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

Print ISBN: 978-3-527-32327-2, also available in Adobe PDF format ISBN: 978-3-527-62682-3

Becker, K. (ed.)

Apicomplexan Parasites

Molecular Approaches toward Targeted Drug Development

2011

Print ISBN: 978-3-527-32731-7, also available as digital format

Caffrey, C.R. (ed.)

Parasitic Helminths

Targets, Screens, Drugs and Vaccines

2012

Print ISBN: 978-3-527-33059-1, also available as digital format

Jäger, T., Koch, O., Flohé, L. (eds.)

Trypanosomatid Diseases

Molecular Routes to Drug Discovery

2013

Print ISBN: 978-3-527-33255-7, also available as digital format

Forthcoming Topics of the Series

Gottfried Unden, Eckard Thines, Anja Schüffler (eds.) Antiinfectives

Christian Doerig, Gordon Langsley, Pietro Alano (eds.) Malaria Signaling

Related Titles

Li, R., Stafford, J.A. (eds.)

Kinase Inhibitor Drugs

2009

Print ISBN: 978-0-470-27829-1, also available as digital format

Klebl, B., Müller, G., Hamacher, M. (eds.)

Protein Kinases as Drug Targets

2011

Print ISBN: 978-3-527-31811-7, also available as digital format

Ghosh, A.K. (ed.)

Aspartic Acid Proteases as Therapeutic Targets

2010

Print ISBN: 978-3-527-31811-7, also available as digital format

Smit, M.J., Lira, S.A., Leurs, R. (eds.)

Chemokine Receptors as Drug Targets

2011

Print ISBN: 978-3-527-32118-6, also available as digital format

Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose. No warranty can be created or extended by sales representatives or written sales materials. The Advice and strategies contained herein may not be suitable for your situation. You should consult with a professional where appropriate. Neither the publisher nor authors shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages.

Library of Congress Card No.: applied for

British Library Cataloguing-in-Publication Data

A catalogue record for this book is available from the British Library.

Bibliographic information published by the Deutsche Nationalbibliothek

The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the Internet at <http://dnb.d-nb.de>.

© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Boschstr. 12, 69469 Weinheim, Germany

Wiley-Blackwell is an imprint of John Wiley & Sons, formed by the merger of Wiley's global Scientific, Technical, and Medical business with Blackwell Publishing.

All rights reserved (including those of translation into other languages). No part of this book may be reproduced in any form – by photoprinting, microfilm, or any other means – nor transmitted or translated into a machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law.

Print ISBN: 978-3-527-33235-9

ePDF ISBN: 978-3-527-67539-5

ePub ISBN: 978-3-527-67537-1

Mobi ISBN: 978-3-527-67538-8

oBook ISBN: 978-3-527-67540-1

Cover Design Adam-Design, Weinheim, Germany

Typesetting Thomson Digital, Noida, India

Foreword: Protein Kinases in Parasites

Today, despite the fact that this is not obvious to the vast majority of the people leaving in industrialized countries, a large part of the world is still massively suffering and dying from parasitic diseases as a result of the lack of efficacious and/or affordable treatments. Each year 30,000 people pass away due to human African Trypanosomiasis (HAT or African sleeping sickness), a disease caused by the parasite Trypanosoma brucei spp. Available treatments for this disease are poor, with unacceptable efficacy and safety profiles, particularly in the late phase of the infection when the parasite has invaded the central nervous system. In South and Central America, Trypanosoma cruzi is the infectious agent of Chagas' disease (American Trypanosomiasis) which represents the most important parasitic infection in this part of the world. It is affecting more than 10 million people, with about 100 million people at risk. Leishmaniasis is due to the infection by protozoa of the genus Leishmania and is affecting more than 10 million people worldwide. These parasites live in the alimentary tract of blood-sucking sand flies, and as nonflagellate intracellular forms mostly within the macrophages of mammalian hosts. The severity of the disease is ranging from cutaneous and/or mucosal to visceral infection. Malaria occurs following infection by Plasmodium spp. and is the most prevalent parasitic disease, affecting more than 250 million of people per year and still responsible for almost a million deaths, the vast majority of which impacting children below 5 years. Not only unicellular parasites bear a huge impact on global public health: parasitic helminths (worms), such as Schistosoma ssp, also represent a serious public health problem, mostly in the developing world. In view of such a dramatic situation, more than ever, it is crucial that the entire scientific community in basic research and industries develops all possible strategies leading to an arsenal of therapeutic weapons that will efficiently treat patients and eradicate these diseases. Among possible drug targets, enzymes that modulate the level of phosphorylation of parasite and host proteins such as protein kinases (PKs) and protein phosphatases are interesting candidates.

