Handbook of Venoms and Toxins of Reptiles

Cover
Half Title
Title Page
Copyright Page
Table of Contents
Preface
About the Editor
Contributors
Section I Introduction and Technologies Used in Toxinology
	Chapter 1 Reptile Venoms and Toxins: Unlimited Opportunities for Basic and Applied Research
		1.1 Introduction
		1.2 Venom – Definition, Composition and Variation
			1.2.1 What Is a Venom?
			1.2.2 Venom Composition – General Trends
				1.2.2.1 Proteins and Peptides
				1.2.2.2 Metal Ions
			1.2.3 Variation – Levels and Sources
				1.2.3.1 Viperid Venom Composition
				1.2.3.2 Elapid Venom Composition
				1.2.3.3 Venoms from Rear-fanged Snakes (“Colubridae”)
				1.2.3.4 Helodermatid Venom Composition
			1.2.4 Unusual Aspects of Venoms
		1.3 Conservation of Venomous Reptiles
			1.3.1 Habitat Modification and Effects on Reptile Populations
		1.4 Conclusions
		References
	Chapter 2 Present and Future of Snake Venom Proteomics Profiling
		2.1 Introduction: The Mutually Enlightening Relationship between Ecological and Translational Venomics
		2.2 Bottom-Up Snake Venomics: Concepts and Workflow
		2.3 Top-Down Proteomics: Towards Proteoform-Resolved Venom Proteomes
		2.4 The Evils of Quantification: Towards Absolute Quantification of Venom Proteomes
		2.5 Concluding Remarks and a Look Into the Future
		2.6 Acknowledgments
		References
	Chapter 3 Applications of Genomics and Related Technologies for Studying Reptile Venoms
		3.1 Introduction
		3.2 The Genomic Context for Reptile Venoms
			3.2.1 What a “Complete Genome” Is, and Why They Are Not Created Equal
			3.2.2 The Structural and Evolutionary Context for Venom in Squamate Reptile Genomes
			3.2.3 Venom Gene Cluster Structure, and Why Venom Genes Are Difficult to Assemble and Identify Accurately
			3.2.4 Where Are Venom Genes Located in the Genome?
		3.3 Regulation of Venom Genes – The Black Box Linking the Genome With Venom
			3.3.1 Towards an Understanding of Venom Regulation
			3.3.2 Genomes Add Value to Transcriptomic and Proteomic Data
			3.3.3 Understanding the Factors that Direct the Regulation of Venom Production
		3.4 Population-Level Studies of Venom Variation and Evolution
			3.4.1 Population-Level Sampling of Venomous Reptile Genomes
			3.4.2 The Relevance of Hybrid Zones for Studying Venom
		3.5 Conclusions
		References
	Chapter 4 Snake Venom Gland Transcriptomics
		4.1 Introduction
		4.2 Venom Gland Transcriptome Assembly
			4.2.1 Assembly Programs
			4.2.2 Evaluation of Assembly Quality
		4.3 Toxin Annotation
			4.3.1 Known Toxins
			4.3.2 Uncharacterized Toxins
		4.4 Quantifying Toxin Gene Expression
		4.5 Regulation of Toxin Gene Expression
			4.5.1 Toxin Transcripts
			4.5.2 MicroRNAs
		4.6 RNA-Seq Evolutionary Insights
			4.6.1 Venom Evolution
			4.6.2 Natural History of Venomous Organisms
		4.7 Conclusions
		References
	Chapter 5 X-ray Crystallography and Structural Studies of Toxins
		5.1 Introduction
		5.2 A Brief History: Milestones
		5.3 Outline of the Steps to Crystallize Proteins
			5.3.1 The Magic of Crystallization
			5.3.2 The X-ray Diffraction Experiment
			5.3.3 Solving the Structure: the Phase Problem
		5.4 Resolution and What It Means
		5.5 Snake Venom Toxin Structural Timeline
			5.5.1 Crystallization of Snake Venom Proteins
			5.5.2 Catalytic Mechanisms
			5.5.3 Multimeric Forms
			5.5.4 Nuclear Magnetic Resonance in the Study of Macromolecular Toxins
		5.6 Future Prospects
		5.7 Acknowledgments
		References
	Chapter 6 Envenomations and Treatment: Translating between the Bench and the Bedside
		6.1 Origin of Antivenom Development
		6.2 Translational Research
		6.3 Phases of Translation
			6.3.1 The Bench
			6.3.2 Phases of Drug Development
		6.4 Barriers to Progression During Each Phase
			6.4.1 Translational Challenges at the Preclinical Development Phase
			6.4.2 Common Problems Experienced During Clinical Trials
		6.5 Medications from Venom
		6.6 Antivenoms and Novel Technologies
		6.7 Conclusions
		References
	Chapter 7 Current Assessment of the State of Snake Venom Toxinological Research with a View to the Future
		7.1 Introduction
		7.2 Snake Antivenom Research
			7.2.1 Validation of Antivenoms
			7.2.2 Novel Approaches to Antivenom Production
			7.2.3 Non-Antibody-Based Approaches to Neutralize Venoms for Therapeutic Applications
