Peptidic inhibitors of lipopolysaccharide

Lipopolysaccharide (LPS) triggers a sequence of defense reactions leading to the septic shock that causes more than 100.000 deaths annually in the U.S.A. alone. We will study the binding of known peptidic LPS inhibitors (natural defense peptides or fragments of LPS binding proteins) to LPS using nuclear magnetic resonance (NMR) techniques, and perform computer modeling of the complexes. They will be compared to the structures of the peptide fragments in the parent proteins in cases where their X-ray structure is known, and hypotheses of the pattern of LPS binding to proteins and peptides will be developed. The hypotheses will be tested by synthesis and in vitro activity (i.e. LPS inhibition) measurements of modified peptide sequences. The peptides that perform well in the tests will enter a new cycle of NMR measurements and molecular modeling; additionally, their toxicity will be monitored. The purpose of the project is to set up the basis for the rational design of new peptidic LPS inhibitors.