Synthesis of a d-Ala-d-Ala peptide isostere via olefin cross-metathesis and evaluation of vancomycin binding

The alkene peptide isostere for the d-Ala-d-Ala dipeptide was synthesized via a convergent approach utilizing olefin cross-metathesis. The new isostere was then evaluated for binding to the last resort antibiotic, vancomycin. The alkene isostere exhibited a KD = 90 μM in comparison to the native peptide (KD = 2.3 μM) and Lac mutant (KD = 2300 μM). This study demonstrates that loss of binding in vancomycin resistant strains as a result of a d-Ala to d-Lac mutation is from both the loss of a crucial hydrogen bond and introduction of a repulsive lone pair interaction.