Synthesis of a d-Ala-d-Ala peptide isostere via olefin cross-metathesis and evaluation of vancomycin binding |
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Authors: | Ryan K. Quinn Amelia L. Cianci Jennifer A. Beaudoin Bianca R. Sculimbrene |
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Affiliation: | College of the Holy Cross, Chemistry Department, 1 College St., Worcester, MA 01610, United States |
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Abstract: | 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. |
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