Titles of the Series “Drug Discovery in Infectious Diseases”

Selzer, P. M. (ed.)

Antiparasitic and Antibacterial Drug Discovery

From Molecular Targets to Drug Candidates

2009

ISBN: 978-3-527-32327-2

Becker, K. (ed.)

Apicomplexan Parasites

Molecular Approaches toward Targeted Drug Development

2011

ISBN: 978-3-527-32731-7

Conor R. Caffrey (ed.)

Parasitic Helminths

Targets, Screens, Drugs and Vaccines

2012

ISBN 978-3-527-33059-1

Forthcoming Topics of the Series

• Protein Phosphorylation in Parasites: Novel Targets for Antiparasitic Intervention

Related Titles

Lucius, R., Loos-Frank, B., Grencis, R. K., Striepen, B., Poulin, R. (eds.)

The Biology of Parasites

2014

ISBN: 978-3-527-32848-2

Lamb, T.

Immunity to Parasitic Infections

2013

ISBN: 978-0-470-97247-2

Zajac, A. M., Conboy, G. A. (eds.)

Veterinary Clinical Parasitology

2012

ISBN: 978-0-8138-2053-8

Scott, I., Sutherland, I.

Gastrointestinal Nematodes of Sheep and Cattle

Biology and Control

2009

ISBN: 978-1-4051-8582-0.

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Foreword

Drug Discovery for Neglected Diseases – Past and Present and Future

The kinetoplastid diseases – sleeping sickness, the leishmaniases, and Chagas disease – are “neglected diseases of poverty,” afflicting millions of people and collectively responsible for over 100 000 deaths per annum. No vaccines are available and current insect vector control methods and other public health measures are insufficient to eliminate them. The currently available drug therapies are far from satisfactory due to issues such as poor efficacy, toxicity, the need for hospitalization, the requirement for prolonged parenteral treatment, and high cost. This book is a timely attempt to address some of these unmet medical needs.

It is somewhat ironic that, at the beginning of the twentieth century, many of the ground-breaking developments in drug discovery were driven by economic and colonial expansion in Africa and Asia. The African trypanosome in particular was an early model for experimental chemotherapy along two main lines of investigation: synthetic dyes, and organic arsenicals and antimonials (for further details, see reviews by Williamson [1] and Steverding [2]). Indeed, the first synthetic compound to cure an infectious disease in an animal model was the dye, Trypan red (Ehrlich, 1904), which was a forerunner of suramin (1916–1920), the first effective trypanocidal drug for human African trypanosomiasis (HAT). The demonstration by Thomas and Breinl in 1905 of the trypanocidal activity in mice of atoxyl (p-aminophenylarsonic acid) formed the basis of Ehrlich's pioneering work on organic arsenicals that culminated in the development of arsphenamine (606, Salvarsan) for the treatment of syphilis (Ehrlich and Hata, 1910) and tryparsamide for the treatment of HAT (Jacobs and Heidelberger, 1919). Tryparsamide, which caused blindness in 10–20% of patients, was finally replaced by melarsoprol (Friedheim, 1949). Trivalent antimony, in the form of tartar emetic, was shown to be trypanocidal in mice (Plimmer and Thompson, 1908), but lacked efficacy in humans. However, potassium antimony tartrate was found to have some activity in the treatment of leishmaniasis (Vianna, 1912) and was the forerunner of the pentavalent antimonial drugs, sodium stibogluconate (Pentostam®) and meglumine antimonate (Glucantime®), both introduced in the 1940s. Along with the diamidine, pentamidine (1937), all of these drugs are still in use today.