First, the kinomes of parasites like kinetoplastids and apicomplexans could reveal promising taxon-specific drug targets. Indeed, signalling pathways are well known to allow any organism to adapt to its environment by coordinating intracellular processes. Bioinformatics approaches revealed a total of 176 PKs in T. brucei, 190 in T. cruzi and 199 in L. major. Compared to trypanosomatids, the human kinome contains 3 times more protein kinases while the size of the Plasmodium kinome is only about half that of trypansomatids. Trypanosomatids and Plasmodium do not contain receptor-linked tyrosine kinases, but possess divergent kinases with no orthologues in the mammalian kinome (Ward P, Equinet L, Packer J, Doerig C. 2004. BMC Genomics; Parsons, M, Worthey E, Ward P, Mottram J. 2005. BMC Genomics). The fact that trypanosomatids exhibit a large set of PKs, covering approximately 2% of each genome, suggests that phosphorylation may play a key role in the biology of most parasites.

Despite differences in kinome sizes and composition from one parasite to another, major signalling pathways and functions are conserved. Motility, for instance, is an essential attribute that allows some parasites finding their target cells in human hosts and/or arthropod vectors. In apicomplexans, this key driving force depends on a unique component whereby adhesins contained in the micronemes are released onto the parasite apical extremity and translocated to the posterior end of the cell, thus propelling the parasite forward. In Toxoplasma gondii, Calcium-dependent protein kinase 1 (TgCDPK1) is an essential regulator of calcium-dependent exocytosis and this could well be the case in most of the opportunistic human parasites. Recently, the phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2α) was described elevated in dormant forms of apicomplexan parasites such as Plasmodium spp. and Toxoplasma gondii. (Zhang M. et al., Eukaryotic Cell, 2013).

Kinases have been shown to be essential for survival of parasites in their mammalian hosts. Nevertheless, a parasite kinase-specific small molecule inhibitor still awaits to be identified and the question whether drugging the parasite kinome is more a dream or a reality begs for an answer. In complex parasite life cycles such as that of Plasmodium, most of the key developmental forms of the parasite such as sexual and liver stages rely on protein kinase-mediated regulations as highlighted by C. Doerig (Nat. Chem. Biol.) commenting the work of Kato et al. who has demonstrated that Pf CDPK1 plays a key role in asexual blood stage egress. Considering the 3-dimensional structure of protein kinases, there are increasing evidences that the ATP-binding pocket represents a druggable site. Specific kinomes like the one of Plasmodium display sufficient specificity, compared to the human one, to represent a potentially fertile source of novel targets. Interestingly, the counteracting biochemical reactions driven by Plasmodium phosphatases are similarly specific enough to envisage drug discovery programs targeting molecular events that are modulated by these enzymes (Wilkes and Doerig BMC genomics 2008).

Since helminths are Metazoan and have therefore a kinome that is very similar to that of their hosts, it is unlikely that highly selective targets will be identified. However, the kinome still remains an attractive target in this case to: precisely because of similarities between the helminthic and human kinomes, “piggy-back” approaches exploiting the wealth of resources devoted to targeting human kinases in the context of diseases such as cancer and neurodegenerative diseases is an attractive option as a strategy to combat diseases caused by worms.

