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Exploring Peptide Topologies in Search for New Drugs

English title Exploring Peptide Topologies in Search for New Drugs
Applicant Reymond Jean-Louis
Number 140349
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 01.04.2012 - 31.03.2015
Approved amount 625'000.00
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Keywords (8)

cell penetrating peptides; dendrimers; antimicrobial agents; anticancer agents; gene and siRNA delivery; biofilms; combinatorial libraries; peptides

Lay Summary (English)

Lead
Lay summary
This proposal aims to assemble amino acids to form dendritic and polycyclic topologies not found in naturally occurring peptides and proteins, and explore the biological properties of the resulting macromolecules. In nature amino acids assemble to form mostly linear or monocyclic structures. We have recently established efficient solid-phase peptide synthesis (SPPS) procedures to prepare peptides with branched (dendritic) and bicyclic topologies which are not accessible by natural biosynthetic pathways. Our preliminary results show that such peptides offer a promising and versatile platform for drug design. This line of research is original and has not been followed by other groups in peptide chemistry, where research is focused almost exclusively on linear or monocyclic peptide analogs of natural sequences . Synthesizing peptide topologies not found in nature such as peptide dendrimers and polycyclic peptides as proposed here provides an original and fundamentally new window of opportunity to design bioactive compounds.
Because peptide based molecules can be assembled with well established protocols from a diversity of amino acid building blocks, the versatility is very large. Furthermore, peptide based drugs have the advantage to pose relatively few toxicology and metabolisation problems because they are made of generally non-toxic amino acids. Beside its fundamental appeal in terms of expansion of the accessible chemical space into new areas, the project focuses on significant targets of current medicinal importance with significant preliminary activities in the area of antibiotics, gene therapy and cancer therapy, and might lead to innovative drugs.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Cytotoxic peptide conjugates of dinuclear arene ruthenium trithiolato complexes
Giannini Federico, Bartoloni Marco, Paul Lydia E. H., Süss-Fink Georg, Reymond Jean-Louis, Furrer Julien (2015), Cytotoxic peptide conjugates of dinuclear arene ruthenium trithiolato complexes, in MedChemCom, 2015(6), 347-350.
A catalytically essential motif in the external loop 5 of the bacterial oligosaccharyltransferase PglB
Lizak C., Gerber S., Zinne C., Michaud Gaëlle, Schubert M., Chen F., Bucher M., Darbre Tamis, Zenobi R., Reymond Jean-Louis, Locher K.P. (2014), A catalytically essential motif in the external loop 5 of the bacterial oligosaccharyltransferase PglB, in The Journal of Biological Chemistry, (289), 735-746.
Combining Topology and Sequence Design for the Discovery of Potent Antimicrobial Peptide Dendrimers against Multidrug-Resistant Pseudomonas aeruginosa
Stach Michaela, Siriwardena Thissa, Köhler Thilo, van Delden Christian, Darbre Tamis, Reymond Jean-Louis (2014), Combining Topology and Sequence Design for the Discovery of Potent Antimicrobial Peptide Dendrimers against Multidrug-Resistant Pseudomonas aeruginosa, in Angewandte Chemie, 2014(53), 1-6.
Designed cell penetrating peptide dendrimers efficiently internalize cargo into cells
Eggimann Gabriela A., Blattes Emilyne, Buschor Stefanie, Biswas Rasomoy, Kammer Stephan M., Darbre Tamis, Reymond Jean-Louis (2014), Designed cell penetrating peptide dendrimers efficiently internalize cargo into cells, in ChemComm, 2014(50), 7254-7257.
Stereoselective synthesis and structure determination of a bicyclo[3.3.2]decapeptide
Bartoloni Marco, Waltersperger Sandro, Bumann Mario, Stocker Achim, Darbre Tamis, Reymond Jean-Louis (2014), Stereoselective synthesis and structure determination of a bicyclo[3.3.2]decapeptide, in Arkivoc, 2014(3), 113-123.
CH-π "T-Shape" Interaction with Histidine Explains Binding of Aromatic Galactosides to Pseudomonas aeruginosa lectin LecA
Kadam Rameshwar U., Garg Divita, Schwartz Julian, Visini Ricardo, Sattler Michael, Stocker Achim, Darbre Tamis, Reymond Jean-Louis (2013), CH-π "T-Shape" Interaction with Histidine Explains Binding of Aromatic Galactosides to Pseudomonas aeruginosa lectin LecA, in ACS Chem. Biol, (8), 1925-1930.
Convergent synthesis and cellular uptake of multivalent cell penetrating peptides derived from Tat, Antp, pVEC, TP10 and SAP
Eggimann Gabiela A., Buschor Stefanie, Darbre Tamis, Reymond Jean-Louis (2013), Convergent synthesis and cellular uptake of multivalent cell penetrating peptides derived from Tat, Antp, pVEC, TP10 and SAP, in Org. Biomol. Chem., 11(39), 6717-6733.
Electrostatics and flexibility drive membrane recognition and early penetration by the antimicrobial peptide dendrimer bH1
Ravi H. K., Stach Michaela, Soares T.A., Darbre Tamis, Reymond Jean-Louis, Cascella Michele (2013), Electrostatics and flexibility drive membrane recognition and early penetration by the antimicrobial peptide dendrimer bH1, in Chemical Communications, 49(78), 8821-8823.
Expanding the Topological Space of Bioactive Peptides
Reymond Jean-Louis, Darbre Tamis (2013), Expanding the Topological Space of Bioactive Peptides, in Chimia, (67), 864-867.
Glycopeptide dendrimers as Pseudomonas aeruginosa biofilm inhibitors.
Reymond Jean-Louis, Bergmann Myriam, Darbre Tamis (2013), Glycopeptide dendrimers as Pseudomonas aeruginosa biofilm inhibitors., in Chemical Society reviews, 42(11), 4814-22.
Mechanism of bacterial oligosaccharyltransferase: in vitro quantification of sequon binding and catalysis.
Gerber Sabina, Lizak Christian, Michaud Gaëlle, Bucher Monika, Darbre Tamis, Aebi Markus, Reymond Jean-Louis, Locher Kaspar P (2013), Mechanism of bacterial oligosaccharyltransferase: in vitro quantification of sequon binding and catalysis., in The Journal of biological chemistry, 288(13), 8849-61.
Multivalent glycoconjugates as anti-pathogenic agents.
Bernardi Anna, Jiménez-Barbero Jesus, Casnati Alessandro, De Castro Cristina, Darbre Tamis, Fieschi Franck, Finne Jukka, Funken Horst, Jaeger Karl-Erich, Lahmann Martina, Lindhorst Thisbe K, Marradi Marco, Messner Paul, Molinaro Antonio, Murphy Paul V, Nativi Cristina, Oscarson Stefan, Penadés Soledad, Peri Francesco, Pieters Roland J, Renaudet Olivier, Reymond Jean-Louis, Richichi Barbara, Rojo Javier, Sansone Francesco (2013), Multivalent glycoconjugates as anti-pathogenic agents., in Chemical Society reviews, 42(11), 4709-27.
Peptide Dendrimer/Lipid Hybrid Systems are Efficient DNA Transfection Reagents: Structure-Activity Relationships Highlight the Role of Charge Distribution Across Dendrimer Generations
Kwok Albert A., Eggimann Gabriela, Reymond Jean-Louis, Darbre Tamis, Hollfelder Florian (2013), Peptide Dendrimer/Lipid Hybrid Systems are Efficient DNA Transfection Reagents: Structure-Activity Relationships Highlight the Role of Charge Distribution Across Dendrimer Generations, in ACS Nano, 7(5), 4668-4682.
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 & biomolecular chemistry, 11(2), 344-52.
Structure-Based Optimization of the Terminal Tripeptide in Glycopeptide Dendrimer Inhibitors of Pseudomonas aeruginosa Biofilms Targeting LecA
Kadam Rameshwar U., Bergmann Myriam, Garg Divita, Gabrieli Gabriele, Stocker Achim, Darbre Tamis, Reymond Jean-Louis (2013), Structure-Based Optimization of the Terminal Tripeptide in Glycopeptide Dendrimer Inhibitors of Pseudomonas aeruginosa Biofilms Targeting LecA, in Chem. Eur. J., (19), 17054-17063.
Unexpected reactivity and mechnism of carboxamide activation in bacterial N-linked protein glycosylation
Lizak C., Gerber S., Michaud Gaëlle, Schubert M., Fan Y. Y., Bucher M., Darbre Tamis, Aebi M., Reymond Jean-Louis, Locher K. P. (2013), Unexpected reactivity and mechnism of carboxamide activation in bacterial N-linked protein glycosylation, in Nature Communications, 4, 2627.

