Equipping Coiled-Coil Peptide Dimers With Furan Warheads Reveals Novel Cross-Link Partners

Laia Miret-Casals; Sander Van De Putte; Dorien Aerssens; Julien Diharce; Pascal Bonnet; Annemieke Madder

doi:10.3389/fchem.2021.799706

Equipping Coiled-Coil Peptide Dimers With Furan Warheads Reveals Novel Cross-Link Partners

Front Chem. 2022 Feb 16:9:799706. doi: 10.3389/fchem.2021.799706. eCollection 2021.

Authors

Laia Miret-Casals¹, Sander Van De Putte¹, Dorien Aerssens¹, Julien Diharce², Pascal Bonnet², Annemieke Madder¹

Affiliations

¹ Department of Organic and Macromolecular Chemistry, Organic and Biomimetic Chemistry Research Group, Faculty of Science, Ghent University, Ghent, Belgium.
² Institut de Chimie Organique et Analytique, Université d'Orléans, UMR CNRS 7311, Orléans, France.

Abstract

Using a coiled-coil peptide dimer as a model system to explore furan reactivity, we describe novel cross-link partners of furan warheads for site-specific cross-linking. We demonstrate that replacement of weak interhelical ionic contacts with a furan moiety and its potential cross-link partner affords covalently connected coiled-coil motifs upon furan activation. We describe for the first time the reaction of the activated furan warhead with cysteine and tyrosine, besides the previously reported lysine, thus enhancing the versatility of the furan cross-link methodology by the possibility to target different amino acids. The present in vitro validation of "furan-armed" α-helices provides further grounds for exploiting furan technology in the development of furan-modified ligands/proteins to target proteins in a covalent way through various amino acid side chains.

Keywords: coiled-coil peptide; cross-link (CL); furan oxidation; molecular modeling; peptide–protein interaction; protein–protein interaction (PPI); singlet oxygen.