Toxins and Hemostasis

R. Manjunatha Kini · Kenneth J. Clemetson ·Francis S. Markland · Mary Ann McLane ·Takashi MoritaEditors

Toxins and Hemostasis

From Bench to Bedside

123

EditorsDr. R. Manjunatha KiniNational University of SingaporeDepartment of Biological Sciences14, Science Drive 4Singapore 117543Singaporedbskinim@nus.edu.sg

Dr. Francis S. MarklandUniversity of Southern CaliforniaBiochemistry and Molecular BiologyKeck School of MedicineHealth Sciences Campus/9270Los Angeles, California 90089USAmarkland@usc.edu

Takashi MoritaMeiji Pharmaceutical UniversityBiochemistryNishio Kiyose 2-522-1Tokyo 204-8588Japantmorita@my-pharm.ac.jp

Dr. Kenneth J ClemetsonUniversity of BerneDepartment of HaematologyInselspitalCH-3010 BernSwitzerlandclemetson@tki.unibe.ch

Dr. Mary Ann McLaneUniversity of DelawareMedical Technology305G Willard Hall Educ BldNewark Delaware 19716USAmclane@udel.edu

ISBN 978-90-481-9294-6 e-ISBN 978-90-481-9295-3DOI 10.1007/978-90-481-9295-3Springer Dordrecht Heidelberg London New York

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Preface

Those who are inspired by a model other thanNature, a mistress above all masters, are laboringin vain.

– Leonardo da Vinci

Nature is wonderful; organisms, whether plants, animals or microbes, haveevolved through competition (including predator-prey and host-parasite compe-titions) and natural selection. In this long drawn out process, they have devel-oped, been fine-tuned and improvised a number of strategies to stay ahead ofthe competition. Human beings have been fascinated how living organisms havesolved very complicated problems by simple innovative methods (For details,see http://asknature.org/). These clever strategies have inspired a number ofnew technologies, such as Velcro fasteners, Gecko adhesive tapes without glue,photosynthesis-inspired fuel cells, and insect-inspired autonomous robots (Fordetails, see http://www.biomimicryinstitute.org/).

A number of pharmaceutical drugs were designed, based on natural compounds.A classical example is the development of antimalarial drugs from the alkaloidquinine isolated from the barks of Cinchona trees. Anecdotal evidence for the anti-malarial properties of Cinchona dates back to seventeenth century although theindigenous populations used it even earlier. Since then several hundreds of drugswere designed and developed based on plant secondary metabolites and substancesisolated from animals, microbes and fungi. Despite our computational and syn-thetic organic chemistry capabilities, nature has inspired the design of new chemicalentities. Epibatidine – an alkaloid isolated from a frog (Epipedobates tricolor), isa potent analgesic (200 times as effective as morphine). Based on this nicotinicacetylcholine receptor antagonist, a potent pain-killer ABT-594 (Tebanicline) wasdesigned and developed. Thus nature provided a large number of templates for thedevelopment of therapeutic agents.

Over the last two decades, protein biotherapeutics have gained popularity and arefast becoming the major part of the pharmaceutical market. The high affinity, high

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specificity binding to target receptors/ion channels and the consequent low toxicityand side-effects profile of protein drugs are extremely attractive as lead moleculesin drug development. Endogenous proteins (such as factor VIIa, erythropoietin andinsulin) as well as humanized or chimeric monoclonal antibodies to targeted specificantigens (such as tumor necrosis factor α, vascular endothelial growth factor, andcytokines) are some of the successful protein therapeutics. In addition, we also useexogenous proteins as potential prototypes in the development of protein biother-apeutics. These exogenous factors have evolved for millions of years as a part ofpredator-prey and host-parasite competitions. They target specific and critical phys-iological processes that play crucial roles in the survival of the organism. The aim inediting this book is to bring out the complexities of structure-function relationshipsand mechanisms of exogenous proteins with crucial roles in cardiovascular andhematological disorders and recent progress in understanding them. Such exoge-nous factors are found in venoms of snakes, scorpions, spiders and other venomousanimals, saliva of hematophagous animals as well as in many microorganisms. The43 review chapters are written by leading experts in their field from 22 differentcountries. The book focuses on various aspects ranging from modern approaches tothe analysis of venom/saliva contents and identification for new active componentsto the wealth and diversity of structures and mechanisms of these proteins. It alsohighlights the development of these proteins as (a) novel therapeutic agents for thetreatment/prevention of cardiovascular and cerebrovascular diseases as well as can-cer; and (b) diagnostic agents for the identification of a number of hereditary defectsand other hematological disorders.

