carbohydrates; combinatorial chemistry; drug delivery; ligation; molecular modelling; Peptides; Dendrimers; enzyme models; antimicrobials; biofilms; glycopeptides
Geotti-Bianchini Piero, Darbre Tamis, Reymond Jean-Louis (2013), pH-tuned metal coordination and peroxidase activity of a peptide dendrimer enzyme model with a Fe(II)bipyridine at its core, in Organic and Biomolecular Chemistry
, 2013(11), 344-352.
Reymond Jean-Louis, Darbre Tamis (2012), Peptide and glycopeptide dendrimer apple trees as enzyme models and for biomedical applications, in Organic & Biomolecular Chemistry
, 10(8), 1483-1492.
Reymond Jean-Louis, Kadam Rameshwar U., Bergmann Myriam, Hurley Matthew, Garg Divita, Cacciarini Martina, Swiderska Magdalena A., Nativi Cristina, Sattler Michael, Smyth Alan R., Williams Paul, Camara Miguel, Stocker Achim, Darbre Tamis (2011), A Glycopeptide dendrimer inhibitor of the Galactose Specific Lectin LecA and of Pseudomonas aeruginosa Biofilms, in Angewandte Chemie International Edition
, 50(45), 10631-10635.
Reymond Jean-Louis, Maillard Noélie, Biswas Rasomoy, Darbre Tamis (2011), Combinatorial Discovery of Peptide Dendrimer Enzyme Models Hydrolyzing Isobutyryl Fluorescein, in ACS Combinatorial Science
, 13(3), 310-320.
Reymond Jean-Louis, Darbre Tamis (2011), Combinatorial Libraries of Dendritic Glycoclusters, in Renaudet Olivier (ed.), Bentham e-books, France, 116-128.
Reymond Jean-Louis, Bartoloni Marco, Kadam Rameshwar U., Schwartz Julian, Furrer Julien, Darbre Tamis (2011), Expanding the accessible chemical space by solid phase synthesis of bicyclic homodetic peptides, in Chemical Communications
, 47(4), 12634-12636.
Reymond Jean-Louis, Maillard Noélie, Babiak Peter, Syed Salahuddin, Biswas Rasomoy, Mandrich Luigi, Manco Giuseppe (2011), Five-Substrate Cocktail as a Sensor Array for Measuring Enzyme Activity Fingerprints of Lipases and Esterases, in Analytical Chemistry
, 83(4), 1437-1442.
Reymond Jean-Louis, Johansson Emma M. V., Kadam Rameshwar U., Rispoli Gabriele, Crusz Shanika A., Bartels Kai-Malte, Diggle Stephen P., Camara MIguel, Williams Paul, Jaeger Karl-Erich, Darbre Tamis (2011), Inhibition of Pseudomonas aeruginosa biofilms with a glycopeptide dendrimer containing D-amino acids, in MedChemComm
, 2(5), 418-420.
Reymond Jean-Louis, Stach Michaela, Maillard Noélie, Kadam Rameshwar U., Kalbermatter David, Meury Marcel, Page Malcolm G.P., Fotiadis Dimitrios, Darbre Tamis (2011), Membrane disrupting antimicrobial peptide dendrimers with multiple amino termini, in MedChemComm
, 3(1), 86-89.
Reymond Jean-Louis, Uhlrich Nicolas A., Darbre Tamis (2011), Peptide dendrimer enzyme models for ester hydrolysis and aldolization prepared by convergent thioether ligation, in Organic & Biomolecular Chemistry
, 9(20), 7071-7084.
Reymond Jean-Louis, Darbre Tamis (2011), Peptide Dendrimers as Artificial Proteins, in Campagnia Sebastiano (ed.), John Wiley & Sons, UK, 505-528.
Reymond Jean-Louis, Botelho Tiago O., Guevara Tibisay, Marrero Aniebrys, Arêde Pedro, Fluxa Viviana S., Oliveira Duarte C., Gomis-Rüth F. Xavier (2011), Structural and functional analyses reveal that Staphylococcus aureus antibiotic resistance factor HMRA is a zinc-dependent endopeptidase, in The Journal of Biological Chemistry
, 286(29), 25697-25709.
