Substitution-Induced Mechanistic Switching in SNAr-Warheads for Cysteine Proteases
Collin Zimmer1, Jan Brauer2, Dorota Ferenc2
1Institute of Pharmaceutical and Biomedical Sciences, University of Mainz, Staudingerweg 5, 55128 Mainz, Germany.
Abstract:
The aim of this study was to investigate the transition from non-covalent reversible over covalent reversible to covalent irreversible inhibition of cysteine proteases by making delicate structural changes to the warhead scaffold. To this end, dipeptidic rhodesain inhibitors with different N-terminal electrophilic arenes as warheads relying on the SNAr mechanism were synthesized and investigated. Strong structure-activity relationships of the inhibition potency, the degree of covalency, and the reversibility of binding on the arene substitution pattern were found. The studies were complemented and substantiated by molecular docking and quantum-mechanical calculations of model systems. Furthermore, the improvement in the membrane permeability of peptide esters in comparison to their corresponding carboxylic acids was exemplified.
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