Tuesday, January 18, 2022

Lysine-Targeting Reversible Covalent Inhibitors with Long Residence Time

Rahi M. Reja, Wenjian Wang, Yuhan Lyu, Fredrik Haeffner, and Jianmin Gao

Journal of the American Chemical Society 2021
DOI: 10.1021/jacs.1c12702

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.


4-Oxo-β-lactams as Covalent Inhibitors of the Mitochondrial Intramembrane Protease PARL

Shanping Ji, Kathrin Bach, Vijay Madhav Miriyala, Jan Dohnálek, Miguel Riopedre-Fernandez, Martin Lepšík, Merel van de Plassche, Roeland Van...