			7.2.4 Summary
		7.3 Snake Toxin Isolation and Characterization
			7.3.1 Characterization of Venom Toxins Belonging to Known Structural and Functional Classes
			7.3.2 Characterization of the Molecular and Structural Elements of Toxins That Define Toxin Activity
			7.3.3 Characterization of Venom Toxins with Undescribed Biological Activities
			7.3.4 Summary
		7.4 Snake Venomics
			7.4.1 Transcriptomics and Proteomics
			7.4.2 Genomics and Metabolomics
			7.4.3 Summary
		7.5 Snake Venom and Drug Discovery
			7.5.1 Discovering a New Drug from Snake Venoms
			7.5.2 Anti-Hypertension Drug Discovery
			7.5.3 Pro- and Anticoagulant Drug Design
			7.5.4 Antimicrobial and Antitumor Drug Design
			7.5.5 Ion Channel Blockers and Analgesics
			7.5.6 Summary
		7.6 Snake Venom and Evolution
			7.6.1 Snake Biology and Evolution
			7.6.2 Snake Venom Evolution
			7.6.3 Summary
		7.7 Snake Venom Pathophysiology
			7.7.1 Clinical Characterization and Descriptions of Envenoming
			7.7.2 Pharmacokinetics and Pharmacodynamics of Envenomation and Antivenom Administration
		7.8 Non-Antibody-Based Antivenom Agents
			7.8.1 Traditional Medicine Applied to Toxinology
			7.8.2 Natural and Synthetic Inhibitors Applied as Antivenom
			7.8.3 Aptamers Applied to Snakebite Diagnosis and Treatment
			7.8.4 Biosynthetic Oligoclonal Antivenom (BOA) Associated with Small Molecule Enzyme Inhibitors Approach
			7.8.5 Summary
		References
Section II Venom Gland Structure, Systematics and Ecology
	Chapter 8 Reptile Venom Glands: Form, Function, Future, Concepts and Controversies
		8.1 Introduction
		8.2 Gland Structure
			8.2.1 Phylogeny
			8.2.2 Anatomy of Reptilian Oral Glands
				8.2.2.1 Lizards
				8.2.2.2 Front-Fanged Venomous Snakes
				8.2.2.3 Non-Front-Fanged Snakes and Technicalities of Terminology
		8.3 Functions of the Venom Apparatus
			8.3.1 Delivery of Oral Secretions
			8.3.2 Biological Roles of NFFC Venom
			8.3.3 Multi-Functionality of Venoms
				8.3.3.1 Locomotor Inhibition
				8.3.3.2 Precipitous Hypotension and Prey Subjugation
				8.3.3.3 Other “Means to an End”: Unique Snake Venom Toxins and Prey Subjugation
			8.3.4 Clinical Implications of NFFC Venoms: Comparable to Elapids, Atractaspis spp. and Viperids?
		8.4 Discussion and Conclusions
			8.4.1 Multiple Functions and Biological Role(s) in the Wild
			8.4.2 “Protovenoms”: Exapted for Later Roles
		8.5 Dedication
		8.6 Acknowledgments
		References
	Chapter 9 Advances in Venomous Snake Systematics, 2009–2019
		9.1 Introduction
		9.2 Taxonomic Changes to Venomous Reptiles
			9.2.1 Old World Elapid Snakes – Subfamily Elapinae
				9.2.1.1 Bungarus – Kraits
				9.2.1.2 Calliophis – Asian Coralsnakes
				9.2.1.3 Hemibungarus – Philippine False Coralsnakes
				9.2.1.4 Micrurus – New World Coralsnakes
				9.2.1.5 Naja – Cobras
				9.2.1.6 Sinomicrurus – Asian Coralsnakes
			9.2.2 Australasian and Marine Elapid Snakes – Subfamily Hydrophiinae
				9.2.2.1 Acanthophis – Death Adders
				9.2.2.2 Aipysurus – Seasnakes
				9.2.2.3 Antaioserpens – Burrowing Snakes
				9.2.2.4 Emydocephalus – Turtle-Headed Seasnakes
				9.2.2.5 Hydrophis – Seasnakes
				9.2.2.6 Pseudechis – Australian Blacksnakes
				9.2.2.7 Pseudonaja – Australian Brownsnakes
				9.2.2.8 Toxicocalamus – Forest Snakes
				9.2.2.9 Vermicella – Bandy-Bandys
			9.2.3 Fea’s Vipers – Subfamily Azemiopinae
			9.2.4 Pitvipers – Subfamily Crotalinae
				9.2.4.1 Agkistrodon – Moccasins
				9.2.4.2 Atropoides / Metlapilcoatlus – Jumping Vipers
				9.2.4.3 Bothriechis – Palm Pitvipers
				9.2.4.4 Lance-Headed Pitvipers (Bothrops and Relatives) – Genus-Level Classification
				9.2.4.5 Bothrops – Lanceheads
				9.2.4.6 Cerrophidion – Montane Pitvipers
				9.2.4.7 Crotalus – Rattlesnakes
				9.2.4.8 Sistrurus – Pigmy Rattlesnakes
				9.2.4.9 Gloydius – Asian Moccasins
				9.2.4.10 Ophryacus – Mexican Horned Pitvipers
				9.2.4.11 Asiatic Pitvipers (Trimeresurus and Relatives) – Genus-Level Classification
				9.2.4.12 Subgenus Trimeresurus
				9.2.4.13 Subgenus Parias
				9.2.4.14 Subgenus Himalayophis
				9.2.4.15 Subgenus Popeia
				9.2.4.16 Subgenus Sinovipera
				9.2.4.17 Hypnale – Hump-Nosed Pitvipers
				9.2.4.18 Ovophis – Mountain Pitvipers
