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

Chemical communications (Cambridge, England)2021PMID: 34036992

Plain Language Summary

Develops furan warhead-based chemical biology tools for site-specific covalent trapping of the weak, dynamic thymosin β4-actin protein-protein interaction (PPI). Uses the known TB4-actin complex structure to validate furan-armed TB4 derivatives that cross-link specifically to actin at the TB4 binding site. Identifies lysine as the furan warhead target residue. Provides proof-of-concept for TB4-based covalent inhibitors—useful research tools for studying actin dynamics and potential therapeutic leads targeting pathological TB4-actin interactions.

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.

Authors

Miret-Casals, Laia; Vannecke, Willem; Hoogewijs, Kurt; Arauz-Garofalo, Gianluca; Gay, Marina; Díaz-Lobo, Mireia; Vilaseca, Marta; Ampe, Christophe; Van Troys, Marleen; Madder, Annemieke