Collaboration

Group / person Country
Types of collaboration
Prof. F Hollfelder / University of Cambridge UK Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Dr. J. Furrer / UniBE Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Markus Aebi / ETHZ Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Kurt Ballmer-Hofer/PSI Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Exchange of personnel
Prof. A. Stocker/UniBE Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Prof. K. Locher/ETHZ Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Associated projects

Number Title Start Funding scheme
125020 Peptide and Glycopeptide Dendrimers as Artificial Proteins 01.04.2009 Project funding (Div. I-III)
155982 Controlling multi-antibiotic resistant bacteria with antimicrobial peptide dendrimers (AMPD) 01.10.2015 Bilateral programmes
159941 A Chemical Space Approach to Bioactive Peptides 01.04.2015 Project funding (Div. I-III)
159941 A Chemical Space Approach to Bioactive Peptides 01.04.2015 Project funding (Div. I-III)
116555 Peptide Dendrimers as Synthetic Artificial Proteins for Catalysis and Binding 01.04.2007 Project funding (Div. I-III)
145003 A new Zeiss LSM 710 laser scanning microscope for the DCR LCI Core Facility 01.12.2012 R'EQUIP

Abstract

This proposal aims to assemble amino acids to form dendritic and polycyclic topologies not found in naturally occurring peptides and proteins, and explore the biological properties of the resulting macromolecules. In nature amino acids assemble to form mostly linear or monocyclic structures. We have recently established efficient solid-phase peptide synthesis (SPPS) procedures to prepare peptides with branched (dendritic) and bicyclic topologies which are not accessible by natural biosynthetic pathways. Our preliminary results show that such peptides offer a promising and versatile platform for drug design. This line of research is original and has not been followed by other groups in peptide chemistry, where research is focused almost exclusively on linear or monocyclic peptide analogs of natural sequences . Synthesizing peptide topologies not found in nature such as peptide dendrimers and polycyclic peptides as proposed here provides an original and fundamentally new window of opportunity to design bioactive compounds. Because peptide based molecules can be assembled with well established protocols from a diversity of amino acid building blocks, the versatility is very large. Furthermore, peptide based drugs have the advantage to pose relatively few toxicology and metabolisation problems because they are made of generally non-toxic amino acids. Beside its fundamental appeal in terms of expansion of the accessible chemical space into new areas, the project focuses on significant targets of current medicinal importance with significant preliminary activities in the area of antibiotics, gene therapy and cancer therapy, and might lead to innovative drugs.
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