From the 1950s, subsequent drug treatments have largely been discovered by serendipity through repurposing of existing drugs used for other indications. The nitrofuran, nifurtimox, and the nitroimidazole, benznidazole, used for the treatment of Chagas disease arose from research into nitro-compounds as antibacterial agents. Amphotericin B, isolated in 1953, was originally developed for the treatment of systemic mycoses, but later found use in the treatment of visceral leishmaniasis in the 1990s as the expensive, but highly efficacious liposomal formulation (AmBisome®) or as the cheaper, but more toxic amphotericin B deoxycholate. Both formulations were included in the World Health Organization's Essential Medicines List in 2009. The off-patent aminoglycoside, paromomycin, originally developed as an oral treatment for intestinal infections in the 1960s, finally gained approval as paromomycin intramuscular injection for the treatment of visceral leishmaniasis in India in 2006. Two anticancer agents, the phospholipid analog, miltefosine, registered as the first oral treatment for visceral leishmaniasis in India in 2002, and eflornithine (now in combination with oral nifurtimox as nifurtimox–eflornithine combination therapy (NECT), 2009) for the treatment of HAT caused by Trypanosoma brucei gambiense complete the woefully inadequate treatment options for these diseases. Notably, none of these newer developments have completely displaced their forerunners that were developed prior to the 1950s.

After nearly a century of research, only 10 novel chemical entities for three diseases is a singularly unimpressive output by the pharmaceutical industry. The reason for this lamentable performance is not hard to find. Poor economic return on investment by pharma is a major factor, since these are diseases of poverty. The thalidomide disaster of the late 1950s kick-started regulatory demands for greater patient safety resulting in ever-increasing development costs. Blockbuster drugs were “in;” smaller, less profitable markets were “out.” Ninety percent of research and development was aimed at 10% of the world's unmet medical need – the so-called “10–90 gap.” The drive for greater efficiency and profitability through mergers and acquisitions resulted in the loss of parasitology expertise in most pharma companies. Medicinal chemists were seduced by combinatorial chemistry without due regard for chemical space and drug-likeness. Miniaturization of chemical synthesis restricted the use of animal disease models and shifted emphasis towards target screening. Intellectual property rights were increasingly used as an obstructive, rather than an enabling tool.

At the end of the twentieth century, the situation had become so dire that a radical new approach was required. One of the most encouraging developments was the founding of “public–private partnerships” (PPPs), such as the Drugs for Neglected Diseases initiative (DNDi) and Medicines for Malaria Venture (MMV) – non-profit organizations who strive to forge drug discovery partnerships between multiple academic, biotech, and pharma partners with funding from the governmental and charitable sector [3]. PPPs were initially met with much skepticism, but by 2005, an analysis by Mary Moran and colleagues concluded that PPPs were responsible for three-quarters of an expanded research and development portfolio for neglected diseases [4]. Another important development was the publication of annotated genomes for T. brucei, L. major, and T. cruzi in 2005 [5–7]. As Barry Bloom optimistically prophesized 10 years earlier “Sequencing bacterial and parasitic pathogens . . . could buy the sequence of every virulence determinant, every protein antigen and every drug target . . . for all time” [8]. Certainly, pathogen genomes are proving to be a valuable resource for target discovery, but without a deeper understanding of parasite biology the full potential of these genomes will not be realized. About the same time as genome sequencing was getting underway, C.C. Wang threw down the gauntlet that academics needed genetic evidence of essentiality to justify their claims of the therapeutic potential of their research field [9]. This dogma has now been refined and extended to include chemical evidence of druggability, driven by a defined therapeutic product profile [10]. These challenges have encouraged some academics to move out of their traditional comfort zones to fill the early-stage drug discovery gap in translational medicine not adequately covered by the PPPs [11]. The concept of “one gene, one target, one drug” has been very much at the forefront of current academic (and industry) thinking, with structure-based design an important adjunct in this strategy. Thus, it is timely that much of this book is devoted to the identification of metabolic peculiarities in the kinetoplastids that can be chemically and genetically validated as drug targets.

