Glycopeptide dendrimers with high affinity for the fucose-binding lectin LecB from Pseudomonas aeruginosa. 2009

Elena Kolomiets, and Magdalena A Swiderska, and Rameshwar U Kadam, and Emma M V Johansson, and Karl-Erich Jaeger, and Tamis Darbre, and Jean-Louis Reymond
Department of Chemistry and Biochemistry, University of Berne, Switzerland.

The fucose-specific lectin LecB is implicated in tissue binding and biofilm formation by the opportunistic pathogen Pseudomonas aeruginosa, which causes severe respiratory tract infections mainly in immunocompromised patients or cancer patients undergoing chemotherapy. With a view to developing multivalent LecB inhibitors as novel antibacterial agents, a combinatorial library containing 15 625 tetravalent C-fucosyl peptide dendrimers with the basic structure (CFuc-X(6)X(5)X(4))(4)(LysX(3)X(2)X(1))(2)LysIleHisNH(2) (CFuc=alpha-L-fucosyl acetic acid, X(1-6)=amino acids, Lys=lysine branching) was screened for lectin binding using on-bead binding assays. Ten tetravalent and three octavalent dendrimers derived from the identified sequences were prepared by solid-phase peptide synthesis (SPPS), cleaved from the resin, and purified by preparative HPLC. Relative affinities of these soluble ligands to LecB were determined by an enzyme-linked lectin assay (ELLA). Strong binding was observed for tetravalent and octavalent ligands, with up to 440-fold enhancement in potency over fucose for the octavalent cationic dendrimer 2G3 (CFuc-LysPro)(8)(LysLeuPhe)(4)(LysLysIle)(2)LysHisIleNH(2)). Mono- and divalent controls showed affinities similar to fucose, highlighting the importance of multivalency for binding. Docking studies showed that the C-fucosyl group of the dendrimers can adopt the same binding mode as fucose itself, with the peptide arms protruding from the binding pocket and establishing specific contacts with the lectin.

UI MeSH Term Description Entries
D008024 Ligands A molecule that binds to another molecule, used especially to refer to a small molecule that binds specifically to a larger molecule, e.g., an antigen binding to an antibody, a hormone or neurotransmitter binding to a receptor, or a substrate or allosteric effector binding to an enzyme. Ligands are also molecules that donate or accept a pair of electrons to form a coordinate covalent bond with the central metal atom of a coordination complex. (From Dorland, 27th ed) Ligand
D008969 Molecular Sequence Data Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories. Sequence Data, Molecular,Molecular Sequencing Data,Data, Molecular Sequence,Data, Molecular Sequencing,Sequencing Data, Molecular
D011550 Pseudomonas aeruginosa A species of gram-negative, aerobic, rod-shaped bacteria commonly isolated from clinical specimens (wound, burn, and urinary tract infections). It is also found widely distributed in soil and water. P. aeruginosa is a major agent of nosocomial infection. Bacillus aeruginosus,Bacillus pyocyaneus,Bacterium aeruginosum,Bacterium pyocyaneum,Micrococcus pyocyaneus,Pseudomonas polycolor,Pseudomonas pyocyanea
D006020 Glycopeptides Proteins which contain carbohydrate groups attached covalently to the polypeptide chain. The protein moiety is the predominant group with the carbohydrate making up only a small percentage of the total weight. Glycopeptide
D012235 Rhodamines A family of 3,6-di(substituted-amino)-9-benzoate derivatives of xanthene that are used as dyes and as indicators for various metals; also used as fluorescent tracers in histochemistry. Rhodamine
D015394 Molecular Structure The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds. Structure, Molecular,Molecular Structures,Structures, Molecular
D050091 Dendrimers Tree-like, highly branched, polymeric compounds. They grow three-dimensionally by the addition of shells of branched molecules to a central core. The overall globular shape and presence of cavities gives potential as drug carriers and CONTRAST AGENTS. Dendrimer,Dendritic Compounds,Dendritic Polymers,Dendrons,Compound, Dendritic,Dendritic Compound,Dendritic Polymer,Polymer, Dendritic,Polymers, Dendritic
D018360 Crystallography, X-Ray The study of crystal structure using X-RAY DIFFRACTION techniques. (McGraw-Hill Dictionary of Scientific and Technical Terms, 4th ed) X-Ray Crystallography,Crystallography, X Ray,Crystallography, Xray,X Ray Crystallography,Xray Crystallography,Crystallographies, X Ray,X Ray Crystallographies
D020650 Combinatorial Chemistry Techniques A technology, in which sets of reactions for solution or solid-phase synthesis, is used to create molecular libraries for analysis of compounds on a large scale. Chemistry Techniques, Combinatorial,Techniques, Combinatorial Chemistry,Chemistry Technic, Combinatorial,Chemistry Technics, Combinatorial,Chemistry Technique, Combinatorial,Combinatorial Chemistry Technic,Combinatorial Chemistry Technics,Combinatorial Chemistry Technique,Technic, Combinatorial Chemistry,Technics, Combinatorial Chemistry,Technique, Combinatorial Chemistry
D037102 Lectins Proteins that share the common characteristic of binding to carbohydrates. Some ANTIBODIES and carbohydrate-metabolizing proteins (ENZYMES) also bind to carbohydrates, however they are not considered lectins. PLANT LECTINS are carbohydrate-binding proteins that have been primarily identified by their hemagglutinating activity (HEMAGGLUTININS). However, a variety of lectins occur in animal species where they serve diverse array of functions through specific carbohydrate recognition. Animal Lectin,Animal Lectins,Isolectins,Lectin,Isolectin,Lectin, Animal,Lectins, Animal

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