Venoms to Drugs: Venom As a Source for the Development of Human Therapeutics
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Venoms to Drugs Venom as a Source for the Development of Human Therapeutics RSC Drug Discovery Series Editor-in-Chief: Professor David Thurston, King’s College, London, UK Series Editors: Professor David Rotella, Montclair State University, USA Professor Ana Martinez, Medicinal Chemistry Institute-CSIC, Madrid, Spain Dr David Fox, Vulpine Science and Learning, UK Advisor to the Board: Professor Robin Ganellin, University College London, UK Titles in the Series: 1: Metabolism, Pharmacokinetics and Toxicity of Functional Groups 2: Emerging Drugs and Targets for Alzheimer’s Disease; Volume 1 3: Emerging Drugs and Targets for Alzheimer’s Disease; Volume 2 4: Accounts in Drug Discovery 5: New Frontiers in Chemical Biology 6: Animal Models for Neurodegenerative Disease 7: Neurodegeneration 8: G Protein-Coupled Receptors 9: Pharmaceutical Process Development 10: Extracellular and Intracellular Signaling 11: New Synthetic Technologies in Medicinal Chemistry 12: New Horizons in Predictive Toxicology 13: Drug Design Strategies: Quantitative Approaches 14: Neglected Diseases and Drug Discovery 15: Biomedical Imaging 16: Pharmaceutical Salts and Cocrystals 17: Polyamine Drug Discovery 18: Proteinases as Drug Targets 19: Kinase Drug Discovery 20: Drug Design Strategies: Computational Techniques and Applications 21: Designing Multi-Target Drugs 22: Nanostructured Biomaterials for Overcoming Biological Barriers 23: Physico-Chemical and Computational Approaches to Drug Discovery 24: Biomarkers for Traumatic Brain Injury 25: Drug Discovery from Natural Products 26: Anti-Inammatory Drug Discovery 27: New Therapeutic Strategies for Type 2 Diabetes: Small Molecules 28: Drug Discovery for Psychiatric Disorders 29: Organic Chemistry of Drug Degradation 30: Computational Approaches to Nuclear Receptors 31: Traditional Chinese Medicine 32: Successful Strategies for the Discovery of Antiviral Drugs 33: Comprehensive Biomarker Discovery and Validation for Clinical Application 34: Emerging Drugs and Targets for Parkinson’s Disease 35: Pain Therapeutics; Current and Future Treatment Paradigms 36: Biotherapeutics: Recent Developments using Chemical and Molecular Biology 37: Inhibitors of Molecular Chaperones as Therapeutic Agents 38: Orphan Drugs and Rare Diseases 39: Ion Channel Drug Discovery 40: Macrocycles in Drug Discovery 41: Human-based Systems for Translational Research 42: Venoms to Drugs: Venom as a Source for the Development of Human Therapeutics How to obtain future titles on publication: A standing order plan is available for this series. A standing order will bring delivery of each new volume immediately on publication. For further information please contact: Book Sales Department, Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge, CB4 0WF, UK Telephone: +44 (0)1223 420066, Fax: +44 (0)1223 420247 Email: [email protected] Visit our website at www.rsc.org/books Venoms to Drugs Venom as a Source for the Development of Human Therapeutics Edited by Glenn F. King Institute for Molecular Bioscience, The University of Queensland, Australia Email: [email protected] RSC Drug Discovery Series No. 42 Print ISBN: 978-1-84973-663-3 PDF eISBN: 978-1-84973-787-6 ISSN: 2041-3203 A catalogue record for this book is available from the British Library © The Royal Society of Chemistry 2015 All rights reserved Apart from fair dealing for the purposes of research for non-commercial purposes or for private study, criticism or review, as permitted under the Copyright, Designs and Patents Act 1988 and the Copyright and Related Rights Regulations 2003, this publication may not be reproduced, stored or transmitted, in any form or by any means, without the prior permission in writing of The Royal Society of Chemistry or the copyright owner, or in the case of reproduction in accordance with the terms of licences issued by the Copyright Licensing Agency in the UK, or in accordance with the terms of the licences issued by the appropriate Reproduction Rights Organization outside the UK. Enquiries concerning reproduction outside the terms stated here should be sent to The Royal Society of Chemistry at the address printed on this page. The RSC is not responsible for individual opinions expressed in this work. The authors have sought to locate owners of all reproduced material not in their own possession and trust that no copyrights have been inadvertently infringed. Published by The Royal Society of Chemistry, Thomas Graham House, Science Park, Milton Road, Cambridge CB4 0WF, UK Registered Charity Number 207890 For further information see our web site at www.rsc.org Preface “You would do well to mark the various forms of the Viper.