				9.2.4.19 Protobothrops – Asian Lanceheads or Habus
			9.2.5 Old World Vipers – Subfamily Viperinae
				9.2.5.1 Atheris – Bush Vipers
				9.2.5.2 Bitis harenna – Bale Mountains Adder
				9.2.5.3 Causus rasmusseni - Rasmussen’s Night Adder
				9.2.5.4 Cerastes boehmei
				9.2.5.5 African Daboia – Moorish Vipers
				9.2.5.6 Echis – Saw-Scaled Vipers
				9.2.5.7 Macrovipera – Blunt-Nosed or Levantine Vipers
				9.2.5.8 Montivipera – Mountain Vipers
				9.2.5.9 Vipera – Eurasian Vipers
			9.2.6 Stiletto Snakes – Family Lamprophiidae, Subfamily Atractaspidinae
			9.2.7 Sand Snakes – Family Lamprophiidae, Subfamily Psammophiinae
			9.2.8 Colubrid Snakes – Colubridae
				9.2.8.1 Subfamily Colubrinae
				9.2.8.2 Subfamily Natricinae
				9.2.8.3 Subfamily Dipsadinae
				9.2.8.4 Boiga (Cat Snakes)
			9.2.9 Mud Snakes – Family Homalopsidae
			9.2.10 Beaded Lizards – Family Helodermatidae
		9.3 Other Significant Developments
		References
	Chapter 10 Biochemical Ecology of Venomous Snakes
		10.1 Introduction
		10.2 Predator–Prey Dynamics
		10.3 Venomous Snake Feeding Ecology
		10.4 Biochemical Ecology of Venomous Snakes
			10.4.1 General Dietary Trends in Venom Composition
				10.4.1.1 Generalist Toxins
				10.4.1.2 Prey-Specific Toxins
			10.4.2 Behavioral Ecology
			10.4.3 Venom for Defense
			10.4.4 Environment and Habitat
			10.4.5 Venom Resistance
		10.5 Venom Variation
		10.6 Conclusions
		References
	Chapter 11 Resistance of Native Species to Reptile Venoms
		11.1 Introduction
		11.2 Venomous Reptiles as Predators or Prey?
		11.3 Venom-Resistant Prey
			11.3.1 Squirrels
			11.3.2 Rats, Mice, and Voles
			11.3.3 Reptiles, Amphibians, and Other Species
		11.4 Venom Resistance in Predators
			11.4.1 Marsupials
			11.4.2 Placental Mammals
			11.4.3 Reptiles and Amphibians
		11.5 Future Directions
		Acknowledgments
		References
Section III Reptile Venom Non-Enzymatic Toxins
	Chapter 12 Three-Finger Toxins
		12.1 Introduction
		12.2 Structure of 3FTxs
			12.2.1 Dimer Formation
			12.2.2 Post-Translational Modifications
		12.3 Function of 3FTxs
			12.3.1 α-Neurotoxins
				12.3.1.1 Short-Chain Neurotoxins
				12.3.1.2 Long-Chain Neurotoxins
				12.3.1.3 Long-Chain Neurotoxin Dimers
			12.3.2 κ-Neurotoxins
			12.3.3 Non-Conventional Neurotoxins
			12.3.4 Muscarinic Toxins
			12.3.5 Cardiotoxins
			12.3.6 Acetylcholinesterase Inhibitors
			12.3.7 L-Type Calcium Channel Inhibitors
			12.3.8 Platelet Aggregation Inhibitors
			12.3.9 Anticoagulant Toxins
			12.3.10 Adrenoceptor Toxins
			12.3.11 Prey-Specific Toxins
			12.3.12 Ω-Neurotoxins
			12.3.13 Gamma Aminobutyric Acid (GABA) Receptor Toxins
			12.3.14 Acid-Sensing Ion Channel (ASICs) Toxins
			12.3.15 Ion Channel Activator Toxins
			12.3.16 Orphan Toxins
		12.4 Origin and Evolution
		12.5 Conclusions
		Acknowledgments
		References
	Chapter 13 Myotoxin a, Crotamine and Defensin Homologs in Reptile Venoms
		13.1 Introduction
		13.2 Myotoxins
		13.3 Myotoxin a
			13.3.1 Fundamental Structure and Presence in Snake Venom
			13.3.2 Envenomation and Mechanisms of Action
		13.4 Crotamine
			13.4.1 Fundamental Structure and Mechanisms of Action
			13.4.2 Genetics
			13.4.3 Biodistribution and Tissue Targeting
			13.4.4 Other Biological Activities of Crotamine
				13.4.4.1 Anti-microbial Activity
				13.4.4.2 Cell-Penetrating Peptide (CPP) with Antitumoral and Metabolic Activity
				13.4.4.3 Effects on Central Nervous System (CNS)
				13.4.4.4 Antiparasitic and Other Undisclosed Properties
		13.5 β-Defensins
			13.5.1 Genetics of β-Defensin-Like Genes
			13.5.2 Biochemical Structure/Pharmacological Characteristics
			13.5.3 Other Properties
		13.6 Conclusions
		Acknowledgments
		References
	Chapter 14 Reptile Venom Disintegrins
		14.1 Introduction: Integrins and Their Snake Venom Antagonists
		14.2 Snake Venom Metalloproteinases and the Emergence of Disintegrins
		14.3 Disintegrin Domains: Structure and Evolution
		14.4 Disintegrins: Structure–Function Correlations
		14.5 Disintegrin Purification and Cloning
		14.6 Biological Roles of Disintegrins
		14.7 Disintegrins as Potential Therapeutics
		14.8 Concluding Remarks
		References
	Chapter 15 Reptile Venom Cysteine-Rich Secretory Proteins
		15.1 Introduction
		15.2 Structural Features of CRiSPs
			15.2.1 Brief History of CRiSPs
