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A Chemical Space Approach to Bioactive Peptides

English title A Chemical Space Approach to Bioactive Peptides
Applicant Reymond Jean-Louis
Number 159941
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 01.04.2015 - 31.03.2018
Approved amount 700'000.00
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Keywords (5)

antimicrobial agents; dendrimers; biofilms; gene and siRNA delivery; peptides

Lay Summary (French)

Lead
Exploration de l'Espace Chimique des Peptides Bioactifs
Lay summary

L’espace chimique se définit comme l’ensemble de tous les composés chimiques possibles, en particulier les molécules à activité thérapeutique, des petites molécules telles que l’aspirine jusqu’aux agents biologiques telles que les anticorps. Le concept même d’espace chimique suggère de s’intéresser à toutes les molécules possibles y-compris et surtout celles qui sont encore inconnues. Ce projet concerne les peptides, une classe de molécules de taille intermédiaire qui consistent en des chaînes linéaires jusqu’à 50 acides aminés. Si l’on utilise des acides diaminés ou des diamino acides comme points de branchement, on accède à des peptides branchés ayant des topologies entièrement nouvelles telles que les dendrimères peptidiques et les peptides polycycliques. Contrairement aux peptides linéaires, ces peptides branchés sont stables dans le sérum. Ils ont aussi des propriétés biologiques remarquables qui résultent de leur multivalence (dendrimères) et de leur rigidité conformationelle (peptides polycycliques). Les quatre projets suivants sont étudiés ici : 1) la modélisation de l’espace chimique des peptides branchés par méthode chimioinformatique ; 2) les dendrimères peptidiques comme agents de transfection d’ADN et d’ARN et comme antibiotiques ; 3) les inhibiteurs de biofilm ; 4) la synthèse et l’activité biologique des peptides bicycliques pontés.

Direct link to Lay Summary Last update: 29.04.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
Lipidated Peptide Dendrimers Killing Multidrug-Resistant Bacteria
Siriwardena Thissa N., Stach Michaela, He Runze, Gan Bee Ha, Javor Sacha, Heitz Marc, Ma Lan, Cai Xiangjun, Chen Peng, Wei Dengwen, Li Hongtao, Ma Jun, Koehler Thilo, van Delden Christian, Darbre Tamis, Reymond Jean-Louis (2017), Lipidated Peptide Dendrimers Killing Multidrug-Resistant Bacteria, in JACS, Journal of the American Chemical Society, 140(1), 423-432.
Design, crystal structure and atomic force microscopy study of thioether ligated D,L-cyclic antimicrobial peptides against multidrug resistant Pseudomonas aeruginosa
He Runze, Di Bonaventura Ivan, Visini Ricardo, Gan Bee Ha, Fu Yongchun, Probst Daniel, Lüscher Alexandre, Köhler Thilo, van Delden Christian, Stocker Achim, Hong Wenjing, Darbre Tamis, Reymond Jean-Louis (2017), Design, crystal structure and atomic force microscopy study of thioether ligated D,L-cyclic antimicrobial peptides against multidrug resistant Pseudomonas aeruginosa, in Chemical Science, 8, 7464-7475.
Chemical space guided discovery of antimicrobial bridged bicyclic peptides against Pseudomonas aeruginosa and its biofilms
Di Bonaventura Ivan, Jin Xian, Visini Ricardo, Probst Daniel, Javor Sacha, Gan Bee Ha, Michaud Gaëlle, Natalello Antonio, Doglia Silvia Maria, Köhler Thilo, van Delden Christian, Stocker Achim, Darbre Tamis, Reymond Jean-Louis (2017), Chemical space guided discovery of antimicrobial bridged bicyclic peptides against Pseudomonas aeruginosa and its biofilms, in Chemical Science, 8(10), 6784-6798.
Efficient Transfection of siRNA by Peptide Dendrimer–Lipid Conjugates
Kwok A., Eggimann G. A., Heitz M., Reymond Jean-Louis, Hollfelder F., Darbre T. (2016), Efficient Transfection of siRNA by Peptide Dendrimer–Lipid Conjugates, in ChemBioChem Communications, 17, 2223-2229.
Anti-Microbial Dendrimers against Multidrug-Resistant P. aeruginosa Enhance the Angiogenic Effect of Biological Burn-wound Bandages
Abdel-Sayed P., Kaeppli A., Siriwardena T., Darbre T., Perron K., Jafari P., Reymond J.-L., Pioletti D. P., Applegate L. A. (2016), Anti-Microbial Dendrimers against Multidrug-Resistant P. aeruginosa Enhance the Angiogenic Effect of Biological Burn-wound Bandages, in Nature: Scientific Reports, 6, 1-10.
X-ray structure of a lectin-bound DNA duplex containing an unnatural phenanthrenyl pair
Roethlisberger P, Istrate A., Marcaida Lopez M. J., Visini R., Stocker A., Reymond J.-L., Leumann C. J. (2016), X-ray structure of a lectin-bound DNA duplex containing an unnatural phenanthrenyl pair, in Chemical Communications, 52(26), 4749-4752.
Overcoming antibiotic resistance in Pseudomonas aeruginosa biofilms using glycopeptide dendrimers
Michaud Gaëlle, Visini Ricardo, Bergmann Myriam, Salerno Gianluca, Bosco Rosa, Gillon Emilie, Richichi Barbara, qNativi Cristina, Imberty Anne, Stocker Achim, Darbre Tamis, Reymond Jean-Louis (2015), Overcoming antibiotic resistance in Pseudomonas aeruginosa biofilms using glycopeptide dendrimers, in Chemical Science, 7, 166-182.
PDB-Explorer: a web-based interactive map of the protein data bank in shape space
Jin Xian, Awale Mahendra, Zasso Michaël, Kostro DAniel, Patiny Luc, Reymond J.-L. (2015), PDB-Explorer: a web-based interactive map of the protein data bank in shape space, in BMC Bioinformatics, 16(339), 1-15.
In Vitro Activity of the Novel Antimicrobial Peptide Dendrimer G3KL against Multidrug-Resistant Acinetobacter baumannii and Pseudomonas aeruginosa
PIres João, Siriwardena Thissa N., Stach Michaela, Tinguely Regula, Kasraian Sara, Luzzaro Francesco, Leib Stephen L., Darbre Tamis, Reymond Jean-Louis, Endimiani Andrea (2015), In Vitro Activity of the Novel Antimicrobial Peptide Dendrimer G3KL against Multidrug-Resistant Acinetobacter baumannii and Pseudomonas aeruginosa, in Antimicrobial Agents and Chemotherapy, 59(12), 7915-7918.
Multivalency effects on Pseudomonas aeruginosa biofilm inhibition and dispersal by glycopeptide dendrimers targeting lectin LecA
Bergmann Myriam, Michaud Gaëlle, Visini Ricardo, Jin Xian, Gillon Emilie, Stocker Achim, Imbertry Anne, Darbre Tamis, Reymond Jean-Louis (2015), Multivalency effects on Pseudomonas aeruginosa biofilm inhibition and dispersal by glycopeptide dendrimers targeting lectin LecA, in Organic & Biomolecular Chemistry, 14, 138-142.
Structural Insight into Multivalent Galactoside Binding to Pseudomonas aeruginosa Lectin LecA
Visini Ricardo, Jin Xian, Bergmann Myriam, Michaud Gaëlle, Pertici Francesca, Fu Ou, Pukin Aliaksei, Branson Thomas R., Thies-Weesie Dominique M. E., Kemmink Johan, Gillon Emilie, Imberty Anne, Stocker Achim, Darbre Tamis, Pieters Roland J., Reymond Jean-Louis (2015), Structural Insight into Multivalent Galactoside Binding to Pseudomonas aeruginosa Lectin LecA, in ACS Chemical Biology, 10, 2455-2462.
Bridged bicyclic peptides as potential drug scaffolds: synthesis, structure, protein binding and stability
Bartoloni Marco, Jin Xian, Marcaida Marie José, Banha João, Dibonaventura Ivan, Bongoni Swathi, Bartho Kathrin, Gräbner Olivia, Sefkow Michael, Darbre Tamis, Reymond Jean-Louis (2015), Bridged bicyclic peptides as potential drug scaffolds: synthesis, structure, protein binding and stability, in Chemical Science, 6, 5473-5490.