However, what of the future? Experience in industry and in academia suggests that the rate of validation of new targets is failing to keep pace with the rate of attrition of currently validated targets. Despite initial promise, the target-based approach has yielded disappointing results in anti-bacterial discovery in pharma [12] and lessons need to be learned from this if we are to avoid making the same mistakes. Rapid and robust methods of genetic target validation are still needed for parasites causing visceral leishmaniasis and Chagas disease, and we need a better understanding of basic biology to understand why targets fail. Certainly, not all targets are equal from a medicinal chemistry point of view. Greater attention needs to be paid to drug likeness [13] and ligand efficiency [14] for lead selection. Screening of fragment libraries using biophysical methods should help to weed out “undruggable” targets without recourse to expensive high-throughput screens [15]. From a pharmacology perspective, cytocidal activity is much preferable to cytostatic, so biologists should address this question early in discovery. Likewise, the potential ease for resistance arising as a result of point mutations in a single-target strategy should be a research priority for biologists. Systems biology suggests that exquisitely selective, single-target compounds may exhibit lower than desired clinical efficacy compared with multitarget drugs due to the robustness of biological networks [16]. Thus, polypharmacology (network pharmacology) is undergoing a resurgence of interest. Given the paucity of validated druggable targets, phenotypic screening is undergoing a revival aided by access to large compound collections held by pharma and the development of suitable miniaturized whole-parasite screens and mammalian counter-screens. This approach has the advantage of addressing the key druggability issues of cell permeability, desirable cytocidal activity, and a suitable parasite–host selectivity window. Phenotypic screening can also identify compounds hitting non-protein targets (e.g., amphotericin B) or compounds that act as pro-drugs (e.g., nitroimidazoles). However, the future challenge will be to identify the often complex mode(s) of action of such phenotypic hits (target deconvolution), and to use modern technologies to improve the potency and selectivity of these molecules [17]. Finally, we should ask ourselves whether our compound collections are too “clean” in terms of chemical reactivity. After all, arsenicals, antimonials, nitro-drugs, and eflornithine all undergo reaction with one or more targets, and about one-quarter of all drugs that inhibit enzymes are essentially irreversible reactions [18].

I believe that there is every cause for optimism in the battle against neglected diseases. As long as “donor fatigue” does not set in, and industry continues to engage in a positive and productive manner with academia, future prospects look better than at any time in history. However, we should all remember the dictum by Sir James Black “to first purge your project of wishful thinking” if we are to succeed!

Dundee, UK

Alan Fairlamb

References

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Acknowledgment

This publication is supported by COST.

COST – the acronym for European Cooperation in Science and Technology – is the oldest and widest European intergovernmental network for cooperation in research. Established by the Ministerial Conference in November 1971, COST is presently used by the scientific communities of 36 European countries to cooperate in common research projects supported by national funds.

The funds provided by COST – less than 1% of the total value of the projects – support the COST cooperation networks (COST Actions) through which, with EUR 30 million per year, more than 30 000 European scientists are involved in research having a total value which exceeds EUR 2 billion per year. This is the financial worth of the European added value which COST achieves.

A “bottom-up approach” (the initiative of launching a COST Action comes from the European scientists themselves), “à la carte participation” (only countries interested in the Action participate), “equality of access” (participation is open also to the scientific communities of countries not belonging to the European Union), and “flexible structure” (easy implementation and light management of the research initiatives) are the main characteristics of COST.

As precursor of advanced multidisciplinary research COST has a very important role for the realization of the European Research Area (ERA) anticipating and complementing the activities of the Framework Programmes, constituting a “bridge” towards the scientific communities of emerging countries, increasing the mobility of researchers across Europe, and fostering the establishment of “Networks of Excellence” in many key scientific domains such as: Biomedicine and Molecular Biosciences; Food and Agriculture; Forests, their Products and Services; Materials, Physical, and Nanosciences; Chemistry and Molecular Sciences and Technologies; Earth System Science and Environmental Management; Information and Communication Technologies; Transport and Urban Development; Individuals, Societies, Cultures, and Health. It covers basic and more applied research and also addresses issues of a prenormative nature or of societal importance.

Web: http://www.cost.eu

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Neither the COST Office nor any person acting on its behalf is responsible for the use which might be made of the information contained in this publication. The COST Office is not responsible for the external websites referred to in this publication.

