biostudies-literatureReja RMDivision of ChemistryOno Pharma FoundationNational Institute of General Medical SciencesNIGMS NIH HHSNIH HHS1152-1157https://www.ebi.ac.uk/biostudies/studies/S-EPMC8928449biostudies-literatureUnknown144(3)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.Journal of the American Chemical SocietyLysine-Targeting Reversible Covalent Inhibitors with Long Residence Time.PMC8928449GM102735CHE-1904874R01 GM102735R01 GM124231S10 OD026910Haeffner FLyu YGao JWang WReja RMfalseLysine-Targeting Reversible Covalent Inhibitors with Long Residence Time.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.2022-01-01T00:00:00Z2022 Jan2026-05-09T13:44:43.393Z2025-04-07T03:19:38.805ZS-EPMC89284493504065810.1021/jacs.1c12702