrinsically disordered peptides, late-stage diversification, macrocyclisation, molecular dynamics, stapled peptides, Suzuki-Miyaura cross-coupling, ACCELERATED MOLECULAR-DYNAMICS, ALPHA-HELICAL PEPTIDES, ENZYMATIC HALOGENATION, TRYPTOPHAN, ARYLATION, MACROCYCLIZATION, DIVERSIFICATION, MILD, SIMULATIONS, STABILITY

URI

https://hdl.handle.net/11511/95357

Journal

BEILSTEIN JOURNAL OF ORGANIC CHEMISTRY

DOI

https://doi.org/10.3762/bjoc.18.1

Collections

Department of Chemistry, Article

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Citation Formats

H. Gruss et al., “Peptide stapling by late-stage Suzuki-Miyaura cross-coupling,” BEILSTEIN JOURNAL OF ORGANIC CHEMISTRY, vol. 18, pp. 0–0, 2022, Accessed: 00, 2022. [Online]. Available: https://hdl.handle.net/11511/95357.