Lysine-Targeting Reversible Covalent Inhibitors with Long Residence Time
Rahi M Reja1, Wenjian Wang1, Yuhan Lyu1
1Department of Chemistry, Boston College, 2609 Beacon Street, Chestnut Hill, Massachusetts 02467, United States.
None:
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.
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