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 K(D)=90 microM in comparison to the native peptide (K(D)=2.3 microM) and Lac mutant (K(D)=2300 microM). 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.