Last but not least, the host-parasite interface might well be a target of choice to avoid induction of drug resistance and spreading. Plasmodium infection of host cells takes advantage of the plasticity of this parasite and the different forms produced along its complex life cycle. For instance during the infection of human hepatocytes (liver stage of Plasmodium's life cycle), not only part of the parasite kinome is solicited but some human protein kinases in liver cells such as MET, PRKWNK1, SGK2, STK35 and PKCζ seem to be crucial to Plasmodium sporozoite invasion mechanism and differentiation/growth (Prudêncio M. et al., 2008, PLoS Pathogens). Evidence is emerging that even in the erythrocyte, host signalling pathways are activated and required for parasite survival (Sicard et al 2011). Host protein kinases such as MEKs and downstream MAPKs may play a key role in the host immune response to Plasmodium. Indeed, these protein kinases have been shown to regulate the production of pro-inflammatory cytokines produced in response to specific markers of various infectious agents that may modulate the specificity and effectiveness of adaptive immunity. Thus, small molecules could be used as immunomodulatory tools to control pathogen infections and resulting diseases by regulating specific host protein kinases. (Zhu J. et al., 2009, J. Biol. Chem.).

In the present book, the bioinformatics approach leading to the study of parasite kinomes and phosphatomes will be described and followed by chapters addressing the functional analysis of some of the key enzymes. The potential roles of host cell kinome and phosphatome will be discussed. Finally, opportunities for drug discovery programs targeting parasite protein kinases and phosphatases will be explored in protozoan and helminthic parasites alike. There is no doubt that the holistic view described in this book will contribute to the future success of new efficacious and affordable therapeutics to treat the world population severely impacted by parasitic diseases.

Geneva, July 2013

Didier Leroy

Preface

Diseases caused by eukaryotic pathogens have been a scourge of human populations ever since the emergence of our species. Many of the major lineages of eukaryotes, from Excavata (Giardia), through Discicristata (Trypanosoma, Leishmania), Amoebozoa (Entamoeba) and Alveolata (Plasmodium, Toxoplasma, Eimeria), to Opisthokonta (metazoans, fungi), include species that have adapted to a parasitic lifestyle and have co-evolved with their hosts in the lineage that led to Homo sapiens. The burden imposed by parasitic diseases is disproportionally large in the poorest nations. While there has been immense progress in controlling some of these diseases in the second half of the XXth century, notably through the use of specific drugs, the global picture remains very gloomy: first, pathogens have responded to novel treatments by developing resistance against the drugs; thus, for example, that wonder antimalarial drug, chloroquine, has now become ineffective in a majority of malaria-affected countries. Even the latest generation of antimalarial drugs, based on artemisinin, shows signs of losing efficacy in some parts of the world. Second, many of these diseases have remained grossly neglected in terms of investment in research and development of novel control agents, largely because of the poor marketing prospects such agents would offer. Clearly, a renewed effort is urgently needed to address this global issue. Fortunately, awareness has increased in the last decade, which has led to an increase of funding from public institutions such as the European Commission and the research councils and agencies of many governments, as well as private bodies such as the Bill & Melinda Gates foundation. Furthermore, new organisational tools now exist to fund such research; for example, the Medicines for Malaria Venture (MMV, www.mmv.org), a Public-Private Partnership based in Geneva, and the Drugs for Neglected Diseases initiative (DNDi, www.dndi.org), have already had a tangible impact in this area. To eventually bring parasitic diseases under effective control, it is crucial that existing funding for fundamental research on eukaryotic pathogens is maintained and expanded, so as to prime the drug development pipeline. A high priority on the agenda is to develop control agents with un-tapped mechanisms of action.

Protein phosphorylation is an enormously important phenomenon in the biology of eukaryotic cells, where it regulates essentially all complex processes. This fundamental role has singled out protein kinases as potential targets for anticancer agents, and indeed, a number of protein kinase inhibitors have reached the market in this context.

Could protein kinases represent targets for the treatment of parasitic diseases as well? A group of about 25 researchers interested in this idea convened in Paris in 2001, at the first EU-COST-funded meeting on “Protein kinases of eukaryotic parasites”. This forum has reconvened in Glasgow in 2005, and in Lausanne in 2010. By then, the attending community had grown to 80 people, and significant progress had been achieved in (i) our fundamental understanding of the complement of parasite protein kinases and protein phosphatases (kinome and phosphatome) and the function of these enzymes in the biology of the parasites, and (ii) the identification of specific kinase targets in many eukaryotic parasites, and, in a few cases, of parasite kinase inhibitors. It was also emerging that the phosphorylation machinery in the host was playing a crucial role in parasite survival and development, suggesting that kinase inhibitors developed against cancer might be re-positioned for the treatment of parasitic diseases.

