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Synthetic Protein Epitope Mimetics and Applications as Anti-infectives

English title Synthetic Protein Epitope Mimetics and Applications as Anti-infectives
Applicant Robinson John A.
Number 146381
Funding scheme Project funding (Div. I-III)
Research institution Institut für Chemie Universität Zürich
Institution of higher education University of Zurich - ZH
Main discipline Organic Chemistry
Start/End 01.06.2013 - 31.05.2016
Approved amount 508'175.00
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Keywords (5)

peptidomimetic; synthetic vaccine; peptide; antibiotic; chemical biology

Lay Summary (German)

Lead
This research project involves the study of novel small synthetic molecules (called protein epitope mimetics) that can mimic the functions of large macromolecules, such as proteins. We plan to study novel mimetics with antimicrobial activity that may become useful as a new antibiotics to combat the growing problem of drug resistance in human pathogenic bacteria. We also plan to design and study new mimetics that may be useful as vaccine candidates to prevent infection by HIV-1.
Lay summary

Inhalt und Ziel des Forschungsprojekts

Das Hauptziel des Forschungsprojektes besteht in der Entwicklung kleiner neuartiger synthetischer Moleküle, die im Kampf gegen Infektionskrankheiten wie z.B. bakterielle Infektionen oder Virusinfektionen, insbesondere HIV-1, für die breite Bevölkerung von grossem Nutzen sein können. Es wurden bereits Mimetika entwickelt, die eine starke antimikrobielle Aktivität gegenüber Pseudomonas-Bakterien aufweisen. Weiterführend soll nun untersucht werden, wie diese Antibiotika das Bakterium angreifen (d.h. die Wirkungsweise). Desweiteren wollen wir neue Antibiotika entwickeln, die gegen andere wichtige human-pathogene Keimen wie z.B. Escherichia coli und Acinetobacter baumanii, wirksam sind. Für die Entwicklung neuer therapeutischer Wirkstoffe gegen HIV-1 werden wir mit Virologen der UZH zusammenarbeiten. Ein wichtiges Ziel ist dabei die Fortschritte in der strukturellen Impfstoffkunde zu nutzen, um kleine Molekülepitop-Mimetika als potenzielle Impfstoffe gegen den Virus zu entwerfen.

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Aufgrund der zunehmenden Entstehung resistenter pathogener Bakterienstämme, die mit konventionellen Antibiotika kaum noch zu behandeln sind, kommt der Entwicklung neuer Antibiotika eine immer grössere Bedeutung zu. Demgegenüber steht ein  Rückgang der Antibiotika-Forschungsprogramme  grosser Pharmaunternehmen in den letzten 20 Jahren, was dazu geführt hat, dass nur noch sehr wenige neue Antibiotika entwickelt werden, die dem Anstieg resistententer Keime entgegenwirken können. Das vorliegende Projekt kann durch die Erforschung neuer Ansätze für Antibiotika und Impfstoffe mit neuartigen Wirkungsmechanismen einen wichigen Beitrag zur Lösung dieses Problems leisten.

Direct link to Lay Summary Last update: 25.04.2013

Lay Summary (English)

Lead
This research project involves the study of novel small synthetic molecules (called protein epitope mimetics) that can mimic the functions of large macromolecules, such as proteins. We plan to study novel mimetics with antimicrobial activity that may become useful as a new antibiotics to combat the growing problem of drug resistance in human pathogenic bacteria. We also plan to design and study new mimetics that may be useful as vaccine candidates to prevent infection by HIV-1.
Lay summary

 

 