Preface

Infections caused by parasites of the trypanosomatid family are considered to belong to the most neglected diseases. They comprise the African sleeping sickness (Trypanosoma brucei rhodesiense, T. brucei gambiense), the Chagas' disease in Latin America (T. cruzi), the black fever or Kala-Azar (Leishmania donovani) and other forms of Leishmaniasis (various Leishmania species). They affect about 30 million of people and account for half a million of fatalities per year. Trypanosomatids also cause substantial economic losses by affecting life stock (T. brucei brucei, T. congolense, T. evansi). Available treatments of the diseases are unsatisfactory in terms of safety and efficacy. Industrial commitments to meet the therapeutic needs remain limited because of unfavourable economic perspectives for drugs acting on diseases that prevail in countries with poor socio-economic conditions. In fact, currently used drugs are overwhelmingly those developed many decades ago when the ‘Western World’ had still to be concerned about the health of administrators and soldiers in their tropical colonies.

The present book originates from an interdisciplinary network of academic and industrial researchers devoted to the development of “new drugs for neglected diseases”. The initiative was sponsored by the European Union (COST Action CM0801) and in the beginnings was largely restricted to Europe. Over the four years of its operation, however, the exchange of experience and cooperative projects expanded far beyond its geographical basis, particularly by integrating countries in Latin America, Africa and Asia where the diseases are endemic. The progress achieved by this network is reflected in many of the contributions to the book. The editors, however, took care not just to present a ‘progress report’ but the state-of-the-art in the entire field of drug discovery for trypanosomatid diseases, as reviewed by leading scientists from all over the world. It is hoped that the compiled knowledge will become instrumental to shorten the time from basic discoveries to the urgently needed new drugs for the neglected diseases.

The editor's heartfelt thanks go to the contributing authors for their excellent work, to the series editor Paul M. Selzer for his constructive advice, and to the COST Office in Brussels for financial support.

Braunschweig, Ingelheim, Potsdam, Germany
March 2013

Timo Jäger
Oliver Koch
Leopold Flohé

List of Contributors

José María Alunda¹

Universidad Complutense

Department of Animal Health

Faculty of Veterinary Medicine

Avenida Puerta de Hierro s/n

28040 Madrid

Spain

jmalunda@ucm.es

María Noel Alvarez

Departamento de Bioquímica and

Center for Free Radical and

Biomedical Research

Facultad de Medicina

Universidad de la República

Avenida General Flores 2125

11800 Montevideo

Uruguay

Luisana Avilán

Universidad de los Andes

Laboratorio de Fisiología

Facultad de Ciencias

La HechiceraAv. Alberto Carnevalli

Mérida 5101

Venezuela

Cyrus J. Bacchi

Pace University

The Haskins Laboratories

41 Park Row

New York, NY 10038

USA

Michael P. Barrett¹

University of Glasgow

Wellcome Trust Centre for Molecular Parasitology

Institute of Infection, Immunity and Inflammation

College of Medical, Veterinary and Life Sciences

120 University Place

Glasgow G12 8TA

UK

michael.barrett@glasgow.ac.uk

Torsten Barth

Eberhard Karls Universität Tübingen

Interfakultäres Institut für Biochemie

Hoppe-Seyler-Strasse 4

72076 Tübingen

Germany

torsten.barth@uni-tuebingen.de

Mathias Beig

MSD Animal Health Innovation GmbH

Zur Propstei

55270 Schwabenheim

Germany

Rachel Bezalel-Buch

The Hebrew University-Hadassah Medical School

Department of Microbiology and Molecular Genetics

Kuvin Center for the Study of Infectious and Tropical Diseases

Institute for Medical Research Israel–Canada

PO Box 12272

Jerusalem 91120

Israel

Maurizio Botta¹

University of Siena

Faculty of Pharmacy

Via Aldo Moro 2

53100 Siena

Italy

botta.maurizio@gmail.com

Barry A. Bunin

Collaborative Drug Discovery, Inc.

