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.
Quinn
Ryan K
RK
College of the Holy Cross, Chemistry Department, Worcester, MA 01610, USA.
Cianci
Amelia L
AL
Beaudoin
Jennifer A
JA
Sculimbrene
Bianca R
BR
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*
D000475:Alkenes; D000900:Anti-Bacterial Agents; D004151:Dipeptides; C002956:alanylalanine; D014640:Vancomycin