This book is a product of concerted team effort of all members of the Registry ofExogenous Factors Affecting Thrombosis and Haemostasis, a subcommittee of theScientific Standardization Committee of the International Society of Thrombosisand Haemostasis as well as some of members of the International Society ofToxinology. The primary intent in producing this book is to elevate awareness andenthusiasm in the field of exogenous factors. We hope that it will provide greaterimpetus to the search for novel proteins based on naturally occurring exogenous fac-tors. The book should also remind us of the importance of preservation of diversityof species, even those that are often considered dangerous and nuisance organisms,to allow access in the future to venoms, salivary gland extracts and other tissues,which could permit new discoveries and development of novel therapeutics fora number of life-threatening diseases. It celebrates the role of biotechnology andadvances in newer technologies that are faster and more sensitive thus the way tomany new discoveries. As the first book dealing extensively with exogenous fac-tors in the last 25 years it should provide a modern, easily accessible referenceto the different approaches being used to solve complex, contemporary problemsin protein chemistry and pharmacology of exogenous factors. It also updates ourunderstanding of the structure-function relationships and mechanisms of action ofexogenous factors and provides insights into future directions for solving manyremaining challenges. Thus this book helps to foster a wider interest in isolation

Preface vii

and characterization of novel proteins, to entice new, talented researchers into thisfield, and to generate more enthusiasm in the field.

Singapore, Singapore R. Manjunatha KiniBerne, Switzerland Kenneth J. ClemetsonLos Angeles, California Francis S. MarklandWilmongton, Delaware Mary Ann McLaneTokyo, Japan Takashi Morita

Acknowledgments

In 1985 the first meeting of scientists working on snake venom proteins whichaffected thrombosis and hemostasis was organized as the “Symposium on AnimalVenoms and Hemostasis (July 20–21, 1985)” in conjunction with the Xth Congressof the International Society of Thrombosis and Haemostasis. The organizing com-mittee included Hubert Pirkle, Francis S. Markland, Patrick Gaffney, ZbigniewLatallo and Neville Marsh. Marcel Dekker, Inc. published the proceedings of thismeeting as a book “Hemostasis and Animal venoms” edited by Hubert Pirkle andFrancis Markland. No meeting was organized for the next 15 years. However, sev-eral years ago, as a Co-Chairman of the Registry of Exogenous Hemostatic Factors,a subcommittee of the International Society on Thrombosis and Haemostasis(ISTH), I proposed that the committee should consider organizing an internationalconference focused on the exogenous factors. The then chairman, Neville Marsh,and other co-chairmen, Francis Markland and Jan Rosing recognized the need forsuch international conferences. The committee unanimously agreed to organizeinternational conferences every 4 years after the Congress of the ISTH. When Iwas the Chairman of the subcommittee, I discussed this issue with Ian Peake andGilbert White, the President and Executive Director of ISTH, respectively, and theystrongly supported the idea and encouraged us. As a result, the Second InternationalConference on Exogenous Factors Affecting Thrombosis and Hemostasis was heldat the Pasteur Institute, Paris, France in 2001 under the leadership of Cassian Bon.The Third Conference was held at the University of Technology Sydney, Australiain 2005 under the leaderships of Kevin Broady and Neville Marsh. The proceed-ings of both these conferences were published as a special issue of Haemostasis,and Pathophysiology of Haemostasis and Thrombosis, respectively. As the FourthConference coincided with the 25th year of the first meeting, we decided to publisha book highlighting the progress made in the last 25 years. The Fourth Conferencewas held at the University of Massachusetts, Boston, USA under the leadership ofMaryAnn McLane and the main content of this book is the proceedings of the meet-ing. To have a complete coverage, we also approached some of the leading scientistsin the field. They all readily accepted our invitation to contribute to this book.

Firstly, I would like to thank all the Chairmen, Co-Chairmen and members ofour subcommittee, past and present, for their continuous and unconditional sup-port and encouragement. It was this true spirit that made it possible to organize the

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International conferences every 4 years. I am especially indebted to the strong sup-port by Neville Marsh, Francis Markland, Jan Rosing, Kenneth Clemetson, TakashiMorita and MaryAnn McLane. Secondly, I thank Gilbert White and Ian Peake alongwith Cathy Cole, ISTH Executive Secretary, for their support and encouragementduring the initial stages. I thank Dr. Ryan McCleary for his assistance during proofreading of the book. I also thank all the subsequent Presidents of ISTH Congresses(Dominique Meyer, Colin Chesterman, Barbara Furie and Bruce Furie) for theirsupport. Along with the other editors I thank all the contributors to this book fortheir timely and very professional submission of the chapters. Without their efforts,this book would not have been possible. I appreciate all their time and efforts.