1633 Bayshore Highway Suite 342

Burlingame, CA 94010

USA

Ana J. Cáceres

Universidad de los Andes

Laboratorio de Enzimología de Parásitos

Facultad de Ciencias

La HechiceraAv. Alberto Carnevalli

Mérida 5101

Venezuela

Helena Castro¹

Universidade do Porto

Instituto de Biologia Molecular e Celular

Rua do Campo Alegre 823

4150-180 Porto

Portugal

hcastro@ibmc.up.pt

Juan José Cazzulo

Universidad Nacional General San Martín/CONICET

Instituto de Investigaciones Biotecnológicas (IIB/INTECH)

Campus Miguelete

Avenida 25 de Mayo y Francia

1650 San Martín

Buenos Aires

Argentina

jcazzulo@iibintech.com.ar

Marcelo A. Comini¹

Institut Pasteur de Montevideo

Group Redox Biology of Trypanosomes

Mataojo 2020

11400 Montevideo

Uruguay

mcomini@pasteur.edu.uy

Juan-Luis Concepción

Universidad de los Andes

Laboratorio de Enzimología de Parásitos

Facultad de Ciencias

La Hechicera

Av. Alberto Carnevalli

Mérida 5101

Venezuela

Carlos Cordeiro¹

Universidade de Lisboa

Faculdade de Ciências

Departamento de Química e Bioquímica

Centro de Química e Bioquímica

Edifício C8 Campo Grande

1749-016 Lisboa

Portugal

cacordeiro@fc.ul.pt

María Jesús Corral-Caridad

Universidad Complutense

Department of Animal Health

Faculty of Veterinary Medicine

Avenida Puerta de Hierro s/n

28040 Madrid

Spainmariajco@ucm.es

Maria Paola Costi¹

University of Modena and Reggio Emilia

Department of Life Science

Via Campi 183

41125 Modena

Italy

mariapaola.costi@unimore.it

Darren J. Creek

University of Glasgow

Wellcome Trust Centre for Molecular Parasitology

Institute of Infection, Immunity and Inflammation

College of Medical, Veterinary and Life Sciences

120 University Place

Glasgow G12 8TA

UK

and

University of Melbourne

Department of Biochemistry and Molecular Biology

Bio21 Molecular Science and Biotechnology Institute

Flemington Road

Parkville

Victoria 3010

Australia

Elisabeth Davioud-Charvet¹

UMR CNRS 7509

European School of Chemistry, Polymers and Materials (ECPM)

Bioorganic and Medicinal Chemistry

25 rue Becquerel

67087 Strasbourg Cedex 2

France

elisabeth.davioud@unistra.fr

Harry P. de Koning¹

University of Glasgow

Institute of Infection

Immunity and Inflammation

College of Medical

Veterinary and Life Sciences

120 University Place

Glasgow G12 8TA

UK

Harry.de-Koning@glasgow.ac.uk

Vincent Delespaux

Institute of Tropical Medicine Antwerpen

Department of Biomedical Sciences

Nationalestraat 155

2000 Antwerp

Belgium

Patricia S. Doyle¹

University of California San Francisco

Department of Pathology and Sandler Center for Drug Discovery

1700 4th Street 508

San Francisco, CA 94158-2330

USA

patricia.doyle.engel@gmail.com

Michael Duszenko¹

Eberhard Karls Universität Tübingen

Interfakultäres Institut für Biochemie

Hoppe-Seyler-Strasse 4

72076 Tübingen

Germany

michael.duszenko@uni-tuebingen.de

Sean Ekins¹

Collaborative Drug Discovery, Inc.

