Project

Back to overview

Ruthenium Complexes for the Treatment of Protozoan Diseases of Medical and Veterinary Importance

Applicant Furrer Julien
Number 173718
Funding scheme Sinergia
Research institution Departement für Chemie und Biochemie Universität Bern
Institution of higher education University of Berne - BE
Main discipline Interdisciplinary
Start/End 01.09.2017 - 31.08.2021
Approved amount 1'547'903.00
Show all

All Disciplines (5)

Discipline
Interdisciplinary
Physical Chemistry
Organic Chemistry
Inorganic Chemistry
Cellular Biology, Cytology

Keywords (8)

in vivo; Toxoplasmosis; auxotrophies; metabolomics; ruthenium complexes; biodistribution; HRMAS NMR spectroscopy; protozoan parasites

Lay Summary (French)

Lead
Nouvelles molécules à base de ruthénium pour le traitement de maladies induites par des parasites apicomplexes (toxoplasmose, malaria)
Lay summary
Les maladies telles que la Malaria, toxoplasmose, neosporose, la maladie du sommeil et bien d'autres sont causées par des parasites dits apicomplexes. Ce sont des maladies qui induisent de graves problèmes, humains et économiques, dans les pays touchés.
Malheureusement, le développement de nouveaux médicaments contre ces parasites reste très limité, bien que les traitements actuels soient de moins en moins efficaces, avec en particulier l'apparition de nombreuses résistances.
Dans le cadre de ce projet, des spécialistes en chimie, biologie moléculaire et parasitologie vont joindre leurs forces pour exploiter des molécules à bases de ruthénium, actuellement candidates pour être utilisées contre le cancer, afin d'en faire des molécules potentiellement anti parasitiques.
Dans ce projet, nous nous concentrerons dans un premier temps sur le parasite T. gondii, car celui-ci est considéré comme un organisme modèle pour les études cliniques et pharmacologiques.
Plus précisément, nous envisageons d'exploiter les auxotrophies du parasite T gondii, telles que l'arginine, les purines, les polyamines, que le parasite doit récupérer de son organisme hôte pour survivre. En conjuguant nos complexes de ruthénium à ces molécules, nous espérons augmenter la prise de ces complexes par les parasites. Les plus prometteurs d'entre eux, identifiés par des mesures in vitro, seront également évalués in vivo. Nous tenterons également d'identifier les cibles cellulaires et comprendre le ou les mécanismes d'action.
En parallèle, d'autres études in vitro seront effectuées contre les parasites Plasmodium, Trypanosoma, Giardia, afin d'obtenir des informations sur le potentiel de ces complexes comme médicaments antiparasitiques.
A la fin du projet, nous espérons être en mesure d'avoir 3-5 complexes actifs et sélectifs contre un ou plusieurs de ces parasites, ainsi que de bonnes efficacités in vivo. Il sera ainsi envisageable de passer aux tests précliniques et cliniques.
Direct link to Lay Summary Last update: 09.06.2017

Responsible applicant and co-applicants

Employees

Project partner

Publications

Publication
Anti-parasitic dinuclear thiolato-bridged arene ruthenium complexes alter the mitochondrial ultrastructure and membrane potential in Trypanosoma brucei bloodstream forms
Jelk Jennifer, Balmer Vreni, Stibal David, Giannini Federico, Süss-Fink Georg, Bütikofer Peter, Furrer Julien, Hemphill Andrew (2019), Anti-parasitic dinuclear thiolato-bridged arene ruthenium complexes alter the mitochondrial ultrastructure and membrane potential in Trypanosoma brucei bloodstream forms, in Experimental Parasitology, 205, 107753-107753.
Organometallic compounds in drug discovery: Past, present and future
Ong Yih Ching, Gasser Gilles (2019), Organometallic compounds in drug discovery: Past, present and future, in Drug Discovery Today: Technologies, 0.
Polymer encapsulation of ruthenium complexes for biological and medicinal applications
Villemin Elise, Ong Yih Ching, Thomas Christophe M., Gasser Gilles (2019), Polymer encapsulation of ruthenium complexes for biological and medicinal applications, in Nature Reviews Chemistry, 3(4), 261-282.
Metal Compounds against Neglected Tropical Diseases
Ong Yih Ching, Roy Saonli, Andrews Philip C., Gasser Gilles (2018), Metal Compounds against Neglected Tropical Diseases, in Chemical Reviews, 119(2), 730-796.
The significance of cryptosporidiosis for the health of calves in SwitzerlandDie Bedeutung der Cryptosporidiose für die Kälbergesundheit in der Schweiz
Olias P, Dettwiler I, Hemphill A, Deplazes P, Steiner A, Meylan M (2018), The significance of cryptosporidiosis for the health of calves in SwitzerlandDie Bedeutung der Cryptosporidiose für die Kälbergesundheit in der Schweiz, in Schweiz Arch Tierheilkd, 160(6), 363-374.

