Discovery of high-affinity peptide ligands for vancomycin

Nianhuan Yao, Chun Yi Wu, Wenwu Xiao, Kit Lam

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Vancomycin, an important antibiotic against medically relevant gram-positive bacteria such as methicillin-resistant Staphylococcus aureus, exerts its antibacterial effects by binding with moderate affinity to the C-terminal Lys-D-Ala-D-Ala motif (Kaa) of the bacterial cell wall peptide precursor, Essential for Kaa binding to vancomcyin is the free-carboxyl group on the terminal D-Ala in Kaa. In efforts to identify other Kaa-based peptides which bind vancomycin with higher affinity, we utilized our one-bead-one-compound (OBOC) combinatorial library approach, a method which has been widely used to discover highly specific ligands against various receptors, In standard OBOC peptide libraries, the C-terminal end of the synthesized peptide is tethered to a solid-support/resin, however, this study reports development of a synthetic strategy for generating OBOC peptide libraries with a free D-Ala-D-Ala carboxyl end. We screened these "OBOC inverted" peptide libraries against vancomycin, and discovered a series of peptide ligands with strong consensus, which bind vancomycin. To further optimize these ligands, two highly focused Kaa-containing OBOC combinatorial peptidomimetic libraries were designed synthesized, and screened against vancomycin under more stringent conditions. Peptidomimetic ligans which bind vancomycin with higher affinity than Kaa were identified. The dissociation constant of one of these ligands, Lys(Ac)-HOCit-Glu-Cha-Lys(3,5-dihydroxybenzoyl)-D-Ala-D-Ala (9), as determined by surface plasmon resonance, was 1.03 μM, roughly a 50-fold improvement in affinity compared to Kaa (KD = 50 μM.

Original languageEnglish (US)
Pages (from-to)421-432
Number of pages12
JournalBiopolymers - Peptide Science Section
Volume90
Issue number3
DOIs
StatePublished - 2008

Fingerprint

Vancomycin
Peptides
Ligands
Peptide Library
Peptidomimetics
Methicillin
Surface Plasmon Resonance
Gram-Positive Bacteria
Surface plasmon resonance
Methicillin-Resistant Staphylococcus aureus
Cell Wall
Antibiotics
Bacteria
Resins
Cells
Anti-Bacterial Agents
alanylalanine

Keywords

  • Dissociation constant (K)
  • OBOC combinatorial inverted peptide library
  • Peptide ligands
  • Vancomycin

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Biomaterials
  • Organic Chemistry
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Discovery of high-affinity peptide ligands for vancomycin. / Yao, Nianhuan; Wu, Chun Yi; Xiao, Wenwu; Lam, Kit.

In: Biopolymers - Peptide Science Section, Vol. 90, No. 3, 2008, p. 421-432.

Research output: Contribution to journalArticle

Yao, Nianhuan ; Wu, Chun Yi ; Xiao, Wenwu ; Lam, Kit. / Discovery of high-affinity peptide ligands for vancomycin. In: Biopolymers - Peptide Science Section. 2008 ; Vol. 90, No. 3. pp. 421-432.
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