1633 Bayshore Highway Suite 342

Burlingame, CA 94010

USA

sekins@collaborativedrug.com

and

Collaborations in Chemistry

5616 Hilltop Needmore Road

Fuquay Varina, NC 27526

USA

and

University of Maryland

Department of Pharmaceutical Sciences

20 North Pine Street

Baltimore, MD 21201

USA

and

University of Medicine & Dentistry of New Jersey (UMDNJ)

Robert Wood Johnson Medical School

Department of Pharmacology

675 Hoes lane

Piscataway, NJ 08854

USA

Juan C. Engel

University of California San Francisco

Department of Pathology and Sandler Center for Drug Discovery

1700 4th Street 508

San Francisco, CA 94158-2330

USA

juan.engel@ucsd.edu

Alan Fairlamb¹

Division of Biological Chemistry & Drug Discovery

College of Life Sciences

University of Dundee

Dundee DD1 5EH

UK

a.h.fairlamb@dundee.ac.uk

Stefania Ferrari

University of Modena and Reggio Emilia

Department of Life Science

Via Campi 183

41125 Modena

Italy

António E.N. Ferreira

Universidade de Lisboa

Faculdade de Ciências

Departamento de Química e Bioquímica

Centro de Química e Bioquímica

Edifício C8 Campo Grande

1749-016 Lisboa

Portugal

Leopold Flohé

Otto-von-Guericke-Universität Magdeburg

Chemisches Institut

Universitätsplatz 2

39106 Magdeburg

Germany

Thibault Gendron

UMR CNRS 7509

European School of Chemistry, Polymers and Materials (ECPM)

Bioorganic and Medicinal Chemistry

25 rue Becquerel

67087 Strasbourg Cedex 2

France

Vadim N. Gladyshev¹

Harvard Medical School

Division of Genetics

Department of Medicine

Brigham and Women's Hospital

75 Francis Street

Boston, MA 02115

USA

vgladyshev@rics.bwh.harvard.edu

Ricardo Gomes

Universidade de Lisboa

Faculdade de Ciências

Departamento de Química e Bioquímica

Centro de Química e Bioquímica

Edifício C8 Campo Grande

1749-016 Lisboa

Portugal

Melisa Gualdrón-López

Université catholique de Louvain

Research Unit for Tropical Diseases

de Duve Institute

Avenue Hippocrate 74

La Hechicera

Av. Alberto Carnevalli

1200 Brussels

Belgium

Martín Hugo

Departamento de Bioquímica and

Center for Free Radical and Biomedical Research

Facultad de Medicina

Universidad de la República

Avenida General Flores 2125

11800 Montevideo

Uruguay

Robert T. Jacobs

Scynexis, Inc.

PO Box 12878

Research Triangle Park NC 27709-2878

USA

Timo Jäger

German Centre for Infection Research (DZIF)

Inhoffenstraße 7

38124 Braunschweig

Germany

timo.jaeger@dzif.de

Oliver Koch¹

Junior Research Group Leader “Medicinal Chemistry”

Chemical Biology – Faculty of Chemistry

Technische Universität Dortmund

Otto-Hahn-Straße 6

44227 Dortmund

Oliver.Koch@tu-dortmund.de

R. Luise Krauth-Siegel

Heidelberg University

Biochemistry Center

Im Neuenheimer Feld 328

69120 Heidelberg

Germany

Bruno K. Kubata

Research for Health Africa & Pharma Innovation

AU/NEPAD Agency Regional Office in Nairobi

C/o the AU/Inter African Bureau for Animal Resources

P.O. BOX 13601-00800

Kenya

brunokubata@yahoo.com

Don Antoine Lanfranchi

UMR CNRS 7509

European School of Chemistry, Polymers and Materials (ECPM)

