Structure of a Synthetic Fragment of the Lipopolysaccharide (LPS) Binding Protein When Bound to LPS and Design of a Peptidic LPS Inhibitor

• Published in: Journal of medicinal chemistry Vol. 48; no. 24; pp. 7911 - 7914
• Main Authors: Pristovšek, Primož, Simčič, Saša, Wraber, Branka, Urleb, Uroš
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01.12.2005
• Subjects: Acute-Phase Proteins - chemistry; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Carrier Proteins - chemistry; Cells, Cultured; General aspects; Humans; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - metabolism; Lipopolysaccharides - antagonists & inhibitors; Lipopolysaccharides - pharmacology; Magnetic Resonance Spectroscopy; Medical sciences; Membrane Glycoproteins - chemistry; Models, Molecular; Molecular Structure; Peptide Fragments - chemical synthesis; Peptide Fragments - chemistry; Peptide Fragments - pharmacology; Pharmacology. Drug treatments; Tumor Necrosis Factor-alpha - metabolism; Peptides; NMR spectrometry; In vitro; Modeling; Biological activity; Binding protein; Synthetic product; Peptide fragment; Polypeptide; Molecular model; Lipopolysaccharide; Inhibitor; Endotoxemia
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm050762a

Peptidic lipopolysaccharide (LPS) antagonists are the subject of intensive research. We report an NMR and modeling study of LBP-14 (RVQGRWKVRASFFK), a synthetic fragment of the LPS binding protein (LBP). In a mixture with LPS we observed the transferred nuclear Overhauser effect and determined the LPS-bound structure of LBP-14 that was used for docking calculations to LPS. The derived complex was used to design a peptide that displayed more than 50% increase in LPS inhibition in vitro.