I had approached several publishers to ask if they were interested in publishingthis book. All the publishers I talked to were very supportive of the project andwanted to publish the book. But Thijs van Vlijmen, Springer Science (BiomedicalUnit | Life Sciences) approached this project very efficiently and was the firstone to come up with all the necessary paperwork. Throughout the project, hewas extremely supportive. I appreciate his energy and enthusiasm, and his confi-dence in us. I also thank the Springer staff, Andre Tournois (Production) and NinaWilhelm (Marketing) for their efforts. I appreciate the efforts of the Integra staff,Leah Georgina for timely typesetting and the fantastic layout of the book. I thankAnne Nee Yong for selecting the exciting picture and eStudio Calamar S.L. for thebeautiful cover design.

I am especially grateful to my wife, Nobue, who is ever so supportive, tolerantand considerate. Finally, I thank my family, friends and teachers for their confidenceand constant moral support.

Contents

1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1Kenneth J. Clemetson and R. Manjunatha Kini

Part I From Bench to Bedside

2 From the Bothrops Jararaca Bradykinin PotentiatingPeptides to Angiotensin Converting Enzyme Inhibitors . . . . . . . 13Sérgio Henrique Ferreira

Part II The Omics – The Search Is On

3 Sialomic Perspectives on the Evolution of Blood-FeedingBehavior in Arthropods: Future Therapeutics by Natural Design . 21B.J. Mans and I.M.B. Francischetti

4 Snake Venomics, Antivenomics, and Venom Phenotyping:The Ménage à Trois of Proteomic Tools Aimedat Understanding the Biodiversity of Venoms . . . . . . . . . . . . 45Juan J. Calvete

5 Insights in to Venom and Toxin Activitiesand Pharmacological/Therapeutic Potential UsingGene Expression Profiling . . . . . . . . . . . . . . . . . . . . . . . 73Jay W. Fox

6 Bioactive Peptides and Proteins from Wasp Venoms . . . . . . . . . 83Ren Lai and Cunbao Liu

7 The Theory of Intraspecies Variation is Not the Exception,But Simply the Rule: The Diverse Hemostatic Activitiesof Snake Venoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97Alexis Rodríguez-Acosta, Belsy Guerrero, and Elda E. Sánchez

8 Tiny Ticks are Vast Sources of Antihaemostatic Factors . . . . . . 113Mária Kazimírová, Cho Yeow Koh, and R. Manjunatha Kini

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9 Sialogenins and Immunomodulators Derived from BloodFeeding Parasites . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131Anderson Sá-Nunes and Carlo José Freire de Oliveira

10 Salivary Protease Inhibitors with Non Anti-Hemostatic Functions . 153Jindrich Chmelar, Ivo M.B. Francischetti,and Michalis Kotsyfakis

Part III Anticoagulant Proteins

11 Blood Coagulation Factor IX/Factor X-Binding Protein . . . . . . 167Takashi Morita

12 Bothrojaracin – A Potent Thrombin Inhibitor . . . . . . . . . . . . 179Russolina B. Zingali and Ana Cristina Ferraz Nogueira

13 Anticoagulant Phospholipases A2 Which Bind to theSpecific Soluble Receptor Coagulation Factor Xa . . . . . . . . . . 201Grazyna Faure, Haijin Xu, and Frederick Saul

14 Hematophagy and Inhibition of the Extrinsic and IntrinsicTenase Complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . 219Robson Q. Monteiro, John F. Andersen,and Ivo M.B. Francischetti

15 Thrombin Inhibitors from Haematophagous Animals . . . . . . . . 239Cho Yeow Koh and R. Manjunatha Kini

16 Anticoagulants from Scorpion Venoms . . . . . . . . . . . . . . . . 255N.A. Valdez-Cruz, R. Conde, F.Z. Zamudio, and L.D. Possani

Part IV Antiplatelet Proteins

17 The Discovery of Disintegrins . . . . . . . . . . . . . . . . . . . . . 269Tur-Fu Huang

18 Brief History and Molecular Determinants of Snake VenomDisintegrin Evolution . . . . . . . . . . . . . . . . . . . . . . . . . . 285Juan J. Calvete