The present book is an outcome of the 2010 meeting in Lausanne, and offers a written and updated version of some of the highlights that were presented there. It covers bio-informatics analyses of the kinomes and phosphatomes of selected eukaryotic parasites, recent advances in our fundamental understanding of the biology of selected kinases and phosphatases (inclusive of host signalling elements), and finally the state-of-the-art with respect to anti-parasitic drug discovery efforts targeting protein kinases.

We consider protein kinases offer huge potential for the development of urgently needed control agents against devastating diseases caused by eukaryotic parasites. This will happen only if the research community embraces the idea and constitutes compelling supporting data, so that policymakers and industrial partners can be convinced that there would be a significant return on investment in terms of impact on global public health. The purpose of this book is therefore to stimulate interest of established researchers and students in this topic, which offers a combination of both fascinating biology and potential tangible impact.

The Editors are aware of the significant additional commitment that engaging into the writing of a chapter represents in the busy life of research scientists, and are therefore very grateful to all authors for their timely contributions. We are indebted to the series editor, Dr. Paul M. Selzer of MSD Animal Health Innovation GmbH, for his constant encouragements and active involvement in the preparation of this volume, and to Anne du Guerny, Project Editor at Wiley Blackwell, for her patience and excellent support throughout the publication process.

Melbourne, Paris, and Glasgow September 2013

Christian Doerig, Gerald Späth, and Martin Wiese

Cover Legend

The cover is composed of several illustrations coming from or being related to the articles in this volume. The underlying phylogenetic tree illustrates the evolutionary relationships among eukaryotic species, including model organisms and protozoan pathogens, selected across all eukaryotic supergroups (courtesy of D. Miranda-Saavedra, see chapter 1 for details). The protein structure shows the homology model of EtCRK2 a CDK2-like protein of Eimeria tenella with ATP docked into the ATP binding pocket. The protein is shown as ribbons, while ATP is depicted in ball-and-stick representation with atoms colored according to the CPK model (courtesy of R. J. Marhöfer, see chapter 15 for details). The black matrix panel shows fluorescence microscopy images of different parasites. The top row of the panel shows an intra-erythrocytic Plasmodium falciparum schizont. The mitotic regulator Aurora kinase 3 is labeled in green, the Plasmodium homologue of centrosome protein Centrin-3 is labeled in red and the parasite DNA is stained in blue (courtesy of T. Carvalho, see chapter 1 and 13 for details). The middle row of the panel shows immunofluorescent staining of Trypanosoma brucei bloodstream forms. PKA-like kinase substrates are labeled in red, the paraflagellar rod protein in green as reference for the flagellum, and nuclear and kinetoplast DNA are stained blue with DAPI (courtesy of S. Bachmaier and M. Boshart, see chapter 5 for details).The lower row, from left to right, shows in the 1^st image, eggs of Schistosoma mansoni purified form livers of infected hosts. Due to tyrosine-rich eggshell precursor proteins, which are fused via quinone tanning during eggshell synthesis, green and red auto-fluorescence is observed by fluorescence microscopy (courtesy of C. G. Grevelding, see chapter 16 for details). The 2^nd image shows several human fibroblast cells with large blue nuclei massively infected with a transgenic strain of T. gondii tachyzoites visualized by small blue nuclei expressing GFP in its single mitochondrion. Cellular lipid bodies are stained red with Oil red O (courtesy of F. Seeber, Robert Koch Institute, Berlin, Germany). The 3^rd image shows a section of a Schistosoma mansoni male worm labeled with anti-S. mansoni Insulin Receptor 1 antibodies. The antibody was localized at the basal membrane of the tegument, in muscles and in intestinal epithelium of worms (courtesy of C. Dissous, see chapter 16 for details). The 4^th image shows an Echinococcus multilocularis protoscolex with DAPI/phalloidin staining (courtesy of K. Brehm, see chapter 17 for details).