Direct link to Lay Summary Last update: 25.04.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
A Peptidomimetic Antibiotic Interacts with the Periplasmic Domain of LptD from Pseudomonas aeruginosa
Andolina Gloria, Bencze László-Csaba, Zerbe Katja, Müller Maik, Steinmann Jessica, Kocherla Harsha, Mondal Milon, Sobek Jens, Moehle Kerstin, Malojčić Goran, Wollscheid Bernd, Robinson John A. (2018), A Peptidomimetic Antibiotic Interacts with the Periplasmic Domain of LptD from Pseudomonas aeruginosa, in ACS Chemical Biology, 13(3), 666-675.
Protein Epitope Mimetics: From New Antibiotics to Supramolecular Synthetic Vaccines
Zerbe Katja, Moehle Kerstin, Robinson John A. (2017), Protein Epitope Mimetics: From New Antibiotics to Supramolecular Synthetic Vaccines, in Accounts of Chemical Research, 50(6), 1323-1331.
A Peptidomimetic Antibiotic Targets Outer Membrane Proteins and Disrupts Selectively the Outer Membrane in Escherichia coli
Urfer Matthias (2016), A Peptidomimetic Antibiotic Targets Outer Membrane Proteins and Disrupts Selectively the Outer Membrane in Escherichia coli, in J. Biol. Chem., 291(4), 1921-1932.
Solution Structure and Dynamics of LptE from Pseudomonas aeruginosa
Moehle K. (2016), Solution Structure and Dynamics of LptE from Pseudomonas aeruginosa, in Biochemistry, 55(21), 2936-2943.
Synthesis of a polymyxin derivative for photolabeling studies in the gram-negative bacterium Escherichia coli
vanderMeijden (2015), Synthesis of a polymyxin derivative for photolabeling studies in the gram-negative bacterium Escherichia coli, in J. Pept. Sci., 21(3), 231-235.
Structural aspects of molecular recognition in the immune system. Part II: Pattern recognition receptors
Robinson John (2014), Structural aspects of molecular recognition in the immune system. Part II: Pattern recognition receptors, in Pure Appl. Chem., 86(10), 1483-1538.
Conformation-Dependent Recognition of HIV gp120 by Designed Ankyrin Repeat Proteins Provides Access to Novel HIV Entry Inhibitors
Mann A. (2013), Conformation-Dependent Recognition of HIV gp120 by Designed Ankyrin Repeat Proteins Provides Access to Novel HIV Entry Inhibitors, in J. Virology, 87(10), 5868-5881.
Structural studies of β-hairpin peptidomimetic antibiotics that target LptD in Pseudomonas sp
Schmidt J. (2013), Structural studies of β-hairpin peptidomimetic antibiotics that target LptD in Pseudomonas sp, in Bioorg. Med. Chem., 21(18), 5806-5810.
Synthesis and antimicrobial activity against Pseudomonas aeruginosa of macrocyclic ß-hairpin peptidomimetic antibiotics containing N-methylated amino acids
Vetterli Stefan, Moehle Kerstin, Robinson John A., Synthesis and antimicrobial activity against Pseudomonas aeruginosa of macrocyclic ß-hairpin peptidomimetic antibiotics containing N-methylated amino acids, in Bioorganic and Medicinal Chemistry, 24(24), 6332-6339.

Collaboration

Group / person Country
Types of collaboration
Polyphor AG Switzerland (Europe)
- Industry/business/other use-inspired collaboration
Prof. Daniel Kahne United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Alexandra Trkola, Med. Virologie, UZH Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Prof. Leo Eberl, Microbiology, UZH Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
SCS Fall Meeting 2017 Poster Fighting antimicrobial resistances: CAMPs targeting bacterial essential outer membrane proteins as a new weapon 22.08.2017 Bern, Switzerland Robinson John A.;
International Chemical Biology Society Annual Meeting Talk given at a conference Targeting and Labelling the bacterial outer membrane LPS transporter LptD using antimicrobial peptide 17.11.2014 San Francisco, United States of America Andolina Gloria;
Swiss Summer School 2014 in Chemical Biology Poster Synthesis and SAR of N-methylated beta-hairpin peptidomimetics 01.09.2014 Eurotel Victoria, Villars sur Ollon, Switzerland Vetterli Stefan;
Swiss Summer School 2014 in Chemical Biology Poster Rational design of synthetic vaccines based on protein epitope mimetics 01.09.2014 Eurotel Victoria, Villars sur Ollon, Switzerland Morin Mylène;


Knowledge transfer events



Self-organised

Title Date Place
Neues Antibiotikum in Griffweite 24.03.2015 Universität Zürich, Switzerland

Associated projects

Number Title Start Funding scheme
129724 Design and applications of protein epitope mimetics 01.06.2010 Project funding (Div. I-III)
116176 Design and synthesis of peptidomimetics as antibacterials, antivirals and HIV-1 synthetic vaccine candidates 01.08.2007 Project funding (Div. I-III)

Abstract

The main field of this research involves the design, synthesis and biological activities of novel protein epitope mimetics. Protein epitope mimetics are synthetic molecules designed to mimic the surface epitopes of naturally occurring peptides and proteins that are important for biological activity. The epitopes of most interest here adopt ß-hairpin conformations. Mimetic design involves transplanting the hairpin epitope from the protein target of interest, and attaching this to an organic template. The mimetics then typically comprise cyclic peptides that adopt folded hairpin structures in solution. Using this design strategy we could show in previous work how it was possible to design new molecules with many different types of biological activity. In this project, we plan to continue these studies. We plan to investigate peptidomimetics that possess potent antimicrobial activity against Gram-negative bacteria, and against Pseudomonas spp. in particular. In earlier work we discovered a new family of peptidomimetics, with an unprecedented mechanism of antimicrobial action, involving inhibition of lipopolysaccharide transport by the outer membrane protein LptD. We propose to continue studies on these molecules and investigate how they interact with their target. We also plan to synthesize new derivatives with antibacterial activity against other important Gram-negative pathogens, and study their mechanisms of action. An important goal of this work is to develop new antibiotics that address the growing problem of drug resistance amongst bacteria, both in hospitals and the wider community. Another related area of interest is the study of protein epitopes implicated in mediating immune protection. We plan to synthesize new mimetics of epitopes that have been reported to mediate protection against infection by HIV-1. This work should aid the development of new synthetic vaccines that help to address the global health problem posed by HIV-1.
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