Collaboration

Group / person Country
Types of collaboration
Olias laboratory, Institute of Pathology, University of Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Heussler laboratory, Institute of Cell Biology, University of Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Woods laboratory, Institute of Animal Pathology, University of Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Bütikofer lab, Institute of Biochemistry and Molecular Medicine, University of Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Swiss Chemical Society Fall Meeting 2019 Poster Synthesis and Photophysical Properties of BODIPY-Tethered Trithiolato-Bridged Dinuclear Ruthenium(II)-Arene Compounds 06.09.2019 Zürich, Switzerland Furrer Julien;
Swiss Chemical Society Fall Meeting 2019 Poster TRIAZOLE-LINKED ORGANOMETALLIC ARCHITECTURES - ADDING DIVERSITY TO TRITHIOLATO-BRIDGED DINUCLEAR RUTHENIUM(II)-ARENE COMPOUNDS VIA CuAAC CLICK CHEMISTRY 06.09.2019 Zurich, Switzerland Furrer Julien;
6th European Federation for Medicinal Chemistry Young Medicinal Chemist Symposium Individual talk PHOTOPHYSICAL PROPERTIES AND ANTIPARASITIC ACTIVITY OF BODIPY-TETHERED DINUCLEAR TRITHIOLATO-BRIDGED RUTHENIUM(II)-ARENE COMPLEXES 05.09.2019 Athens, Greece Desiatkina Oksana;
6th European Federation for Medicinal Chemistry Young Medicinal Chemist Symposium Poster Photophysical Properties and Antiparasitic Activity of BODIPY-Tethered Dinuclear Trithiolato-Bridged Ruthenium(II)-Arene Complexes 05.09.2019 Athens, Greece Desiatkina Oksana;
19th International Conference on Biological Inorganic Chemistry Poster HYBRID COMPOUNDS CONSTRUCTED ON A TRITHIOLATHO-BRIDGED DINUCLEAR RUTHENIUM(II)-ARENE SCAFFOLD - SYNTHESIS, STRUCTURAL AND SPECTROSCOPIC CHARACTERIZATION 11.08.2019 Interlaken, Switzerland Desiatkina Oksana;
19th International Conference on Biological Inorganic Chemistry Poster Coumarin-Tagged Dinuclear Trithiolato-Bridged Ruthenium(II)-Arene Complexes – Photophysical Properties and Antiparasitic Activity 11.08.2019 Interlaken, Switzerland Desiatkina Oksana;
ISBOMC Talk given at a conference Organometallic agents based on the group 8 elements Iron and Ruthenium as antiparasitic and anticancer agents 28.07.2019 York, Great Britain and Northern Ireland Ong Yih Ching;
ISBOMC Talk given at a conference Organometallic Compounds against Human and Livestock Animal Parasitic Diseases 28.07.2019 York, Great Britain and Northern Ireland Gasser Gilles;
Centre for Interdisciplinary Research in Animal Health (CIISA), Congress 2018 Talk given at a conference Novel drugs and drug targets for the treatment of toxoplasmosis and other diseases caused by cyst-forming apicomplexans 16.11.2018 Lisbon, Portugal Hemphill Andrew;
1st Year Symposium Individual talk Ruthenium Complexes for the Treatment of Protozoan Diseases of Medical and Veterinary Importance 10.09.2018 Bern, Switzerland Desiatkina Oksana;
Swiss Chemical Society Fall Meeting 2018 Poster Coumarin-labeled Dinuclear Trithiolato-Bridged Ruthenium(II) Arene Complexes - Synthesis, Characterization and Spectral Properties 07.09.2018 Lausanne, Switzerland Furrer Julien; Paunescu Emilia; Desiatkina Oksana;
Swiss Chemical Society Fall Meeting 2018 Poster New star shape Organometallic complexes containing three dinuclear trithiolato-bridged ruthenium(II) arene units 07.09.2018 Lausanne, Switzerland Paunescu Emilia; Furrer Julien;
Swiss Chemical Society Fall Meeting 2018 Poster New Organometallic complexes containing two dinuclear trithiolato bridged ruthenium(II) arene units 07.09.2018 Lausanne, Switzerland Furrer Julien; Paunescu Emilia;
14th European Biological Inorganic Chemistry Conference EuroBIC 14, Poster Synthesis, Spectral Properties and Biological Evaluation of New Conjugates BODIPY – Dinuclear Trithiolato-Bridged Ruthenium Arene Complexes 26.08.2018 Birmingham, Great Britain and Northern Ireland Desiatkina Oksana;
European coccidiosis discussion group, Royal Veterinary College Talk given at a conference Drugs and drug targets in pregnant models for Toxoplasma and Neospora infection 17.05.2018 London, Great Britain and Northern Ireland Hemphill Andrew;
Seminarios investigación platesa, Universidad Complutense de Madrid Individual talk Studies on novel preventive and therapeutic tools to tackle diseases caused by apicomplexan parasites 24.04.2018 Madrid, Spain Hemphill Andrew;
COST Action CM1307 conference Talk given at a conference Ruthenium complexes for the treatment of protozoan diseases 25.10.2017 Lausanne, Switzerland Furrer Julien; Hemphill Andrew; Gasser Gilles;
ApiCOWplexa 2017 Talk given at a conference Drugs and drug targets in pregnant models for Toxoplasma & Neospora infection 11.10.2017 Madrid, Spain Hemphill Andrew; Anghel Nicoleta;