List of Contributors

Roman Affentranger

Douglas Connect

Baermeggenweg 14

4314 Zeiningen

Switzerland

Merhnaz Amani

Structural Genomics Consortium

MaRS South Tower, 7th Floor

101 College Street

Toronto, Ontario

Canada

Alexandra V. Andreeva^*

University of Illinois at Chicago

Department of Pharmacology

909 S. Wolcott Ave

Chicago, IL 60612

USA

alexandravandreeva@gmail.com

Gustavo Arrizabalaga

Indiana University School of Medicine

Departments of Pharmacology & Toxicology, Microbiology & Immunology

635 Barnhill Drive, MS A-503

Indianapolis, IN 46202

USA

Jennifer D. Artz

Structural Genomics Consortium

MaRS South Tower, 7th Floor

101 College Street

Toronto, Ontario

Canada

Mrigya Babuta

Jawaharlal Nehru University

School of Life Sciences

New Delhi, 110067

India

Sabine Bachmaier

Ludwig-Maximilians-Universität München

Fakultät für Biologie, Genetik Biozentrum

Grosshadernerstr. 2-4

82152 Planegg-Martinsried

Germany

Svenja Beckmann

Justus-Liebig-University

Institute for Parasitology

Rudolf-Buchheim-Str. 2

35392 Giessen

Germany

Corinna Benz

University of South Bohemia

Institute of Parasitology

Biology Centre and Faculty of Sciences

esk Budjovice

Czech Republic

Alok Bhattacharya^*

Jawaharlal Nehru University

School of Life Sciences

New Delhi, 110067

India

alok.bhattacharya@gmail.com; alok0200@mail.jnu.ac.in

Sudha Bhattacharya

Jawaharlal Nehru University

School of Environmental Sciences

New Delhi, 110067

India

Ira J. Blader^*

University at Buffalo

Department of Microbiology and Immunology

138 Farber Hall

Buffalo, NY 14214

USA

iblader@buffalo.edu

Michael Boshart^*

Ludwig-Maximilians-Universität München

Fakultät für Biologie, Genetik Biozentrum

Grosshadernerstr. 2-4

82152 Planegg-Martinsried

Germany

boshart@lmu.de

Klaus Brehm^*

University of Würzburg

Institute of Hygiene and Microbiology

Josef-Schneider-Strasse 2

97080 Würzburg

Germany

kbrehm@hygiene.uni-wuerzburg.de

James R. Brown

GlaxoSmithKline

Computational Biology

Quantitative Sciences, R&D

1250 South Collegeville Road, UP1230

Collegeville, PA 19426-0989

USA

Sharon D. Bryant

Inte:Ligand Software Development & Consulting GmbH

Mariahilferstrasse 74B/11

1070 Vienna

Austria

Christin Buro

Justus-Liebig-University

Institute for Parasitology

Rudolf-Buchheim-Str. 2

35392 Giessen

Germany

Alessandro Contini

Università degli Studi di Milano

Dipartimento di Scienze

Farmaceutiche – Sezione di Chimica Organica “A. Marchesini”

Via Venezian 21

20133 Milan

Italy

Hugo Gutierrez de Teran

Uppsala University

Department of Cell and Molecular Biology

BMC

754 29 Uppsala

Sweden

Colette Dissous^*

Inserm U1019

CNRS UMR 8204

Center for Infection and Immunity of Lille (CIIL)