Collaboration

Group / person Country
Types of collaboration
Prof. Christian van Delden/University of Geneva Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Prof. Roland Pieters/University of Utrecht Netherlands (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Anne Imberty/CERMAV Grenoble France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Dr. J. Furrer / UniBE Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Prof. F Hollfelder / University of Cambridge UK Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. A. Stocker/UniBE Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel

Associated projects

Number Title Start Funding scheme
167048 Antimicrobial peptide dendrimers (AMPD) and bicyclic peptides (AMBP) as therapeutic agents against multidrug resistant bacteria 01.03.2017 NRP 72 Antimicrobial Resistance
164025 Automated Peptide Purification System 01.01.2016 R'EQUIP
165997 Exploiting and Extending GDB for Drug Discovery 01.05.2016 Project funding (Div. I-III)
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)
140349 Exploring Peptide Topologies in Search for New Drugs 01.04.2012 Project funding (Div. I-III)
125020 Peptide and Glycopeptide Dendrimers as Artificial Proteins 01.04.2009 Project funding (Div. I-III)
178998 Chemical Space Design of Small Molecules and Peptides 01.04.2018 Project funding (Div. I-III)

Abstract

The “Chemical space” describes the ensemble of all possible chemical compounds, in particular those of interest as drugs for medical use, spanning from small organic molecules such as aspirin to large proteins such as antibodies. The concept of chemical space calls for considering every possible molecule beyond those already known. In this proposal we focus on peptides, an important class of intermediate size molecules found mostly as linear of cyclic chains of up to 50 amino acids. When reflecting on design possibilities, an entire world of new possibilities opens when using diamino acids or amino diacids as branching points in the peptide chain, revealing topologies not found in nature such as multi-branched peptide dendrimers and polycyclic peptides. Unlike linear or monocyclic peptides, these branched peptides are resistant to serum degradation and display remarkable biological properties by multivalency effects (peptide dendrimers) and conformational rigidity (polycyclic peptides). The proposal unfolds in four specific projects to explore the properties of this promising new class of bioactive molecules: computer-aided peptide design, antimicrobials and DNA/si-RNA transfection, biofilm inhibitors, and bridged bicyclic peptides.
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