title: Multivariate design, synthesis, and biological evaluation of peptide inhibitors of FimC/FimH protein-protein interactions in uropathogenic Escherichia coli.
abstract: A peptide library targeting protein-protein interactions crucial for pilus assembly in Gram negative bacteria has been designed using statistical molecular design. A nonamer peptide scaffold was used, with seven positions being varied. The selection was performed in the building block space, and previously known structure-activity data were included in the design procedure. This resulted in a heavily reduced library consisting of 32 peptides which was prepared by solid-phase synthesis. The ability of the peptides to inhibit the protein-protein interaction between the periplasmic chaperone FimC and the pilus adhesin FimH was then determined in an ELISA. Novel peptides with the capability to inhibit the FimC/FimH protein-protein interaction to the same extent as the native FimC peptides were discovered. Multivariate QSAR studies of the response in the ELISA gave valuable information on the properties of amino acids which were preferred at the seven positions in the nonamer scaffold. This information can be used in attempts to develop optimized peptides and peptidomimetics that inhibit pilus assembly in pathogenic bacteria.
authors.affiliation: Department of Chemistry, Organic Chemistry, Umeå University, SE-901 87 Umeå, Sweden.
authors.forename: Andreas
authors.initials: A
authors.lastname: Larsson
authors.forename: Susanne M C
authors.initials: SM
authors.lastname: Johansson
authors.forename: Jerome S
authors.initials: JS
authors.lastname: Pinkner
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Hultgren
authors.forename: Fredrik
authors.initials: F
authors.lastname: Almqvist
authors.forename: Jan
authors.initials: J
authors.lastname: Kihlberg
authors.forename: Anna
authors.initials: A
authors.lastname: Linusson
mesh_terms: D018830:Adhesins, Escherichia coli / Q000737:chemistry; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D015195:Drug Design; D004797:Enzyme-Linked Immunosorbent Assay; D036781:Fimbriae Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D015999:Multivariate Analysis; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship
chemical_list: D018830:Adhesins, Escherichia coli; D001426:Bacterial Proteins; D010455:Peptides; C058769:fimH protein, E coli; D036781:Fimbriae Proteins