Institut Pasteur de Lille

1, rue du Prof. Calmette

59019 Lille

France

Colette.dissous@pasteur-lille.fr

Dirk Dobbelaere

University of Bern

Molecular Pathobiology

Vetsuisse Faculty

3012 Bern

Switzerland

Christian Doerig

Monash University

Department of Microbiology

Wellington Road Building 76

Clayton, Victoria 3800

Australia

David Drewry

GlaxoSmithKline

Department of Chemical Biology

20 T. W. Alexander Drive

Research Triangle Park

Durham, NC 27709

USA

Francisco-Javier Gamo

GlaxoSmithKline

Tres Cantos Medicines Development Campus

Severo Ochoa 2

28760 Tres Cantos

Spain

Jose F. Garcia-Bustos^*

Monash University

Department of Microbiology

Clayton, Victoria 3800

Australia

jose.garcia-bustos@monash.edu

Daniel E. Goldberg^*

Washington University in St Louis

Departments of Medicine and Molecular Microbiology

Howard Hughes Medical Institute

660 S. Euclid Ave

St Louis, MO 63110

USA

goldberg@borcim.wustl.edu

Nadège Gouignard

Institut Pasteur de Lille

Center for Infection and Immunity of Lille (CIIL)

Inserm U1019

CNRS UMR 8204

59019 Lille

France

Christoph G. Grevelding

Justus-Liebig-University

Institute for Parasitology

Rudolf-Buchheim-Str. 2

35392 Giessen

Germany

Tansy C. Hammarton^*

University of Glasgow

College of Medical, Veterinary and Life Sciences

Institute of Infection, Immunity & Inflammation

120 University Place

Glasgow G12 8QQ

UK

Tansy.Hammarton@glasgow.ac.uk

Barry Hardy^*

Douglas Connect

Baermeggenweg 14

4314 Zeiningen

Switzerland

Barry.Hardy@douglasconnect.com

Tanya Hills

Structural Genomics Consortium

MaRS South Tower, 7th Floor

101 College Street

Toronto, Ontario

Canada

Raymond Hui^*

Structural Genomics Consortium

MaRS South Tower, 7th Floor

101 College Street

Toronto, Ontario

Canada

Raymond.hui@utoronto.ca

Natarajan Kannan

University of Georgia

Institute of Bioinformatics

Davison Life Sciences Bldg

120 Green Street

Athens, GA 30602

USA

and

University of Georgia

Department of Biochemistry and Molecular Biology

B122 Life Sciences Bldg

Athens, GA 30602

USA

Mikhail A. Kutuzov^*

University of Illinois at Chicago

Department of Pharmacology

909 S. Wolcott Ave

Chicago, IL 60612

USA

m.kutuzov@usa.net

Didier Leroy^*

Director Drug Discovery

Medicines for Malaria Venture

Rte de Pre Bois 20, 1215

Geneva

leroyd@mmv.org

Silke Leutner

Justus-Liebig-University

Institute for Parasitology

Rudolf-Buchheim-Str. 2

35392 Giessen

Germany

Linda. Y. Lin

Structural Genomics Consortium

MaRS South Tower, 7th Floor

101 College Street

Toronto, Ontario

Canada

Isabelle Lucet

Monash University

Department of Microbiology

Wellington Road

Building 76

Clayton, Victoria 3800

Australia

Dustin J. Maly

University of Washington

Department of Chemistry

Chemistry Building

Seattle, WA 98195

USA

Richard J. Marhöfer

MSD Animal Health Innovation GmbH

Zur Propstei

55270 Schwabenheim

Germany

Keith R. Matthews

University of Edinburgh

School of Biological Sciences

Institute of Immunology and Infection Research

Centre for Immunity, Infection and Evolution

King's Building, West Mains Road

Edinburgh EH9 3JT

UK

Ethan A. Merritt

University of Washington

Department of Biochemistry

1959 NE Pacific Street

Health Sciences Building

Seattle, WA 98195

USA

Diego Miranda-Saavedra^*

Institute of Cellular Medicine

Newcastle University Medical School

Framlington Place

Newcastle upon, Tyne NE2 4HH

UK

diego@ifrec.osaka-u.ac.jp

Jeremy C. Mottram

University of Glasgow

College of Medical, Veterinary and Life Sciences

Institute of Infection, Immunity and Inflammation

Wellcome Trust Centre for Molecular Parasitology

120 University Place