Awards

Title Year
EuroBIC Award 2018
Profesor Honorifico de la Universidad Complutense de Madrid 2018

Associated projects

Number Title Start Funding scheme
165782 The cross-talk between chemotherapy and immunity in murine and ovine neosporosis disease 01.04.2016 Project funding (Div. I-III)
131867 NMR investigation of cellular targets and mechanistic profiles of ruthenium-based drugs 01.01.2011 Project funding (Div. I-III)
144420 Bridged Dinuclear Arene Ruthenium Complexes: Cellular Targets and Mechanistic Profiles Investigated by NMR 01.01.2013 Project funding (Div. I-III)
184662 Effects of a double-edged sword: exploiting the interaction between immunity and chemotherapy in murine and ovine models of congenital neosporosis and toxoplasmosis 01.04.2019 Project funding (Div. I-III)
139078 1.7 mm Micro-Probehead for small volume NMR Spectroscopic Investigations 01.03.2012 R'EQUIP

Abstract

Malaria, cryptosporidiosis, coccidiosis, toxoplasmosis, theileriosis, neosporosis, and besnoitiosis, causedby apicomplexan parasites, as well as African sleeping sickness and giardiasis, are diseases of high humanand/or veterinary relevance, and inflict a dramatic medical and economic burden in affected countries worldwide.1While a plethora of drugs has been, and is being, developed against a wide range of cancers, drug developmentagainst parasitic diseases has been largely neglected, despite the fact that many currently employed antiparasitictherapies exhibit adverse side effects, are not very efficacious, and resistance formation has beenrecognized as a serious constraint.2 In this interdisciplinary project, specialists in medicinal and syntheticchemistry, metabolomics, HRMAS NMR, ICP-MS, medical parasitology, and cell and molecular biology will joinforces to exploit the potential of ruthenium-based anti-cancer drugs, aiming to develop novel chemotherapiesagainst a wide range of protozoan parasites and study their mechanism of action.More specifically, this project is based on the highly promising preliminary results obtained by themembers of this consortium with organometallic ruthenium complexes in in vitro studies on the protozoanparasites Toxoplasma gondii, Plasmodium berghei and Trypanosoma brucei. Ruthenium compounds are knownto cause little side effects, they are well suited towards pharmacological applications, and their production is costefficient,which is especially interesting for in vivo studies and clinical trials. We will primarily focus on T. gondiisince this represents a prime model organism for studies on intracellular parasitism and host-parasiteinteractions. A targeted approach for generating novel compounds will exploit the auxotrophies (polyamines,amino acids, purines, cholesterol, folates), and metabolic peculiarities (for instance folate transport systems) of T.gondii, by conjugating arene ruthenium moieties to metabolites that are essential for the parasite and that have tobe scavenged from the host cell. This will increase uptake and will result in higher and more specific anti-parasiticactivities. From a therapeutic perspective, the strategy to force a parasite to acquire toxic compounds coupled toessential moieties has not yet been exploited, although it has a significant potential. In practical terms, the mostpromising complexes generated in this project will be identified by in vitro screening of T. gondii grown infibroblasts, and for selected drugs the pharmacokinetic properties and biodistribution in different organs in micewill be assessed by ICP-MS. Those conjugates showing favorable in vivo features (high exposure, low toxicity)will be assessed in standardized murine infection models for acute and congenital toxoplasmosis. Further studieson the mechanisms of action of these drugs will include (i) assessment of metabolic changes in T. gondiiemploying HRMAS NMR spectroscopy; (ii) transmission electron microscopy of drug-treated parasites; (iii)identification and characterization of drug-binding proteins and putative targets using affinity chromatography ondrug-conjugated matrices; and (iv) CRISPR-Cas9-mediated knock-out or overexpression of putative druginteraction partners to study phenotypic changes and target validation. In vitro activities of selected rutheniumcomplexes will be further assessed in Plasmodium, Eimeria, Trypanosoma, Giardia, Theileria, Besnoitia andGiardia by several interested collaborating laboratories. This will provide information on a broader applicability ofruthenium complexes, and will serve as a condensation point for (i) future research on these novel anti-parasiticcompounds, and (ii) a potentially more widespread relevance of the identified drug targets.At the end of this project, we will have generated 3-5 compounds with highly selective in vitro toxicityagainst one or several of these protozoan parasites, and excellent in vivo efficacy in mouse models of acute andcongenital toxoplasmosis, ready to be tested in larger animals for prospective advancement to clinical trials. Veryimportantly, this project will be annually assessed by an advisory board composed of highly recognized chemistsand drug development specialists from academia and industry.
-