			15.2.2 CRiSP Domains
			15.2.3 Evolutionary History and Distribution of CRiSPs
		15.3 The Biological Role of CRiSPs in Reptile Venoms
		15.4 Conclusions
		Acknowledgment
		References
	Chapter 16 Bradykinin-Potentiating and Related Peptides from Reptile Venoms
		16.1 Introduction
		16.2 Vasoactive Peptides
			16.2.1 Kinins, Kinin-Like and Bradykinin-Potentiating Peptides
			16.2.2 The BPPs
		16.3 BPP Mechanism of Action
			16.3.1 ACE Inhibition
			16.3.2 NO Production Induction
		16.4 BPP/BK-Related Peptides
			16.4.1 C-Type Natriuretic Peptide
		16.5 Conclusions
		References
	Chapter 17 Exendin-4 and Its Related Peptides
		17.1 Introduction
		17.2 Discovery of Exendin-4 and Identification of Cellular Target
		17.3 Synthesis and Recombinant Expression of Exendin-4
		17.4 Structure–Activity Relationships of Exendin-4
			17.4.1 Structure of Exendin-4
			17.4.2 Interaction Between Exendin-4 and Glucagon-like Peptide-1 (GLP-1) Receptor
				17.4.2.1 First-Stage Interaction with Receptor
				17.4.2.2 Second-Stage Activation of Receptor
		17.5 Pharmacological Actions of Exendin-4
			17.5.1 Insulinotropic Effects
			17.5.2 Cytoprotective and Proliferation-Promoting Effects on Pancreatic β-Cells
			17.5.3 Neuroprotective Effects
			17.5.4 Cardiovascular and Vascular Protective Effects
			17.5.5 Nephroprotective Effects
			17.5.6 Anti-Inflammation and Wound Healing Properties
			17.5.7 Anti-Cancer and Antitumor Effects
			17.5.8 Antioxidative Roles
		17.6 Pharmacokinetics of Exendin-4
			17.6.1 Pharmacokinetics of Exendin-4 in Model Animals
			17.6.2 Pharmacokinetics of Exendin‐4 in Humans
		17.7 Conclusion
		References
	Chapter 18 Reptile Venom C-Type Lectins
		18.1 Structure and Function of Snaclecs and Snake Lectins
		18.2 Snaclecs that Bind to Platelets
			18.2.1 Platelet Receptors Involved in Hemostasis
			18.2.2 Snaclecs That Bind to GPIb
			18.2.3 Snaclecs That Bind to GPVI
			18.2.4 Snaclecs That Bind to CLEC2
			18.2.5 Snaclecs That Bind to Integrin α2β1
			18.2.6 Snaclecs Interacting with Platelets via Undefined Receptors
		18.3 Snaclecs Targeting Plasma Proteins
			18.3.1 Snaclecs That Bind to VWF
			18.3.2 Echicetin Binding IgMκ
			18.3.3 Snaclecs That Bind to Thrombin/Prothrombin
			18.3.4 Snaclecs That Bind to Factor IX or X
		18.4 Class P-III Snake Venom Metalloproteases Containing Snaclec Domains
		18.5 Snake Lectins that Bind Sugars
		18.6 Future Prospects
		Acknowledgments
		References
	Chapter 19 Snake Venom Kunitz-type Inhibitors and Cystatins – Structure and Function
		19.1 Introduction
		19.2 Kunitz-Type Inhibitors
			19.2.1 Structure
			19.2.2 Mechanism of Action
			19.2.3 Functional Roles
				19.2.3.1 Non-Neurotoxic Kunitz-Type Inhibitors
				19.2.3.2 Neurotoxic Kunitz-Type Inhibitors
				19.2.3.3 Complex Formation
			19.2.4 Biomedical Research, Diagnostic and Therapeutic Use
				19.2.4.1 Neurotoxins for Biomedical Research
				19.2.4.2 Hemostasis, Antithrombotic and Anti-Fibrinolytic Agents
				19.2.4.3 Cancer
				19.2.4.4 Diagnostics for Determining Ion Channels Responsible for Diabetic Neuropathy
		19.3 Cystatins
			19.3.1 Snake Venom Cystatins
			19.3.2 Snake Serum Cystatin/Fetuins
		19.4 Conclusions
		References
	Chapter 20 Small Molecular Constituents of Snake Venoms
		20.1 Introduction: a Diversity of Small Compounds in Venoms
		20.2 Nucleosides
			20.2.1 Purine Novelties
		20.3 Neurotransmitters
			20.3.1 Acetylcholine
			20.3.2 γ-Aminobutyric Acid
		20.4 Amines and Alkaloids
			20.4.1 Glycine Betaine
			20.4.2 Taurine
		20.5 Carboxylic Acids
			20.5.1 Carboxylic Acids that Chelate Divalent Cations
			20.5.2 Itaconic and Cis-Aconitic Acids
			20.5.3 4-Guanidinobutyric Acid
			20.5.4 5-Guanidino-2-Oxopentanoic Acid
			20.5.5 Imidazole-4-Acetic Acid
			20.5.6 4-Hydroxyphenylacetic and 4-Hydroxyphenylpyruvic Acids
			20.5.7 Indole-3-Acrylic Acid
		20.6 Peptides
			20.6.1 Dipeptides
			20.6.2 Prolyl Dipeptides
			20.6.3 Pyroglutamyl Dipeptides
			20.6.4 Pyroglutamyl Tripeptides
			20.6.5 pEKW
			20.6.6 pENW
			20.6.7 pEKS
			20.6.8 pEPQ, pEGE, pERI, pERP, pE(NH), pESN, and pEND
			20.6.9 Tetrapeptides and Longer Oligopeptides
			20.6.10 TPPAGPDVGPR
		References
	Chapter 21 Cobra Venom Factor: Structure, Function, Biology, Research Tool, and Drug Lead