Glasgow G12 8TA

UK

Mirela Neculai

Structural Genomics Consortium

MaRS South Tower, 7th Floor

101 College Street

Toronto, Ontario

Canada

Sandra Nelson

Chief Technology OfficerPHD Diagnostics, LLC

632 Russell Street

Covington, Kentucky 41011

USA

Victor Nussenzweig^*

NYU Langone Medical Center

Department of Pathology

550 1st Ave

New York, NY 10016

USA

Victor.Nussenzweig@nyumc.org

Kayode K. Ojo

University of Washington

Department of Medicine

Division of Allergy and Infectious Diseases

750 Republican Street

Seattle, WA 98109

USA

Mahesh Kumar Padwal

National Centre for Cell Science

Ganeshkhind

Pune 411007

India

Ruben Papoian

University of Cincinnati

Drug Discovery Center

2180 East Galbraith Road

Cincinnati, OH 45237

USA

Bhaskar Saha^*

National Centre for Cell Science

Ganeshkhind

Pune 411007

India

sahab@nccs.res.in

Uddipan Sarma

National Centre for Cell Science

Ganeshkhind

Pune 411007

India

William L. Seibel

University of Cincinnati

Drug Discovery Center

Compound Library and Cheminformatics

2180 E. Galbraith Road

Cincinnati, OH 45237

USA

Paul M. Selzer^*

MSD Animal Health Innovation GmbH

Zur Propstei

55270 Schwabenheim

Germany

paul.selzer@msd.de

and

University of Glasgow

College of Medical, Veterinary and Life Sciences

Institute of Infection, Immunity and Inflammation

Wellcome Trust Centre for Molecular Parasitology

120 University Place

Glasgow G12 8TA

UK

and

University of Tübingen

Interfaculty Institute of Biochemistry

Hoppe-Seyler-Str. 4

72076 Tübingen

Germany

Somlata

Jawaharlal Nehru University

School of Life Sciences

New Delhi, 110067

India

Jeff Spitzner

Amperand, Ltd.

311 Kendall PL

Columbus, OH 43205

USA

Raki Sudan

National Centre for Cell Science

Ganeshkhind

Pune 411007

India

William J. Sullivan Jr.

Indiana University School of Medicine

Departments of Pharmacology & Toxicology, Microbiology & Immunology

635 Barnhill Drive, MS A-503

Indianapolis, IN 46202

USA

Balázs Szöó´r^*

University of Edinburgh

School of Biological Sciences

Institute of Immunology and Infection Research

Centre for Immunity, Infection and Evolution

King's Building, West Mains Road

Edinburgh EH9 3JT

UK

balazs.szoor@ed.ac.uk

Eric Talevich

University of Georgia

Institute of Bioinformatics

Davison Life Sciences Bldg

120 Green Street

Athens, GA 30602

USA

Elizabeth Thomas

University of Glasgow

College of Medical, Veterinary and Life Sciences

Institute of Infection, Immunity & Inflammation

120 University Place

Glasgow G12 8QQ

UK

Michael D. Urbaniak^*

Lancaster University

Faculty of Health and Medicine

Division of Biomedical and Life Sciences

Lancaster LA1 4YQ

UK

m.urbaniak@lancaster.ac.uk

Wesley C. Van Voorhis^*

University of Washington

Department of Medicine

Division of Allergy and Infectious Diseases

750 Republican Street

Seattle, WA 98109

USA

wesley@uw.edu

Mathieu Vanderstraete

Inserm U1019

CNRS UMR 8204

Center for Infection and Immunity of Lille (CIIL)

Institut Pasteur de Lille

1, rue du Prof. Calmette

59019 Lille

France

Conrad von Schubert

University of Basel

Growth and Development

Biozentrum

4056 Basel

Switzerland

Amy K. Wernimont

Structural Genomics Consortium

MaRS South Tower, 7th Floor

101 College Street

Toronto, Ontario

Canada

Jeffrey Wiseman

Pharmatrope Ltd

1425 Carolina Place

Downingtown, PA 19335

USA

Kerry Woods^*

University of Bern

Vetsuisse Faculty

Molecular Pathobiology

Langgassstrasse 122

3012 Bern

Switzerland

kerry.woods@vetsuisse.unibe.ch

Min Zhang

NYU Langone Medical Center

Department of Pathology

550 1st Ave

New York, NY 10016

USA

Note

* Corresponding Author

Part One

Bioinformatics