19 Anti-Angiogenesis and Disintegrins . . . . . . . . . . . . . . . . . . 301Stephen Swenson, Radu Minea, Samuel Zidovetzki,Corey Helchowski, Fritz Costa, and Francis S. Markland

20 Hematophagy and Inhibition of Platelet Aggregation . . . . . . . . 331Ivo M.B. Francischetti

21 Snaclecs (Snake C-Type Lectins) that Inhibit Platelet Receptors . . 359Kenneth J. Clemetson

Contents xiii

Part V Fibrinolytic Proteins

22 Plasminogen Activators from Snake Venoms . . . . . . . . . . . . . 371Bernard F. Le Bonniec and Julie Libraire

23 Bat Plasminogen Activator: Desmoteplase – From Batto Bench to Bedside of Stroke Victims . . . . . . . . . . . . . . . . 393Wolfgang Söhngen, Karl-Uwe Petersen, and Mariola Söhngen

24 Fibrolase and Its Evolution to Clinical Trials:A Long and Winding Road . . . . . . . . . . . . . . . . . . . . . . 409Francis S. Markland and Stephen Swenson

25 Streptokinase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429Paul E. Bock and Pablo Fuentes-Prior

Part VI Procoagulant Proteins

26 Activation of Factor X by Snake Venom Proteases . . . . . . . . . . 447Jüri Siigur and Ene Siigur

27 Structural Aspects of the Factor X Activator RVV-Xfrom Russell’s Viper Venom . . . . . . . . . . . . . . . . . . . . . . 465Soichi Takeda

28 Snake Venom Prothrombin Activators – The History . . . . . . . . 485Jan Rosing and Guido Tans

29 Origin and Evolution of Snake Venom Prothrombin Activators . . 501Md. Abu Reza and R. Manjunatha Kini

30 Thrombin-Like Enzymes in Snake Venoms . . . . . . . . . . . . . 519Stephen P. Mackessy

31 Procoagulant Factors from Lonomia Caterpillars . . . . . . . . . . 559Ana Marisa Chudzinski-Tavassi andLinda Christian Carrijo-Carvalho

32 Staphylocoagulase . . . . . . . . . . . . . . . . . . . . . . . . . . . 575Peter Panizzi, Heather K. Kroh, Pablo Fuentes-Prior,and Paul E. Bock

33 Procoagulant Properties of Plant Latex Proteases . . . . . . . . . . 591H.V. Shivaprasad, R. Rajesh, M. Yariswamy, andB.S. Vishwanath

Part VII Platelet Aggregation Inducers

34 The Biologic Activity of Aggretin/Rhodocytin, a SnakeVenom C-Type Lectin Protein (Snaclec) . . . . . . . . . . . . . . . 607Ching-Hu Chung and Tur-Fu Huang

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35 Snaclecs (Snake C-Type Lectins) that Activate Platelets . . . . . . 621Kenneth J. Clemetson

36 The Effect of Bacterial Toxins on Platelet Function . . . . . . . . . 637Steven Kerrigan and Dermot Cox

Part VIII Hypotensive Factors

37 Hypertensive and Hypotensive Snake Venom Components . . . . . 655Avner Bdolah

38 Hypotensive Proteins from Hematophagous Animals . . . . . . . . 673P. Takác, H. Tsujimoto, and D.E. Champagne

Part IX Hemorrhage and Coagulopathies

39 Snakebite-Induced Coagulopathy and Bleeding Disorders . . . . . 699Ponlapat Rojnuckarin

40 Antivenoms and Coagulation . . . . . . . . . . . . . . . . . . . . . 711Elda E. Sánchez, Alexis Rodríguez-Acosta, Esteban Cantu,and Belsy Guerrero

41 Biological Activities of Snake Venom Metalloproteinaseson Platelets, Neutrophils, Endothelial Cells,and Extracellular Matrices . . . . . . . . . . . . . . . . . . . . . . 723Chun-Chieh Hsu and Tur-Fu Huang

Part X Applications

42 Leeches in Microsurgery – An Evidence-Based Approach . . . . . 735Karsten Knobloch

43 Diagnostic Use of Snake Venom Componentsin the Coagulation Laboratory . . . . . . . . . . . . . . . . . . . . 747Anna Maria Perchuc and Marianne Wilmer

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 767

Contributors

John F. Andersen Section of Vector Biology, Laboratory of Malaria and VectorResearch, National Institute of Allergy and Infectious Diseases, National Institutesof Health, Rockville, MD 20852-8132, USA