Bioorganic and Medicinal Chemistry

25 rue Becquerel

67087 Strasbourg Cedex 2

France

Alexei V. Lobanov

Harvard Medical School

Division of Genetics

Department of Medicine

Brigham and Women's Hospital

75 Francis Street

Boston, MA 02115

USA

Philippe M. Loiseau

Université Paris-Sud 11

Faculté de Pharmacie

UMR 8076 CNRS

Chimiothérapie Antiparasitaire

5 rue Jean-Baptiste Clément

92290 Châtenay-Malabry

France

Valeria Losasso

University of Modena and Reggio Emilia

Department of Life Science

Via Campi 183

41125 Modena

Italy

and

Scientific Computing Department, Science and Technology Facilities Council

Daresbury Laboratory

Keckwick Lane

Warrington WA4 4AD

UK

Anita Masic

University of Würzburg

Institute for Molecular Infection Biology

Josef-Schneider-Strasse 2/D15

97080 Würzburg

Germany

Paul A.M. Michels¹

Université catholique de Louvain

Research Unit for Tropical Diseases

de Duve Institute

Avenue Hippocrate 74

1200 Brussels

Belgium

paul.michels@uclouvain.be

Stefan Mogk

Eberhard Karls Universität Tübingen

Interfakultäres Institut für Biochemie

Hoppe-Seyler-Strasse 4

72076 Tübingen

Germany

labor@virtualmogk.de

Heidrun Moll¹

University of Würzburg

Institute for Molecular Infection Biology

Josef-Schneider-Strasse 2/D15

97080 Würzburg

Germany

heidrun.moll@uni-wuerzburg.de

Mattia Mori

University of Siena

Faculty of Pharmacy

Via Aldo Moro 2

53100 Siena

Italy

Frank Oellien

MSD Animal Health Innovation GmbH

Zur Propstei

55270 Schwabenheim

Germany

Cecilia Ortíz

Institut Pasteur de Montevideo

Group Redox Biology of Trypanosomes

Mataojo 2020

11400 Montevideo

Uruguay

cortiz@pasteur.edu.uy

Gonzalo Peluffo

Departamento de Bioquímica and

Center for Free Radical and Biomedical Research

Facultad de Medicina

Universidad de la República

Avenida General Flores 2125

11800 Montevideo

Uruguay

Lucía Piacenza

Departamento de Bioquímica and

Center for Free Radical and Biomedical Research

Facultad de Medicina

Universidad de la República

Avenida General Flores 2125

11800 Montevideo

Uruguay

Sébastien Pomel¹

Université Paris-Sud 11

Faculté de Pharmacie

UMR 8076 CNRS

Chimiothérapie Antiparasitaire

5 rue Jean-Baptiste Clément

92290 Châtenay-Malabry

France

sebastien.pomel@u-psud.fr

Ana Ponces Freire

Universidade de Lisboa

Faculdade de Ciências

Departamento de Química e Bioquímica

Centro de Química e Bioquímica

Edifício C8 Campo Grande

1749-016 Lisboa

Portugal

Wilfredo Quiñones

Universidad de los Andes

Laboratorio de Enzimología de Parásitos

Facultad de Ciencias

La Hechicera

Av. Alberto Carnevalli

Mérida 5101

Venezuela

Rafael Radi¹

Departamento de Bioquímica and

Center for Free Radical and Biomedical Research

Facultad de Medicina

Universidad de la República

Avenida General Flores 2125

11800 Montevideo

Uruguay

rradi@fmed.edu.uy

Boris Rodenko

University of Glasgow

Institute of Infection, Immunity and Inflammation

College of Medical, Veterinary and Life Sciences

120 University Place

Glasgow G12 8TA

boris.rodenko@glasgow.ac.uk

and

The Netherlands Cancer Institute

Department of Chemical Biology

Division of Cell Biology

Plesmanlaan 121

1066 CX Amsterdam

The Netherlands

Poonam Salotra

National Institute of Pathology (ICMR)