		21.1 Introduction
		21.2 Structure and Function of CVF and Its Similarity to Complement Component C3
			21.2.1 Structure of CVF
			21.2.2 The CVF-Dependent C3/C5 Convertase: Similarities to and Differences from the C3b-Dependent Convertase
		21.3 Complement Depletion by CVF
			21.3.1 CVF: An Experimental Tool to Study Complement Function
		21.4 Antibody Conjugates with CVF: Tools for Targeted Complement Activation
		21.5 Why Is CVF in Cobra Venom?
		21.6 Recombinant CVF
		21.7 Hybrid Proteins of CVF and C3: Tools to Study The Structure/Function Relationship of CVF and C3
		21.8 Hybrid Proteins of CVF and Human C3: A Novel Experimental Tool for Therapeutic Complement Depletion
			21.8.1 Lack of Toxicity of Complement Depletion with hCVF
			21.8.2 Immunogenicity of hCVF
		21.9 Conclusions
		21.10 Epilogue
		Acknowledgments
		References
	Chapter 22 Snake Toxins Targeting Diverse Ion Channels
		22.1 Introduction
		22.2 MitTx: A Potent Heterodimer Toxin Activating ASICs
		22.3 Mambalgins: ASICs Inhibitors Promoting Analgesia
		22.4 MmTx1,2: Selective GABAA Modulators
		22.5 Calliotoxin: An NaV Potentiator Producing Spastic Paralysis
		22.6 BomoTx: Indirect Activator of Pain Receptors
		22.7 Conclusions
		References
Section IV Reptile Venom Enzyme Toxins
	Chapter 23 Thrombin-Like Serine Proteinases in Reptile Venoms
		23.1 Introduction
		23.2 Classification and Catalytic Mechanism
		23.3 Biological Activity
		23.4 Structure–Function Relationships
		23.5 Inhibition
		23.6 Isolation and Characterization
		23.7 Therapeutic Uses
		23.8 Diagnostic Applications
		23.9 Conclusions
		References
	Chapter 24 Snake Venom Metalloproteinases
		24.1 Introduction
		24.2 Origin and Evolution
		24.3 Domain Structure and Classification
		24.4 Biological Functions
			24.4.1 P-III SVMPs
			24.4.2 P-II SVMPs
			24.4.3 P-I SVMPs
		24.5 Neutralization of SVMPs
		References
	Chapter 25 Snake Venom Matrix Metalloproteinases (svMMPs): Alternative Proteolytic Enzymes in Rear-Fanged Snake Venoms
		25.1 Introduction: Discovering the svMMPs
		25.2 svMMPs As a Major Venom Component of Certain Xenodontinae Groups
		25.3 Structural Features of svMMPs
		25.4 Origin and Evolution of svMMPs
		25.5 Activities and Predicted Function of svMMPs
		25.6 Conclusions
		References
	Chapter 26 Snake Venom Phospholipase A2 Toxins
		26.1 Introduction
		26.2 Classification and General Properties of Venom Phospholipases A2
			26.2.1 Structural Groups of Venom Phospholipases A2
			26.2.2 Structure and Catalytic Activity of Snake Venom Secreted Phospholipases A2
			26.2.3 Catalytically Inactive Secreted Phospholipase A2 Variants of Snake Venoms
			26.2.4 Evolution of Snake Venom Secreted Phospholipases A2
		26.3 Bioactivities of Snake Venom Secreted Phospholipases A2
			26.3.1 Diversity of Snake Venom Secreted Phospholipase A2 Bioactivities
			26.3.2 Neurotoxic Action of Snake Venom Secreted Phospholipases A2
				26.3.2.1 Pre-Synaptically Neurotoxic sPLA2s
				26.3.2.2 Post-Synaptically Neurotoxic sPLA2s
			26.3.3 Myotoxic Action of Snake Venom Secreted Phospholipases A2
			26.3.4 Inflammatory Action of Snake Venom Secreted Phospholipases A2
				26.3.4.1 Catalytic Activity–Dependent Action
				26.3.4.2 Catalytic Activity–Independent Action
			26.3.5 Action of Snake Venom Secreted Phospholipases A2 on Hemostasis
				26.3.5.1 Catalytic Activity–Dependent Action
				26.3.5.2 Catalytic Activity–Independent Action
		26.4 Receptors for Snake Venom Secreted Phospholipases A2
			26.4.1 Integral Membrane Secreted Phospholipase A2-Binding Proteins
			26.4.2 Soluble Secreted Phospholipase A2-Binding Proteins
		26.5 Concluding Remarks
		Acknowledgments
		References
	Chapter 27 Reptile Venom L-Amino Acid Oxidases – Structure and Function
		27.1 Introduction
		27.2 L-Amino Acid Oxidases
		27.3 Biochemical Characterization of L-Amino Acid Oxidases
		27.4 Biological Properties of SV-LAAOs
			27.4.1 Antimicrobial Effects
			27.4.2 Antiparasitic Effects
			27.4.3 Antiviral Effects
			27.4.4 Apoptosis-Inducing Activities
			27.4.5 Platelet Aggregation
			27.4.6 Inflammatory Activities
		27.5 Conclusions
		References
	Chapter 28 Snake Venom Nucleases, Nucleotidases and Phosphomonoesterases
		28.1 Introduction
		28.2 Nucleases
			28.2.1 DNases (EC 3.1.21.1)
			28.2.2 RNases (E.C. 3.1.21.-)
			28.2.3 Phosphodiesterase (EC. 3.1.4.1)