Avner Bdolah Department of Zoology, George S. Wise Faculty of Life Sciences,Tel Aviv University, Ramat Aviv, Tel Aviv, 69978 Israel

Paul E. Bock Department of Pathology, Vanderbilt University Schoolof Medicine, Nashville, TN 37232-2561, USA

Bernard F. Le Bonniec INSERM U765, Université Paris Descartes, 4 Av. del’Observatoire, 75006 Paris Cedex, France

Juan J. Calvete Laboratorio de Proteinómica Estructural, Instituto deBiomedicina de Valencia, CSIC, Jaime Roig 11, 46010 Valencia, Spain

Esteban Cantu Natural Toxins Research Center, College of Arts and Sciences,Texas A&M University-Kingsville, Kingsville, TX, USA

D.E. Champagne Department of Entomology, and Center for Tropical andEmerging Global Diseases, University of Georgia, Athens, GA 30602-2603, USA

Linda Christian Carrijo-Carvalho Laboratory of Biochemistry and Biophysics,Instituto Butantan, São Paulo, SP, Brazil

Jindrich Chmelar Laboratory of Genomics and Proteomics of Disease Vectors,Institute of Parasitology, Biology Centre, ASCR v.v.i., 37005 Ceske Budejovice,Czech Republic

Ana Marisa Chudzinski-Tavassi Laboratory of Biochemistry and Biophysics,Instituto Butantan, São Paulo, SP, Brazil

Ching-Hu Chung Institute of Pharmacology and Toxicology, Tzu Chi University,Hualien, Taiwan

Kenneth J. Clemetson Department of Haematology, University of Berne,Inselspital, CH-3010 Berne, Switzerland

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xvi Contributors

R. Conde Departamento de Medicina Molecular y Bioprocesos, Instituto deBiotecnología, Universidad Nacional Autónoma de México, Avenida Universidad2001, Col. Chamilpa, Cuernavaca Morelos, 62210, México

Fritz Costa USC/Norris Comprehensive Cancer Center, University of SouthernCalifornia, Keck School of Medicine, Cancer Research Laboratory #106, 1303 N.Mission Road, Los Angeles, CA 90033, USA

Dermot Cox Molecular and Cellular Therapeutics, Royal College of Surgeonsin Ireland, Dublin, Ireland

Grazyna Faure Institut Pasteur, Unité d’Immunologie Structurale; CNRS, URA2185, Département de Biologie Structurale et Chimie, F-75015, Paris, France

Sérgio Henrique Ferreira Department of Pharmacology, University of São Paulo,Av. dos Bandeirantes, 3900, Campus USP, 14049-900, Ribeirão Preto, SP, Brazil

Jay W. Fox Department of Microbiology, University of Virginia School ofMedicine, Charlottesville, VA 22908, USA

I.M.B. Francischetti Section of Vector Biology, Laboratory of Malaria and VectorResearch, National Institute of Allergy and Infectious Diseases, National Institutesof Health, Rockville, MD 20852-8132, USA

Pablo Fuentes-Prior Institut de Recerca, Hospital de la Santa Creu i Sant Pau,08025 Barcelona, Spain

Belsy Guerrero Laboratorio de Fisiopatología, Centro de Medicina Experimental,Instituto Venezolano de Investigaciones Científicas (IVIC), Caracas, RepúblicaBolivariana de Venezuela

Corey Helchowski USC/Norris Comprehensive Cancer Center, University ofSouthern California, Keck School of Medicine, Cancer Research Laboratory #106,1303 N. Mission Road, Los Angeles, CA 90033, USA

Chun-Chieh Hsu Institute of Pharmacology, College of Medicine, NationalTaiwan University, Taipei, Taiwan

Tur-Fu Huang Institute of Pharmacology, College of Medicine, National TaiwanUniversity, Taipei, Taiwan

Mária Kazimírová Institute of Zoology, Slovak Academy of Sciences, DúbravskáCesta 9, SK-84506, Bratislava, Slovakia

Steven Kerrigan Molecular and Cellular Therapeutics, Royal College ofSurgeons in Ireland, Dublin, Ireland

R. Manjunatha Kini Protein Science Laboratory, Department of BiologicalSciences, National University of Singapore, Singapore, 117543, Singapore;Department of Biochemistry and Molecular Biophysics, Medical College ofVirginia, Virginia Commonwealth University, Richmond, VA 13298, USA

