2026 Volume 37 Issue 2 Pages 35-45
Peptide bonds define the structures, physicochemical properties, and function of peptides and proteins. These central roles have made the peptide backbone an attractive target for molecular design. Alkene dipeptide isosteres (ADIs) include the parent (E)-alkene isostere (EADI) and structurally diversified analogues such as fluoroalkene (FADI), chloroalkene (CADI), and methylalkene (MADI), each possessing distinct structural and electronic properties. These advances have transformed ADIs from hydrolysis-resistant peptidomimetics into platforms for peptide backbone engineering.
This Account highlights the molecular design and applications of ADIs for conformational control, modulation of membrane permeability, suppression of selfdegradation, evasion of protease recognition, and, most recently, C5 hydrogen-bond mimicry enabled by the unique electronic properties of chlorine in CADIs.