		28.3 Nucleotidases
			28.3.1 5′-Nucleotidases (E.C. 3.1.3.5)
			28.3.2 ATPases (EC 3.6.1.-)
			28.3.3 ADPases (EC 3.6.1.-)
			28.3.4 Apyrases
		28.4 Phosphomonoesterases
		28.5 Conclusions
		Acknowledgments
		References
	Chapter 29 Reptile Venom Acetylcholinesterases
		29.1 Introduction
			29.1.1 Acetylcholine
			29.1.2 Acetylcholinesterase
			29.1.3 Snake Families Producing Venom Acetylcholinesterase
		29.2 Acetylcholinesterase Structure
			29.2.1 Acetylcholine Hydrolysis Mechanism
			29.2.2 Isoelectric Points and Molecular Weights of Venom Acetylcholinesterases
		29.3 Biochemical and Enzymatic Characteristics
			29.3.1 Turnover Numbers of Acetylcholinesterases
			29.3.2 Acetylcholinesterase Inhibition
			29.3.3 Toxicity of Venom Acetylcholinesterases
			29.3.4 Functional Roles of Residues 70 and 285
			29.3.5 Sequence Similarity of Snake Venom and other Acetylcholinesterases
		29.4 Conclusions
		References
	Chapter 30 Inhibitors of Reptile Venom Toxins
		30.1 Introduction
		30.2 Snake Venom Metalloproteinases (SVMPs)
		30.3 SVMP Inhibitors
			30.3.1 Immunoglobulin Superfamily
			30.3.2 DM 43 – Structural Features
			30.3.3 Cystatin Superfamily
			30.3.4 Ficolin/Opsonin P35 Family
			30.3.5 Indeterminate Protein Family
			30.3.6 SVMP Peptide Inhibitors
		30.4 Snake Venom Phospholipases A2
		30.5 Endogenous Inhibitors of Snake Venom PLA2s
			30.5.1 α-type PLIs
			30.5.2 β-type PLIs
			30.5.3 γ-type PLIs
		References
Section V Global Approaches to Envenomations and Treatments
	Chapter 31 Snakebite Envenomation as a Neglected Tropical Disease: New Impetus for Confronting an Old Scourge
		31.1 Introduction
		31.2 The Global Landscape of Snakebite Envenomation
			31.2.1 A Heavy Burden of Incidence and Mortality
			31.2.2 Snakebite Envenomations Mainly Affect Impoverished Populations
			31.2.3 Beyond Mortality: Snakebite Envenomation as an Expanding Wave of Social Suffering
			31.2.4 Snakebite Envenomation from a “One Health” Perspective
			31.2.5 Antivenoms Are Effective Therapeutic Tools, But There Are Limitations in Their Availability and Accessibility
		31.3 Why Is Snakebite Envenomation a Neglected Tropical Disease?
		31.4 The Long Road to Recognition of the Impact Of Snakebite Envenomations
		31.5 The WHO Strategy for Prevention and Control of Snakebite Envenomation
			31.5.1 Empower and Engage Communities
			31.5.2 Ensure Safe, Effective Treatments
			31.5.3 Strengthen Health Systems
			31.5.4 Increase Partnerships, Coordination and Resources
			31.5.5 Phases and Costs for Implementing the WHO Strategy
		31.6 Conclusions: A Unique Opportunity to Reduce the Burden of Snakebite Envenomation on a Global Basis
		Acknowledgments
		References
	Chapter 32 Current Industrial Production of Snake Antivenoms
		32.1 Introduction
		32.2 Quality Assurance In Antivenom Manufacture: Patients Come First
		32.3 The Antivenom Life Cycle Starts with the Preparation of a Venom Pool
			32.3.1 Establishment and Maintenance of a Venomous Snake Collection
			32.3.2 Venom Pools Production
		32.4 Immunization of Animals with Snake Venom for Hyperimmune Plasma Production
			32.4.1 Management of Plasma Donor Animals
			32.4.2 Immunization Strategies for Boosting Animals’ Immune Response
			32.4.3 Hyperimmune Plasma Collection
		32.5 How Hyperimmune Plasma Is Converted into Purified Antivenom Vials
			32.5.1 Current Downstream Processing for Antivenom Purification
			32.5.2 Technological Platforms for Antivenom Purification
				32.5.2.1 Fractional Precipitation
				32.5.2.2 Enzymatic Digestion
				32.5.2.3 Chromatography
				32.5.2.4 Recent Approaches for Antivenom Purification
			32.5.3 Separation Technologies for Handling Solid-Liquid Mixtures During Purification
			32.5.4 Formulation and Stabilization of Antivenoms
			32.5.5 Pathogen Safety of Antivenoms
		32.6 In-Process and Final Quality Control of Antivenoms
			32.6.1 Preclinical Evaluation of Antivenoms
			32.6.2 Animal Models in Antivenom Quality Assessment
				32.6.2.1 Mouse Model
				32.6.2.2 Rabbit Model
				32.6.2.3 Ethical Use of Animal Models
			32.6.3 Stability Studies of Antivenoms
		32.7 The Issue of Antivenom Distribution and Availability
		32.8 Future Perspectives on Antivenom Supply Sustainability
		Acknowledgments
		References
	Chapter 33 Antivenom in the Age of Recombinant DNA Technology