Contributors xvii

Karsten Knobloch Plastic, Hand and Reconstructive Surgery, Hannover MedicalSchool, Hannover, Germany

Cho Yeow Koh Protein Science Laboratory, Department of Biological Sciences,National University of Singapore, Singapore 117543, Singapore

Michalis Kotsyfakis Laboratory of Genomics and Proteomics of Disease Vectors,Institute of Parasitology, Biology Centre, ASCR v.v.i., 37005 Ceske Budejovice,Czech Republic

Heather K. Kroh Department of Pathology, Vanderbilt University School ofMedicine, Nashville, TN 37232-2561, USA

Ren Lai Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming650023, Yunnan, China

Julie Libraire INSERM U765, Université Paris Descartes, 4 Av. del’Observatoire, 75006 Paris Cedex, France

Cunbao Liu Kunming Institute of Zoology, Chinese Academy of Sciences,Kunming 650023, Yunnan, China

Stephen P. Mackessy School of Biological Sciences, University of NorthernColorado, 501 20th St., CB 92, Greeley, CO 80639-0017, USA

B.J. Mans Parasites, Vectors and Vector-Borne Diseases, OnderstepoortVeterinary Institute, Pretoria, South Africa and the Department of VeterinaryTropical Diseases, University of Pretoria, Pretoria, South Africa

Francis S. Markland Department of Biochemistry and Molecular Biology,University of Southern California, Keck School of Medicine, Cancer ResearchLaboratory #106, 1303 N. Mission Road, Los Angeles, CA 90033, USA

Radu Minea USC/Norris Comprehensive Cancer Center, University of SouthernCalifornia, Keck School of Medicine, Cancer Research Laboratory #106, 1303 N.Mission Road, Los Angeles, CA 90033, USA

Robson Q. Monteiro Instituto de Bioquímica Médica, Universidade Federal doRio de Janeiro, Rio de Janeiro, RJ, Brazil

Takashi Morita Department of host defense and biological Research, JuntendoUniversity School of Medicine, Tokyo 113-8421, Japan

Ana Cristina Ferraz Nogueira Instituto de Bioquímica Medica, Centro deCiências da Saúde, UFRJ, Rio de Janeiro, Brazil

Carlo José Freire de Oliveira Section of Vector Biology, Laboratory of Malariaand Vector Research, National Institute of Allergy and Infectious Diseases,National Institutes of Health, Rockville, MD 20852-8132, USA; Department ofBiochemistry and Immunology, School of Medicine of Ribeirão Preto, Universityof São Paulo, Ribeirão Preto, SP 14049-900, Brazil

xviii Contributors

Peter Panizzi Center for Systems Biology, Massachusetts General Hospital,Boston, MA 02114, USA

Anna Maria Perchuc August Lenz Foundation at the Institute for Prevention ofCardiovascular Diseases, University of Munich, Munich, Germany; Swiss TropicalInstitute, MPI, Basel, Switzerland

Karl-Uwe Petersen PAION Deutschland GmbH, Martinstrasse 10–12, 52062Aachen, Germany

Lourival D. Possani Departamento de Medicina Molecular y Bioprocesos,Instituto de Biotecnología, Universidad Nacional Autónoma de México, AvenidaUniversidad 2001, Col. Chamilpa, Cuernavaca Morelos, 62210, México

R. Rajesh Department of Studies in Biochemistry, University of Mysore,Manasagangothri, Mysore 570 006, Karnataka, India; Department of Microbiologyand Immunology, University of Maryland, Baltimore, MD 21201, USA

Md. Abu Reza Department of Biological Sciences, National University ofSingapore, Singapore 117 543 Singapore; Department of Genetic Engineering andBiotechnology, University of Rajshahi, Rajshahi 6205, Bangladesh

Alexis Rodríguez-Acosta Immunochemistry Section, Tropical Medicine Instituteof the Universidad Central de Venezuela, Caracas, República Bolivariana deVenezuela

Ponlapat Rojnuckarin Division of Hematology, Department of Medicine,King Chulalongkorn Memorial Hospital, Rama IV Rd, Patumwan, Bangkok10330, Thailand

Jan Rosing Department of Biochemistry, Cardiovascular Research InstituteMaastricht (CARIM), Maastricht University, P.O. Box 616, Maastricht, 6200 MD,The Netherlands

Elda E. Sánchez Natural Toxins Research Center, College of Arts and Sciences,Texas A&M University-Kingsville, Kingsville, TX, USA