Reymond Jean-Louis, Euzen Ronan (2011), Synthesis of glycopeptide dendrimers, dimerization and affinity for Concanavalin A, in Bioorganic & Medicinal Chemistry
, 19(9), 2879-2887.
Reymond Jean-Louis, Fluxa Viviana S., Page Malcolm G. P., Maillard Noélie (2010), Bead Diffusion Assay for Discovering Antimicrobial Cyclic Peptides, in Chemical Communications
, 47(5), 1434-1436.
Reymond Jean-Louis, Euzen Ronan (2010), Glycopeptide dendrimers: tuning carbohydrate-lectin interactions with amino acids, in Molecular BioSystems
, 7(2), 411-421.
This proposal embraces the dendrimer approach to artificial proteins by focusing on the use of amino acid building blocks as found in natural proteins. This line of research is original and has not been followed by other groups in the field of dendrimer chemistry, where research is based on organic dendrons unrelated to amino acids. Our challenge is to discover efficient synthetic routes and design principles leading to functionally and structurally defined peptide dendrimers, and to explore the functional range accessible by such structures, which might be similar or different than for natural proteins. Original and useful applications might follow, in particular in the biomedical field where peptide drugs are well developed. In that respect the use of natural amino acid building blocks and solid-phase peptide synthesis allows our peptide dendrimers to be readily produced in large scale. The proposal unfolds into four different projects.Project A: Catalytic peptide dendrimers. Catalysis in aqueous environment is one of the defining properties of protein enzymes which to date remains very difficult to realize in synthetic systems. The dendrimer framework provides an architecture reproducing some of the properties of enzymes, in particular a microenvironment for substrate binding at the dendrimer core and a cooperativity between amino acid side chains in the branches for effective catalysis. We will investigate aldolase-type dendrimers by screening a combinatorial dendrimer library with an active proline at the core using an innovative "off-bead" screening approach allowing to screen catalysis by the dendrimers in solution. We will also examine catalysis in a recently discovered series of alpha-helical peptide dendrimers, the formation of catalytic metal-dendrimer complexes by incorporating bipyridine ligands in the dendrimer structure, and the further development of dendritic vitamin B12-ligands.Project B: Glycopeptide dendrimers. The multivalency of dendrimers is particularly useful to prepare ligands for lectins, an ubiquitous class of carbohydrate binding proteins. Our combinatorial approach to glycopeptide dendrimers offers an unprecedented opportunity to fine-tune the lectin-dendrimer interaction by optimizing topology and amino acid types. We will follow-up on galactosylated peptide dendrimers taxol conjugates that efficiently kill cancer cells in vitro. We will also further develop our newly discovered peptide dendrimer ligands to the bacterial lectin LecB. These dendrimers are potent biofilm inhibitors of Pseudomonas aeruginosa, an antibiotic resistant pathogen which is a major cause of death in immunocompromised and in cystic fibrosis patients, and might therefore lead to new therapies against the bacterium. Project C: Peptide dendrimers by convergent assembly. Solid-phase peptide synthesis delivers peptide dendrimers in excellent yields and purity up to a MW of approximately 5 Kdal (37 amino acids), but not larger. We have discovered that the coupling of cysteine side chains with N-terminal chloroacetamido groups is an efficient ligation reaction giving access to structures of protein size in useful yields by coupling dendrimers onto other dendrimers. This project explores the scope of the reaction for the assembly of higher-valency dendrimers and for the multimerization of antimicrobial peptides by coupling them to dendritic, linear or cyclic peptide cores. Project D: Molecular modelling of peptide dendrimers. Dendrimers, including peptide dendrimers, are conformationally flexible and have so far escaped structural determination by crystallization or NMR. This project focuses on molecular dynamics simulation as an entry into dendrimer structures to better understand the nature of dendrimer-vitamin B12 and dendrimer-lectin interactions. The method has already been validated by a study of esterase peptide dendrimers that has provided an understanding of the dendritic effect in catalysis.