title: Synthesis of a D-Ala-D-Ala peptide isostere via olefin cross-metathesis and evaluation of vancomycin binding.
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 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.
authors.affiliation: College of the Holy Cross, Chemistry Department, Worcester, MA 01610, USA.
authors.forename: Ryan K
authors.initials: RK
authors.lastname: Quinn
authors.forename: Amelia L
authors.initials: AL
authors.lastname: Cianci
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Beaudoin
authors.forename: Bianca R
authors.initials: BR
authors.lastname: Sculimbrene
mesh_terms: D000475:Alkenes / Q000737:chemistry*; D000900:Anti-Bacterial Agents / Q000737:chemistry*; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry; D006860:Hydrogen Bonding; D011485:Protein Binding; D013816:Thermodynamics; D014640:Vancomycin / Q000737:chemistry*
chemical_list: D000475:Alkenes; D000900:Anti-Bacterial Agents; D004151:Dipeptides; C002956:alanylalanine; D014640:Vancomycin