Anderson Sá-Nunes Laboratory of Experimental Immunology, Department ofImmunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo,SP 05508 900, Brazil

Frederick Saul Institut Pasteur, Unité d’Immunologie Structurale; CNRS, URA2185, Département de Biologie Structurale et Chimie, F-75015, Paris, France

H. V. Shivaprasad Department of Studies in Biochemistry, University of Mysore,Manasagangothri, Mysore 570 006, Karnataka, India

Ene Siigur National Institute of Chemical Physics and Biophysics, Tallinn 12618,Estonia

Jüri Siigur Laboratory of Bioorganic Chemistry, National Institute of ChemicalPhysics and Biophysics, Akadeemia tee 23, Tallinn 12618, Estonia

Contributors xix

Mariola Söhngen PAION Deutschland GmbH, Martinstrasse 10–12, 52062Aachen, Germany

Wolfgang Söhngen PAION Deutschland GmbH, Martinstrasse 10–12, 52062Aachen, Germany

Stephen Swenson USC/Norris Comprehensive Cancer Center, University ofSouthern California, Keck School of Medicine, Cancer Research Laboratory #106,1303 N. Mission Road, Los Angeles, CA 90033, USA

P. Takác Institute of Zoology, Slovak Academy of Sciences, Bratislava, Slovakia

Soichi Takeda National Cardiovascular Center Research Institute, Suita, Osaka565-8565, Japan

Guido Tans Department of Biochemistry, Cardiovascular Research InstituteMaastricht (CARIM), Maastricht University, P.O. Box 616, Maastricht, 6200 MD,The Netherlands

H. Tsujimoto Department of Entomology, and Center for Tropical and EmergingGlobal Diseases, University of Georgia, Athens, GA 30602-2603, USA

N. A. Valdez-Cruz Departamento de Medicina Molecular y Bioprocesos, Institutode Biotecnología, Universidad Nacional Autónoma de México, AvenidaUniversidad 2001, Col. Chamilpa, Cuernavaca Morelos, 62210, México

B.S. Vishwanath Department of Studies in Biochemistry, University of Mysore,Manasagangothri, Mysore 570 006, Karnataka, India

Marianne Wilmer Department DXSC, Roche Diagnostics Ltd., Rotkreuz,Switzerland

Haijin Xu Institut Pasteur, Unité d’Immunologie Structurale; CNRS, URA 2185,Département de Biologie Structurale et Chimie, F-75015, Paris, France

M. Yariswamy Department of Studies in Biochemistry, University of Mysore,Manasagangothri, Mysore 570 006, Karnataka, India

F. Z. Zamudio Departamento de Medicina Molecular y Bioprocesos, Instituto deBiotecnología, Universidad Nacional Autónoma de México, Avenida Universidad2001, Col. Chamilpa, Cuernavaca Morelos, 62210, México

Samuel Zidovetzki USC/Norris Comprehensive Cancer Center, University ofSouthern California, Keck School of Medicine, Cancer Research Laboratory #106,1303 N. Mission Road, Los Angeles, CA 90033, USA

Russolina B. Zingali Instituto de Bioquímica Medica, Centro de Ciências daSaúde, UFRJ, Rio de Janeiro, Brazil

About the Editors

R. Manjunatha Kini Dr. Kini graduated fromUniversity of Mysore, India in 1983 and did hispostdoc in Kyushu University, Japan and VirginiaCommonwealth University, Richmond, U.S.A. Thenhe joined National University of Singapore, Singaporein 1994. Currently, he is a Professor in the Departmentof Biological Sciences, National University ofSingapore. He also holds an Affiliate Professorposition in the Department of Biochemistry atMedical College of Virginia, Virginia CommonwealthUniversity, Richmond. He is the founder and ChiefScientific Officer of a small start-up companyProTherapeutics Private Limited, Singapore, which engineers orally and sublin-gually active therapeutic peptides. He has been the Chairman or Co-Chairman of theRegistry of Exogenous Hemostatic Factors, a sub-committee of the InternationalSociety on Thrombosis and Haemostasis since 1998. He was also a memberof the Council of the International Society on Toxinology. Currently, he is anominated Member of the Nomenclature Committee of the International Societyon Toxinology. Dr. Kini is on the editorial board of several international scientificjournals. He has published 148 original articles, 29 reviews, 15 book chapters and31 patent applications. He edited a monograph on Snake venom phospholipasesand was guest editor for three special issues. His research interests includestructure-function relationships and mechanism of action of proteins, particularlysnake venom toxins. The functional sites are used in designing proteins with novelbiological activities and prototypes of therapeutic agents.