		33.1 Introduction: Antivenoms Entering the Field of Biotechnology
		33.2 Snake Venom Toxins as Targets for Monoclonal Antibodies
		33.3 Design Principles for Recombinant Antivenoms
		33.4 Manufacturing Principles for Recombinant Antivenoms
		33.5 Recent Progress in the Development of Recombinant Antivenoms
		33.6 The Road Ahead for Recombinant Antivenoms
		Acknowledgments
		References
	Chapter 34 Epidemiology and Treatment of Reptile Envenomations in the United States
		34.1 Introduction
		34.2 Venomous Reptiles and Envenomation in the United States
			34.2.1 Crotalinae: North American Pitvipers (Agkistrodon, Crotalus, Sistrurus) – Copperheads, Cottonmouths and Rattlesnakes
			34.2.2 Elapidae (Micrurus fulvius, M. tener, Micruroides euryxanthus) – Coral Snakes
			34.2.3 Colubrid Snakes
			34.2.4 Exotic, Non-Native Venomous Snakes
			34.2.5 Venomous Lizard – Gila Monster (Heloderma suspectum)
		34.3 Epidemiology of Reptile Envenomation in the United States
			34.3.1 Background History of Snakebite Epidemiology
			34.3.2 Snakebite Envenomation in the United States
			34.3.3 Gila Monster Envenomation in the United States
			34.3.4 Occupational Snakebites
			34.3.5 Intoxication with Alcohol or Drugs and Snakebite
			34.3.6 Dry Bites
			34.3.7 Snakebite Mortality in the United States
			34.3.8 Envenomation by Dead Snakes
		34.4 Antivenoms in the United States
			34.4.1 Pitviper Antivenoms
			34.4.2 Coral Snake Antivenom
		34.5 Medical Management of Envenomed Patients
			34.5.1 Pitviper Envenomation Medical Management
				34.5.1.1 First Aid and Pre-Hospital Management
				34.5.1.2 Emergency Department Management
				34.5.1.3 Hospital Management
				34.5.1.4 Follow-Up
				34.5.1.5 Pitviper Envenomation and Surgery (Compartment Syndrome)
			34.5.2 Coral Snake Medical Management
			34.5.3 Gila Monster Medical Treatment
		34.6 Toxicology/Toxinology Consultations
		34.7 The Future of Snakebite Medical Treatment
		References
	Chapter 35 Envenomations by Reptiles in Mexico
		35.1 Introduction
		35.2 Epidemiology of Snakebite in Mexico
		35.3 Venomous Reptiles in Mexico
			35.3.1 Viperidae
			35.3.2 Elapidae
			35.3.3 Helodermatidae
		35.4 Mexican Antivenoms
		35.5 Mexican Viper Venoms and Envenomation
			35.5.1 Intraspecific Variation of Viper Venoms
				35.5.1.1 Ontogenetic Variation of Viper Venoms
			35.5.2 Neurotoxic Components of Viper Venoms
			35.5.3 Clinical Cases of Viper Envenomation
			35.5.4 Clinical Cases Caused by C. atrox
		35.6 Mexican Elapid Venoms and Envenomation
			35.6.1 Mexican Coral Snake Venoms
			35.6.2 Clinical Case of Envenomation by M. tener from Tamaulipas, Mexico
		Acknowledgments
		References
	Chapter 36 Snakebite Envenomation in Central America: Epidemiology, Pathophysiology and Treatment
		36.1 Introduction: The Venomous Snakes of Central America
		36.2 Epidemiology
		36.3 Patho-Physiology and Clinical Aspects of Snakebite Envenomation in Central America
			36.3.1 General Considerations
			36.3.2 Envenomations by Species of the Family Elapidae
			36.3.3 Envenomations by Species of the Family Viperidae
				36.3.3.1 Local Effects
				36.3.3.2 Systemic Effects
			36.3.4 The Clinical Laboratory in Monitoring Snakebite Envenomation
			36.3.5 Assessment of the Severity of Envenomation
			36.3.6 Complications in Viperid Snakebite Envenomations
		36.4 Prevention of Snakebites
		36.5 Treatment of Snakebite Envenomation
			36.5.1 First Aid Interventions and Antivenom Use in the Field
			36.5.2 Management of Snakebite Envenomations in Health Centers
				36.5.2.1 Diagnosis and First Interventions
				36.5.2.2 Antivenom Administration
				36.5.2.3 Additional Doses of Antivenom
				36.5.2.4 Ancillary Therapeutic Interventions
		36.6 Concluding Remarks: Reducing the Impact of Snakebite Envenomations in Central America Demands Interventions at Various Levels
		Acknowledgments
		References
	Chapter 37 Snakebite in Southeast Asia: Envenomation and Clinical Management
		37.1 Introduction
		37.2 Venom Properties of Southeast Asian Venomous Snakes
			37.2.1 Terrestrial Elapids
				37.2.1.1 Cobra (Naja spp.) Venoms
				37.2.1.2 King Cobra (Ophiophagus hannah) Venom
				37.2.1.3 Krait (Bungarus spp.) Venoms
				37.2.1.4 Coral Snake (Calliophis spp.) Venoms
			37.2.2 Marine Elapids
			37.2.3 Overview of Southeast Asian Elapid Venom Proteomes
			37.2.4 Viperidae: Crotalinae (Pitvipers)
