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Peptide and Glycopeptide Dendrimers as Artificial Proteins

English title Peptide and Glycopeptide Dendrimers as Artificial Proteins
Applicant Reymond Jean-Louis
Number 125020
Funding scheme Project funding (Div. I-III)
Research institution Departement für Chemie und Biochemie Universität Bern
Institution of higher education University of Berne - BE
Main discipline Organic Chemistry
Start/End 01.04.2009 - 31.03.2012
Approved amount 625'647.00
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Keywords (11)

carbohydrates; combinatorial chemistry; drug delivery; ligation; molecular modelling; Peptides; Dendrimers; enzyme models; antimicrobials; biofilms; glycopeptides

Lay Summary (English)

Lead
Lay summary

This proposal embraced 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 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 was 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 was formulated as four different projects, for each of which a concluding summary is provided.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
pH-tuned metal coordination and peroxidase activity of a peptide dendrimer enzyme model with a Fe(II)bipyridine at its core
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.
Peptide and glycopeptide dendrimer apple trees as enzyme models and for biomedical applications
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.
A Glycopeptide dendrimer inhibitor of the Galactose Specific Lectin LecA and of Pseudomonas aeruginosa Biofilms
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.
Combinatorial Discovery of Peptide Dendrimer Enzyme Models Hydrolyzing Isobutyryl Fluorescein
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.
Combinatorial Libraries of Dendritic Glycoclusters
Reymond Jean-Louis, Darbre Tamis (2011), Combinatorial Libraries of Dendritic Glycoclusters, in Renaudet Olivier (ed.), Bentham e-books, France, 116-128.
Expanding the accessible chemical space by solid phase synthesis of bicyclic homodetic peptides
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.
Five-Substrate Cocktail as a Sensor Array for Measuring Enzyme Activity Fingerprints of Lipases and Esterases
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.
Inhibition of Pseudomonas aeruginosa biofilms with a glycopeptide dendrimer containing D-amino acids
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.
Membrane disrupting antimicrobial peptide dendrimers with multiple amino termini
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.
Peptide dendrimer enzyme models for ester hydrolysis and aldolization prepared by convergent thioether ligation
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.
Peptide Dendrimers as Artificial Proteins
Reymond Jean-Louis, Darbre Tamis (2011), Peptide Dendrimers as Artificial Proteins, in Campagnia Sebastiano (ed.), John Wiley & Sons, UK, 505-528.
Structural and functional analyses reveal that Staphylococcus aureus antibiotic resistance factor HMRA is a zinc-dependent endopeptidase
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.
Synthesis of glycopeptide dendrimers, dimerization and affinity for Concanavalin A
Reymond Jean-Louis, Euzen Ronan (2011), Synthesis of glycopeptide dendrimers, dimerization and affinity for Concanavalin A, in Bioorganic & Medicinal Chemistry, 19(9), 2879-2887.
Bead Diffusion Assay for Discovering Antimicrobial Cyclic Peptides
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.
Glycopeptide dendrimers: tuning carbohydrate-lectin interactions with amino acids
Reymond Jean-Louis, Euzen Ronan (2010), Glycopeptide dendrimers: tuning carbohydrate-lectin interactions with amino acids, in Molecular BioSystems, 7(2), 411-421.

Collaboration

Group / person Country
Types of collaboration
Jülich Forschungszentrum Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
University of Nottingham Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Université de Grenoble France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Basilea Pharmaceuticals Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
University of Florence Italy (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
SCG Fall Meeting Talk given at a conference SCG Fall Meeting 09.09.2011 EPFL Lausanne, Switzerland, Switzerland Uhlich Nicolas; Bergmann Myriam; Biswas Rasomoy; Eggimann Gabriela;
CUSO Summer School, Challenges in Organic Synthesis Poster CUSO Summer School, Challenges in Organic Synthesis 28.08.2011 Villars-sur-Ollon, Switzerland, Switzerland Eggimann Gabriela; Bergmann Myriam; Biswas Rasomoy; Uhlich Nicolas;


Self-organised

Title Date Place
COST meeting CM1102 02.02.2012 Berne, Switzerland, Switzerland

Knowledge transfer events



Self-organised

Title Date Place
Tag der Offenen Tür am DCB Bern 18.06.2011 Bern, Switzerland

Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Open House at Department of Chemistry and Biochemistry, University of Berne German-speaking Switzerland 2011

Associated projects

Number Title Start Funding scheme
140349 Exploring Peptide Topologies in Search for New Drugs 01.04.2012 Project funding (Div. I-III)
116555 Peptide Dendrimers as Synthetic Artificial Proteins for Catalysis and Binding 01.04.2007 Project funding (Div. I-III)
139078 1.7 mm Micro-Probehead for small volume NMR Spectroscopic Investigations 01.03.2012 R'EQUIP
159941 A Chemical Space Approach to Bioactive Peptides 01.04.2015 Project funding (Div. I-III)

Abstract

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.
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