Strategic Alkene Incorporation into Peptide Backbones to Prevent Enzymatic Hydrolysis by Evading Molecular Recognition

Abstract

This study highlighted a novel utility of alkene dipeptide isosteres in peptide backbone modification, specifically at the C-terminal region of ubiquitin. By strategically replacing the Gly75-Gly76 peptide bond with these isosteres, we achieved significant resistance to a deubiquitinating enzyme, effectively preventing enzymatic hydrolysis while preserving the Gly76–Lys isopeptide bond targeted for hydrolysis. These findings demonstrate that strategic incorporation of these isosteres at key enzyme–substrate recognition sites substantially enhances peptide stability against enzymatic hydrolysis. This strategy offers a novel pathway for developing bioactive peptidomimetics and addresses longstanding limitations of conventional isostere applications by evading enzyme recognition.