Strategic alkene incorporation into peptide backbones to prevent enzymatic hydrolysis by evading molecular recognition

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.