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Project
Structural biology of Helicobacter pylori virulence factors (FWOODYS2)
Helicobacter pylori is a widespread human pathogen that is the leading cause of chronic gastritis and is associated with the development of peptic ulcers and gastric cancer. Current medical guidelines advocate Helicobacter eradication therapy in peptic ulcer disease, low-grade gastric MALT lymphoma and after gastric cancer resection. Because Helicobacter pylori is one of the most significant risk factors for gastric cancer, H. pylori eradication has been proposed as a possible primary chemo-preventive strategy to reduce gastric cancer incidence. However, the alarming increase of antibiotic resistance in H. pylori strains has serious implications for current and future antibiotic-based therapies. In addition, only 10-20% of Helicobacter infections will ever progress into clinical disease. A mounting body of evidence indicates disease outcome is highly strain specific and is a function of a limited number of virulence factors.
We will set up a structural biology program of Helicobacter virulence factors for the design of novel, virulence-targeted antibiotics and as an aid for epitope selection in vaccine development programs. Bacterial adherence is a major factor in Helicobacter virulence and its extraordinary longevity of infection. Two major Helicobacter - host interactions are formed between the blood group antigen-binding adhesin BabA and the fucosylated Lewis B and ABO blood group antigens present on gastric epithelial cells and between the sialic acid-binding adhesin SabA and the sialyl-Lewis x/a antigens present on inflamed gastric tissue, erythrocytes and infiltrated neutrophils. A chemical library of pharmacophore-like compounds will be screened for BabA or SabA adhesion inhibitors. The structural characterization of BabA and SabA in complex with their respective glycan receptors by X-ray crystallography will be followed by the structure-guided lead optimization and receptor-based virtual screening of BabA and SabA inhibitors.
We will set up a structural biology program of Helicobacter virulence factors for the design of novel, virulence-targeted antibiotics and as an aid for epitope selection in vaccine development programs. Bacterial adherence is a major factor in Helicobacter virulence and its extraordinary longevity of infection. Two major Helicobacter - host interactions are formed between the blood group antigen-binding adhesin BabA and the fucosylated Lewis B and ABO blood group antigens present on gastric epithelial cells and between the sialic acid-binding adhesin SabA and the sialyl-Lewis x/a antigens present on inflamed gastric tissue, erythrocytes and infiltrated neutrophils. A chemical library of pharmacophore-like compounds will be screened for BabA or SabA adhesion inhibitors. The structural characterization of BabA and SabA in complex with their respective glycan receptors by X-ray crystallography will be followed by the structure-guided lead optimization and receptor-based virtual screening of BabA and SabA inhibitors.
Date:1 Jan 2009 → 31 Dec 2013
Keywords:Applied Biology
Disciplines:Biological sciences