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xxii About the Editors

Kenneth J. Clemetson Dr. Clemetson graduatedfrom University of Cambridge 1968 and completedpostdocs at the University of Alberta, Canada andthe University of California at Santa Barbara. He wasawarded Sc.D. by University of Cambridge in 2007.He was elected as a Fellow of the Royal Society ofChemistry. He is Professor Emeritus of biochemistryin the Department of Medicine at the University ofBerne, Switzerland. Currently, he is working in theDepartment of Haematology. His research interestsinclude structure-function relationships and mecha-nism of action and signalling of blood platelet recep-tors. Snake venom toxins are interesting and novel tools to investigate platelet recep-tor function. They also provide lead structures for the development of pharmacolog-ically active drugs for treatment of disorders involving platelets such as infarcts andstroke. He was a member of Council of the International Society on Thrombosis andHaemostasis and President of the European Thrombosis Research Organization. Hehas also been chairman and co-chairman of the Platelet Physiology subcommitteeand am currently co-chairman of the Registry of Exogenous Hemostatic Factorssubcommittee of the International Society on Thrombosis and Haemostasis. Now,he is on the editorial board of several international scientific journals in the plateletfield. He has published over 230 original articles, reviews, and book chapters andhas several patents.

Francis S. Markland, Jr. Dr. Markland He receivedhis Ph.D. in Physiological Chemistry from JohnsHopkins University in 1964, and completed a twoyear NIH postdoctoral fellowship in the BiologicalChemistry Department, UCLA, School of Medicine.He was appointed assistant professor at UCLA in1966 and received an NIH Career DevelopmentAward from 1968 to 1973. In 1974 he movedto the USC School of Medicine as AssociateProfessor of Biochemistry and a member of theUSC Cancer Center. In 1983 he was appointedProfessor of Biochemistry. Currently, he is Professorof Biochemistry and Molecular Biology, University of Southern California(USC), Keck School of Medicine (KSOM). He served as Acting Chair ofthe Biochemistry Department (1986–1988) and Associate Dean for ScientificAffairs at KSOM (2004–2008). He has served on numerous NIH study sections.Dr. Markland is an internationally recognized expert on proteins from snake venomswith potential clinical application; a metalloproteinase he purified from southerncopperhead venom recently advanced to Phase III clinical trials as therapy for

About the Editors xxiii

peripheral arterial occlusive disease. He is presently working with novel adhesivepeptides with antiangiogenic activity. His laboratory recently succeeded in using anengineered bacterial strain to produce a recombinant version of the venom peptide.He has numerous patents related to his technologies.

Mary Ann McLane Dr. McLane pursued adoctorate in Physiology from Temple University,Philadelphia PA in 1993 and completed a molecularbiology postdoc in the Thrombosis Research Centerat Temple University in 1996. She is a tenured fullProfessor in the Department of Medical Technology,University of Delaware (Newark DE, USA) with ajoint appointment in the Department of BiologicalScience. She is a certified medical laboratory sci-entist specializing in clinical biochemistry, and isthe 2009–2010 President of the American Societyfor Clinical Laboratory Science. She was namednational Laboratorian of the Year in 1999, and received a Lindback TeachingAward in 2002. Dr. McLane has been the Chairman of the Registry of ExogenousHemostatic Factors, a sub-committee of the International Society on Thrombosisand Haemostasis, and organized the 4th International Conference in Boston MA,USA in July 2009 from which came the manuscripts published in this collection.Her research focuses on the anti-cancer activity of the disintegrin eristostatin fromthe viper Eristocophis macmahoni.

Takashi Morita Dr. Morita was born in Osaka,Japan in 1943, and graduated from Osaka Universityin 1967. After four years of working at pharmaceuti-cal company, he finished his Ph. D. in 1977 at OsakaUniversity. After two years of postdoctoral work-ing in Washington University School of Medicine, StLouis, USA, he returned to Japan to be an assistantprofessor of Kyushu University, Faculty of Sciencein 1979. He has been a Professor of Biochemistry,Meiji Pharmaceutical University, Tokyo, between 1986and 2009. He is now Professor Emeritus at MeijiPharmaceutical University, and is a Visiting Professorof Host Defense and Biological Research, Juntendo University School of Medicine,Tokyo. His research interests include structure and function of Vitamin K-dependentcoagulation factors and snake venom proteins such as VEGF and disintegrins.