Lysine-Targeting Reversible Covalent Inhibitors with Long Residence Time
Rahi M. Reja, Wenjian Wang, Yuhan Lyu, Fredrik Hæffner, Jianmin Gao
Abstract
We report a new reversible lysine conjugation that features a novel diazaborine product and much slowed dissociation kinetics in comparison to the previously known iminoboronate chemistry. Incorporating the diazaborine-forming warhead RMR1 to a peptide ligand gives potent and long-acting reversible covalent inhibitors of the staphylococcal sortase. The efficacy of sortase inhibition is demonstrated via biochemical and cell-based assays. A comparative study of RMR1 and an iminoboronate-forming warhead highlights the significance and potential of modulating bond dissociation kinetics in achieving long-acting reversible covalent inhibitors.
Topics & Concepts
ChemistryCovalent bondSortase ASortaseKineticsLysineDissociation (chemistry)CysteinePeptideStereochemistryCombinatorial chemistryBiochemistryBiophysicsAmino acidEnzymeOrganic chemistryBacterial proteinQuantum mechanicsBiologyPhysicsGeneBiochemical and Structural CharacterizationPeptidase Inhibition and AnalysisSignaling Pathways in Disease