			37.2.5 Viperidae: Viperinae (True Vipers)
			37.2.6 Colubridae – Rear-Fanged Venomous Snakes
		37.3 Epidemiology of Snakebite in Southeast Asia
		37.4 Overview of the Management Of Envenomation
			37.4.1 Pre-Hospital Care and First Aid
			37.4.2 History, Physical Examination and Investigation
			37.4.3 Diagnosis
			37.4.4 Specific and Non-specific Treatment
			37.4.5 Antivenom Use and Hypersensitivity Reaction
			37.4.6 Discharge and Further Management
		37.5 Clinical Effects and Management of Envenomation by Important Dangerous Snakes
			37.5.1 Cobras and King Cobra
			37.5.2 Kraits
			37.5.3 Seasnakes
			37.5.4 Pitvipers
			37.5.5 Russell’s Viper
			37.5.6 Other Species
		37.6 Conclusions and Future Directions
		Acknowledgment
		References
	Chapter 38 Snake Envenomation: Therapy and Challenges in India
		38.1 The Burden of Snakebite in India
		38.2 Venomous Snakes of India and the Concept of the “Big Four” Snakes
		38.3 A Brief Account of the Venom Composition of the “Big Four” Snakes of India
		38.4 Geographical Variation in Snake Venom Composition and Clinical Manifestations of Snake Envenomation in India
		38.5 Challenges and Progress of Snakebite Treatment in India
		38.6 Adverse Effects of Antivenom Therapy and Its Treatment
		38.7 Efficient Hospital Management of Snakebite in India: The Major Impediments and Progress
		38.8 Conclusions
		Acknowledgments
		References
	Chapter 39 Snakebite in Africa: Current Situation and Urgent Needs
		39.1 Introduction
		39.2 Individual and Snake Encounter Components
			39.2.1 Description of the Snake Fauna of Africa
			39.2.2 Human Activities Related to Snakebite Risk
			39.2.3 Epidemiology of Snakebites
				39.2.3.1 Surveys in Health Centers
				39.2.3.2 Household Surveys
				39.2.3.3 Therapeutic Choice and Treatment of Snakebites
				39.2.3.4 At-Risk Populations
				39.2.3.5 Evaluation of Therapeutic Needs
		39.3 Clinics and Treatment of Envenomations
			39.3.1 Symptoms
				39.3.1.1 Clinical Heterogeneity of Envenomations
				39.3.1.2 Elapid Envenomations
				39.3.1.3 Viper Envenomations
			39.3.2 Treatment of Envenomation
			39.3.3 Logistical and Socio-Economic Aspects
		39.4 A Proposal for a Plan of Action
			39.4.1 Defining AV Quality Standards
				39.4.1.1 Effectiveness
				39.4.1.2 Safety
				39.4.1.3 Stability
				39.4.1.4 Accessibility
			39.4.2 Identifying At-Risk Populations
			39.4.3 Ensuring a Supply of AVs
			39.4.4 Health Personnel Training
			39.4.5 Information to the Public
			39.4.6 WHO Strategy
		39.5 Conclusions
		References
	Chapter 40 Approaches to Snake Envenomation in Southern Africa
		40.1 Introduction
		40.2 Antivenom in Southern Africa
		40.3 Syndromic Approach to Snake Envenomations
			40.3.1 Syndromic Management: Painful Progressive Swelling
			40.3.2 Syndromic Management: Progressive Weakness
			40.3.3 Syndromic Management: Coagulopathy with Bleeding
			40.3.4 Syndromic Management: Acute Venom-Induced Anaphylaxis
		40.4 Method of Antivenom Administration
		40.5 Identifying the Snake
		40.6 Surgery in the Management of Snake Bites
		40.7 Conclusions
		References
Section VI Reptile Venoms – Production and as a Source of Therapeutics
	Chapter 41 Large-Scale Snake Colonies for Venom Production: Considerations and Challenges
		41.1 Introduction
		41.2 Legal Considerations
		41.3 Ethics
		41.4 Animal Acquisition
			41.4.1 Wild Capture
			41.4.2 Captive Sourced
			41.4.3 Catch and Release
			41.3.4 Quarantine
		41.5 Husbandry
			41.5.1 Personnel
			41.5.2 Tools and Equipment
			41.5.3 General Facility Considerations
			41.5.4 Caging
			41.5.5 Cleaning
			41.5.6 Feeding
			41.5.7 Breeding
			41.5.8 Veterinary Care
			41.5.9 Record-Keeping
		41.6 Venom Extractions
			41.6.1 Restraint Techniques
			41.6.2 Extraction and Frequency
			41.6.3 Venom Handling and Storage
		41.7 Conclusions
		References
	Chapter 42 Toxins to Drugs – Biochemistry and Pharmacology
		42.1 Introduction
			42.1.1 Animal Venoms
			42.1.2 Reptile Venoms
			42.1.3 History of Venoms in Medicine
		42.2 Toxins as Drug Templates
			42.2.1 Evolutionary Aspects
			42.2.2 Biochemistry
			42.2.3 Pharmacology
		42.3 Medical Uses of Reptile Venom Toxins
			42.3.1 Therapeutics
			42.3.2 Diagnostics
			42.3.3 Other Biomedical Applications
			42.3.4 Drugs in Clinical Stage Development
		42.4 Medical Potential of Animal Venoms
		References
Index