Modified glycopeptides related to cell wall peptidoglycan: conformational studies by NMR and molecular modelling

• Published in: Bioorganic & medicinal chemistry Vol. 11; no. 14; pp. 3133 - 3140
• Main Authors: FEHER, Krisztina, PRISTOVSEK, Primoz, SZILHGYI, Laszlo, LJEVAKOVIC, Durdica, TOMASIC, Jelka
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 17.07.2003; Elsevier Science
• Subjects: Acetylmuramyl-Alanyl-Isoglutamine - analogs & derivatives; Acetylmuramyl-Alanyl-Isoglutamine - chemistry; Biological and medical sciences; Brevibacterium - chemistry; Cell Wall - metabolism; Dimethyl Sulfoxide - chemistry; Fundamental and applied biological sciences. Psychology; Glycopeptides - chemistry; Glycopeptides - metabolism; Immunomodulators; Interactions. Associations; Intermolecular phenomena; Magnetic Resonance Spectroscopy - methods; Medical sciences; Models, Molecular; Molecular biophysics; Molecular Conformation; Peptidoglycan - chemistry; Peptidoglycan - metabolism; Pharmacology. Drug treatments; Protein Binding; Thermodynamics; Electrostatic interaction; Molecular dynamics method; NMR spectrometry; Modeling; Disaccharide; Two dimension spectrometry; Immunomodulator; Peptidoglycan; Tetrapeptide; Glycopeptide; Aminoglycoside; Analog; Molecular model; Meso compound; Conformation
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/S0968-0896(03)00244-X

Polymeric peptidoglycans of bacterial cell walls, and smaller glycopeptides derived from them, exhibit versatile biological activities including immunomodulating properties. Peptidoglycan monomer (PGM) was isolated from Brevibacterium divaricatum and novel lipophilic derivatives of PGM bearing either (adamantyl-1-yl)-acetyl or Boc-Tyr substituents (Ad-PGM and BocTyr-PGM respectively) have recently been synthesized. We have obtained full assignments of the 1H and 13C spectra, using 2D NMR techniques, for all three compounds in DMSO solutions. NOESY/ROESY experiments have provided interproton distance restraints that were used in distance geometry modelling calculations to derive conformational preferences for each of these molecules. These data were supplemented with information available from chemical shifts, temperature dependence of amide proton shifts and proton–proton scalar couplings. Analysis of the results suggest that the lipophilic substituents attached to the Dap 3-ε amino group of the parent PGM molecule introduce changes to the conformational preferences of the peptide moiety. In PGM electrostatic interactions between charged end groups apparently promote folded conformations with participation of the long Dap side chain. Derivatives wherein such interactions are suppressed by acylation of the Dap 3-ε amino group are characterized by more extended conformations of the peptide chain. The new synthetic derivatives exhibit biological properties similar to those of the parent PGM. This may indicate that peripheral parts of the peptide chain such as the C-terminal and end groups of the long Dap side chain do not significantly contribute to the binding to receptors or enzymes participating in the biochemical interactions referred to above. Graphic