Furan warheads for covalent trapping of weak protein–protein interactions: cross-linking of thymosin β4 to actin

Abstract

We describe furan as a triggerable ‘warhead’ for site-specific cross-linking using the actin and thymosin β4 (Tβ4)-complex as model of a weak and dynamic protein–protein interaction (PPI) with known 3D structure and with application potential in disease contexts. The identified cross-linked residues demonstrate that lysine is a target for the furan warhead. The presented in vitro validation of covalently acting ‘furan-armed’ Tβ4-variants provides initial proof to further exploit furan-technology for covalent drug design targeting lysines.