… And from the wound she makes there oozes a discharge like oil or, it may be, bloody or colourless, while the skin around starts up into a painful lump, oen greenish, now crimson, or again livid of aspect. At other times it engenders a mass of uid, and about the wound small pimples like blisters rise abbily from the skin, which looks scorched. And all around spread ulcers, some at a distance, others by the wound, emitting a dark blue poison; and over the whole body the piercing bane eats its way with acute inammation; and in the throat and about the uvula retchings following fast upon one another convulse the victim. The body is oppressed with failures of sense in every part, and forthwith in the limbs and loins is seated a burdening, dangerous weakness, and heavy darkness settles in the head”. From Theriaca by Nicander of Colophon, 2nd century BCE (Translation from the Greek poem by A.S.F. Gow and A.F. Scholeld) Humans have been simultaneously enthralled and terried by venomous animals for thousands of years. For some, the merest glimpse of a spider or snake provokes an irrational and debilitating fear. But for many the threat is all too real—venomous animals continue to have devastating effects on human populations, with an estimated 50 000 people dying each year from snake bite in India alone. Yet, strangely, and perhaps perversely, venomous animals have proved to be a source of life-saving drugs. Captopril, the rst blockbuster antihyper- tensive drug, was derived from a peptidic inhibitor of angiotensin-converting enzyme found in the venom of a Brazilian viper. Captopril has saved many more lives than this snake and its close relatives have killed in their millions of years on the planet. There are currently six FDA-approved drugs derived RSC Drug Discovery Series No. 42 Venoms to Drugs: Venom as a Source for the Development of Human Therapeutics Edited by Glenn F. King © The Royal Society of Chemistry 2015 Published by the Royal Society of Chemistry, www.rsc.org vii viii Preface from animal venoms, and they are used to treat a variety of ailments, including hypertension, diabetes, and chronic pain. Research into venoms as a potential source of therapeutics greatly inten- sied over the past decade, with much activity in both academia and the pharmaceutical industry. There are several reasons for this. The dwindling output of new molecular entities combined with the recent success of bio- logics led to renewed interest in natural sources, such as venoms, as a source of drug leads. Increasing patient acceptance of injectable therapies created a more conducive environment for the development of peptide and protein drugs. And nally, our improved understanding of the chemical and phar- macological complexity of animal venoms facilitated the development of more focussed screens to discover venom molecules with desired biological activity. As a result of this increased research activity, the current pipeline of venom-derived drugs is larger than ever, with several venom peptides currently undergoing clinical trials and many more in various stages of preclinical development. This book attempts to capture the current excitement and most important developments in the eld of venoms-based drug discovery. The book begins with an overview of the extant suite of venomous animals and their toxin repertoires before drilling down to detailed case studies and issues surrounding optimisation and manufacturing of venom-derived peptide drugs. Each venom has a specic ecological role, and therefore understanding the context in which a venom has evolved is important for focussing drug discovery efforts. It makes no sense, for example, to focus on neurotoxic spider venoms if one is seeking a drug that modulates blood pressure; hae- motoxic snake venoms are likely to be a better bet. Thus, the book begins with a comprehensive overview of venom evolution and how this relates to biodiscovery. Chapter 2 provides an overview of the diverse range of disulde-rich scaffolds found in animal venoms. These scaffolds have provided a robust structural framework for evolving peptides that are simultaneously potent, selective, and stable. Despite their potential for providing high target potency and selectivity, these disulde-rich scaffolds have an inherently high degree of chemical and pharmacological plasticity, thereby facilitating the design of analogues with greater potential for thera- peutic application. Chapters 3 and 4 review the wide range of approaches that can be used for venoms-based drug discovery, including recent developments in proteomics, transcriptomics, high-throughput target-based screens, and automated electrophysiology. In addition, the case is made for the power of more traditional bioassays using whole animals or isolated tissues. The complex venoms of reptiles, aquatic cone snails, scorpions, and spiders have evolved