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Strategic alkene incorporation into peptide backbones to prevent enzymatic hydrolysis by evading molecular
Kohei Watanabe1, Yoshinori Taguchi2, Takuma Nishizawa1
1Graduate School of Integrated Science and Technology, Shizuoka University, 3-5-1 Johoku, Hamamatsu, Shizuoka, Japan.
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.
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