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

Hendrik Gruß; Rebecca C Feiner; Ridhiwan Mseya; David C Schröder; Michał Jewgiński; Kristian M Müller; Rafał Latajka; Antoine Marion; Norbert Sewald

doi:10.3762/bjoc.18.1

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

Beilstein J Org Chem. 2022 Jan 3:18:1-12. doi: 10.3762/bjoc.18.1. eCollection 2022.

Authors

Affiliations

¹ Department of Chemistry, Bielefeld University, Universitätsstr. 25, 33615 Bielefeld, Germany.
² Department of Technology, Bielefeld University, Universitätsstr. 25, 33615 Bielefeld, Germany.
³ Department of Chemistry, Middle East Technical University, 06800, Ankara, Turkey.
⁴ Department of Bioorganic Chemistry, Wrocław University of Science and Technology, Wybrzeze Wyspianskiego 27, 50-370 Wrocław, Poland.

^# Contributed equally.

Abstract

The development of peptide stapling techniques to stabilise α-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 α-helicity and enhanced binding affinity to its native binding partner β-catenin. An increased proteolytic stability against proteinase K has been demonstrated.

Keywords: Suzuki–Miyaura cross-coupling; accelerated molecular dynamics; halotryptophan; intrinsically disordered peptides; late-stage diversification; macrocyclisation; molecular dynamics; stapled peptides.

Grants and funding

The project was supported in part by a Bielefeld University Ph.D. fellowship to H.G. and by Deutsche Forschungsgemeinschaft (SE609/16-1). The DFT calculations were carried out using hardware and software resources of the Supercomputing and Networking Center in Wroclaw (grant no. 197). R.M. and A.M. gratefully acknowledge the support of NVIDIA Corporation with the donation of a Titan Xp GPU used for this research as well as TUBITAK ULAKBIM High Performance and Grid Computing Center (TRUBA resources) for additional calculations.