Project
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Ruthenium Complexes for the Treatment of Protozoan Diseases of Medical and Veterinary Importance
Applicant |
Furrer Julien
|
Number |
173718 |
Funding scheme |
Sinergia
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Research institution |
Departement für Chemie, Biochemie und Pharmazie Universität Bern
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Institution of higher education |
University of Berne - BE |
Main discipline |
Interdisciplinary |
Start/End |
01.09.2017 - 31.05.2023 |
Approved amount |
1'608'571.00 |
Show all
All Disciplines (5)
Cellular Biology, Cytology |
Keywords (8)
in vivo; Toxoplasmosis; auxotrophies; metabolomics; ruthenium complexes; biodistribution; HRMAS NMR spectroscopy; protozoan parasites
Lay Summary (French)
Lead
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Nouvelles molécules à base de ruthénium pour le traitement de maladies induites par des parasites apicomplexes (toxoplasmose, malaria)
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Lay summary
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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.
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Responsible applicant and co-applicants
Employees
Project partner
Publications
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.
Ong Yih Ching, Gasser Gilles (2019), Organometallic compounds in drug discovery: Past, present and future, in
Drug Discovery Today: Technologies, 0.
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.
Ong Yih Ching, Roy Saonli, Andrews Philip C., Gasser Gilles (2018), Metal Compounds against Neglected Tropical Diseases, in
Chemical Reviews, 119(2), 730-796.
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
Olias laboratory, Institute of Pathology, University of Bern |
Switzerland (Europe) |
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- in-depth/constructive exchanges on approaches, methods or results - Research Infrastructure |
Heussler laboratory, Institute of Cell Biology, University of Bern |
Switzerland (Europe) |
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- in-depth/constructive exchanges on approaches, methods or results - Research Infrastructure |
Woods laboratory, Institute of Animal Pathology, University of Bern |
Switzerland (Europe) |
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- in-depth/constructive exchanges on approaches, methods or results - Research Infrastructure |
Bütikofer lab, Institute of Biochemistry and Molecular Medicine, University of Bern |
Switzerland (Europe) |
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- 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
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Poster
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Synthesis and Photophysical Properties of BODIPY-Tethered Trithiolato-Bridged Dinuclear Ruthenium(II)-Arene Compounds
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06.09.2019
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Zürich, Switzerland
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Furrer Julien;
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Swiss Chemical Society Fall Meeting 2019
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Poster
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TRIAZOLE-LINKED ORGANOMETALLIC ARCHITECTURES - ADDING DIVERSITY TO TRITHIOLATO-BRIDGED DINUCLEAR RUTHENIUM(II)-ARENE COMPOUNDS VIA CuAAC CLICK CHEMISTRY
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06.09.2019
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Zurich, Switzerland
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Furrer Julien;
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6th European Federation for Medicinal Chemistry Young Medicinal Chemist Symposium
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Individual talk
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PHOTOPHYSICAL PROPERTIES AND ANTIPARASITIC ACTIVITY OF BODIPY-TETHERED DINUCLEAR TRITHIOLATO-BRIDGED RUTHENIUM(II)-ARENE COMPLEXES
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05.09.2019
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Athens, Greece
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Desiatkina Oksana;
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6th European Federation for Medicinal Chemistry Young Medicinal Chemist Symposium
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Poster
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Photophysical Properties and Antiparasitic Activity of BODIPY-Tethered Dinuclear Trithiolato-Bridged Ruthenium(II)-Arene Complexes
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05.09.2019
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Athens, Greece
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Desiatkina Oksana;
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19th International Conference on Biological Inorganic Chemistry
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Poster
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HYBRID COMPOUNDS CONSTRUCTED ON A TRITHIOLATHO-BRIDGED DINUCLEAR RUTHENIUM(II)-ARENE SCAFFOLD - SYNTHESIS, STRUCTURAL AND SPECTROSCOPIC CHARACTERIZATION
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11.08.2019
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Interlaken, Switzerland
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Desiatkina Oksana;
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19th International Conference on Biological Inorganic Chemistry
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Poster
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Coumarin-Tagged Dinuclear Trithiolato-Bridged Ruthenium(II)-Arene Complexes – Photophysical Properties and Antiparasitic Activity
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11.08.2019
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Interlaken, Switzerland
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Desiatkina Oksana;
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ISBOMC
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Talk given at a conference
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Organometallic agents based on the group 8 elements Iron and Ruthenium as antiparasitic and anticancer agents
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28.07.2019
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York, Great Britain and Northern Ireland
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Ong Yih Ching;
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ISBOMC
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Talk given at a conference
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Organometallic Compounds against Human and Livestock Animal Parasitic Diseases
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28.07.2019
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York, Great Britain and Northern Ireland
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Gasser Gilles;
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Centre for Interdisciplinary Research in Animal Health (CIISA), Congress 2018
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Talk given at a conference
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Novel drugs and drug targets for the treatment of toxoplasmosis and other diseases caused by cyst-forming apicomplexans
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16.11.2018
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Lisbon, Portugal
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Hemphill Andrew;
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1st Year Symposium
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Individual talk
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Ruthenium Complexes for the Treatment of Protozoan Diseases of Medical and Veterinary Importance
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10.09.2018
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Bern, Switzerland
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Desiatkina Oksana;
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Swiss Chemical Society Fall Meeting 2018
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Poster
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Coumarin-labeled Dinuclear Trithiolato-Bridged Ruthenium(II) Arene Complexes - Synthesis, Characterization and Spectral Properties
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07.09.2018
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Lausanne, Switzerland
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Furrer Julien; Paunescu Emilia; Desiatkina Oksana;
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Swiss Chemical Society Fall Meeting 2018
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Poster
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New star shape Organometallic complexes containing three dinuclear trithiolato-bridged ruthenium(II) arene units
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07.09.2018
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Lausanne, Switzerland
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Paunescu Emilia; Furrer Julien;
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Swiss Chemical Society Fall Meeting 2018
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Poster
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New Organometallic complexes containing two dinuclear trithiolato bridged ruthenium(II) arene units
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07.09.2018
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Lausanne, Switzerland
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Furrer Julien; Paunescu Emilia;
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14th European Biological Inorganic Chemistry Conference EuroBIC 14,
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Poster
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Synthesis, Spectral Properties and Biological Evaluation of New Conjugates BODIPY – Dinuclear Trithiolato-Bridged Ruthenium Arene Complexes
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26.08.2018
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Birmingham, Great Britain and Northern Ireland
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Desiatkina Oksana;
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European coccidiosis discussion group, Royal Veterinary College
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Talk given at a conference
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Drugs and drug targets in pregnant models for Toxoplasma and Neospora infection
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17.05.2018
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London, Great Britain and Northern Ireland
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Hemphill Andrew;
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Seminarios investigación platesa, Universidad Complutense de Madrid
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Individual talk
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Studies on novel preventive and therapeutic tools to tackle diseases caused by apicomplexan parasites
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24.04.2018
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Madrid, Spain
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Hemphill Andrew;
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ApiCOWplexa 2017
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Talk given at a conference
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Drugs and drug targets in pregnant models for Toxoplasma & Neospora infection
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11.10.2017
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Madrid, Spain
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Hemphill Andrew; Anghel Nicoleta;
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Awards
Profesor Honorifico de la Universidad Complutense de Madrid
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2018
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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) |
139078
|
1.7 mm Micro-Probehead for small volume NMR Spectroscopic Investigations |
01.03.2012 |
R'EQUIP |
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) |
198127
|
High-resolution Electron Impact Ionization Mass Spectrometer equipped with a Gas Chromatograph |
01.01.2021 |
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.
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