Safdarjung Hospital Campus

Post Box 4909

New Delhi 110029

India

Puneet Saxena

University of Modena and Reggio Emilia

Department of Life Science

Via Campi 183

41125 Modena

Italy

Caroline Schönfeld

Eberhard Karls Universität Tübingen

Interfakultäres Institut für Biochemie

Hoppe-Seyler-Strasse 4

72076 Tübingen

Germany

caroline.schoenfeld@uni-tuebingen.de

Uta Schurigt

University of Würzburg

Institute for Molecular Infection Biology

Josef-Schneider-Strasse 2/D15

97080 Würzburg

Germany

Karin Seifert¹

London School of Hygiene & Tropical Medicine

Faculty of Infectious and Tropical Diseases

Keppel Street

London WC1E 7HT

UK

karin.seifert@lshtm.ac.uk

Paul M. Selzer¹

MSD Animal Health Innovation GmbH

Zur Propstei

55270 Schwabenheim

Germany

paul.selzer@msd.de

and

University of Tübingen

Interfaculty Institute of Biochemistry

Hoppe-Seyler-Strasse 4

72076 Tübingen

Germany

and

University of Glasgow

Institute of Infection, Immunity and Inflammation

120 University Place

Glasgow G12 8TA

UK

Joseph Shlomai¹

The Hebrew University-Hadassah Medical School

Department of Microbiology and Molecular Genetics

Kuvin Center for the Study of Infectious and Tropical Diseases

Institute for Medical Research

Israel–Canada

PO Box 12272

Jerusalem 91120

Israel

josephs@ekdm.huji.ac.il

Ruchi Singh

National Institute of Pathology (ICMR)

Safdarjung Hospital Campus

Post Box 4909

New Delhi 110029

India

Marta Sousa Silva

Universidade de Lisboa

Faculdade de Ciências

Departamento de Química e Bioquímica

Centro de Química e Bioquímica

Edifício C8 Campo Grande

1749-016 Lisboa

Portugal

Jasmin Stein

Eberhard Karls Universität Tübingen

Interfakultäres Institut für Biochemie

Hoppe-Seyler-Strasse 4

72076 Tübingen

Germany

Jasmin_Stein@gmx.de

Dietmar Steverding¹

University of East Anglia

BioMedical Research Centre

Norwich Medical School

Norwich Research Park

Norwich NR4 7TJ

UK

dsteverding@hotmail.com

Ana M. Tomás

Universidade do Porto

Instituto de Biologia Molecular e Celular

Rua do Campo Alegre 823

4150-180 Porto

Portugal

and

Universidade do Porto

Instituto de Ciências Biomédicas Abel Salazar

Rua de Jorge Viterbo Ferreira 228

4050-313 Porto

Portugal

and

Faculdade de Ciências

Departamento de Química e Bioquímica

Centro de Química e Bioquímica

Edifício C8 Campo Grande

1749-016 Lisboa

Portugal

Madia Trujillo

Departamento de Bioquímica and

Center for Free Radical and Biomedical Research

Facultad de Medicina

Universidad de la República

Avenida General Flores 2125

11800 Montevideo

Uruguay

Julio A. Urbina¹

Instituto Venezolano de Investigaciones Científicas

Centro de Biofisica y Bioquimica

Apartado 21827

Caracas 1020A

Venezuela

and

200 Lakeside Drive No. 503

Oakland, CA 94612-3503

United States

jurbina@mac.com

Isabel M. Vincent

University of Glasgow

Wellcome Trust Centre for Molecular Parasitology

Institute of Infection, Immunity and Inflammation

College of Medical, Veterinary and Life Sciences

120 University Place

Glasgow G12 8TA

UK

and

Université Laval

Centre de Recherche en Infectiologie du CHUL

2705 Boulevard Laurier

Québec G1V 4G2

Canada

Roderick A.M. Williams¹

University of Strathclyde

Strathclyde Institute for Pharmacy and Biological Sciences

161 Cathedral Street

Glasgow G4 0RE

UK

roderick.williams@strath.ac.uk

and

University of the West of Scotland School of Science

High Street

Paisley PA1 2BE

UK

roderick.williams@uws.ac.uk

Nurit Yaffe

The Hebrew University-Hadassah Medical School

Department of Microbiology and Molecular Genetics

Kuvin Center for the Study of Infectious and Tropical Diseases

Institute for Medical Research

Israel–Canada

PO Box 12272

Jerusalem 91120

Israel

Nigel Yarlett¹

Pace University

The Haskins Laboratories and Chemistry and Physical Sciences

41 Park Row

New York, NY 10038

USA

nyarlett@pace.edu

Note

1. Corresponding Author

Part One

Disease Burden, Current Treatments, Medical Needs, and Strategic Approaches