Venoms to Drugs

Venom as a Source for the Development of Human Therapeutics

Glenn F. King

• Publisher: Royal Society of Chemistry
• Year: 2015
• Edition: 1
• eBook ISBN:
  9781782624370
• Topic: Biological Sciences
• Subtopic: Biochemistry
• Index: Biological Sciences

The pharmaceutical industry has become increasingly interested in biologics from animal venoms as a potential source for therapeutic agents in recent years, with a particularly emphasis on peptides. To date six drugs derived from venom peptides or proteins have been approved by the FDA, with nine further agents currently being investigated in clinical trials. In addition to these drugs in approved or advanced stages of development, many more peptides and proteins are being studied in varying stages of preclinical development. This unique book provides an up to date and comprehensive account of the potential of peptides and proteins from animal venoms as possible therapeutics. Topics covered include chemistry and structural biology of animal venoms, proteomic and transcriptomic approaches to drug discovery, bioassays, high-throughput screens and target identification, and reptile, scorpion, spider and cone snail venoms as a platform for drug development. Case studies are used to illustrate methods and successes and highlight issues surrounding administration and other important lessons that have been learnt from the development of approved therapeutics based on venoms. The first text to focus on this fascinating area and bridging an important gap, this book provides the reader with essential and current knowledge on this fast-developing area. Venoms to Drugs will find wide readership with researchers working in academia and industry working in all medicinal and pharmaceutical areas.

CHAPTER 1

Seeing the Woods for the Trees: Understanding Venom Evolution as a Guide for Biodiscovery

BRYAN G. FRY*^a,b, IVAN KOLUDAROV^a, TIMOTHY N. W. JACKSON^a,b, MANDË HOLFORD^c, YVES TERRAT^d, NICHOLAS R. CASEWELL^e, EIVIND A. B. UNDHEIM^a,b, IRINA VETTER^b, SYED A. ALI^a,b,f, DOLYCE H. W. LOW^a, AND KARTIK SUNAGAR^g,h

^aVenom Evolution Lab, School of Biological Sciences, The University of Queensland, St. Lucia, Queensland 4072, Australia; ^bInstitute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland 4072, Australia; ^cThe City University of New York-Hunter College & CUNY Graduate Center and The American Museum of Natural History, New York, New York, USA; ^dMontréal University, Research Institute in Plant Biology, Montreal Botanical Garden, Montreal, Québec, Canada; ^eAlistair Reid Venom Research Unit, Liverpool School of Tropical Medicine, Liverpool L3 5QA, UK; ^fHEJ Research Institute of Chemistry, International Center for Chemical and Biological Sciences (ICCBS), University of Karachi, Karachi 75270, Pakistan; ^gCIMAR/CIIMAR, Centro Interdisciplinar de Investigação Marinha e Ambiental, Universidade do Porto, Rua dos Bragas, 177, 4050-123 Porto, Portugal; ^hDepartamento de Biologia, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre, 4169-007 Porto, Portugal
*E-mail: [email protected]

1.1 The Fundamental Problems

The majority of commercial drugs being used today in both developed and developing countries are based on natural products.¹ Most of these products are based upon plants, but research into animal venoms holds great potential for the discovery of novel medicinally useful natural products.^2,3 Knowledge of the evolutionary origins of venom proteins/peptides and the forces shaping the biodiversity seen today is crucial for efficient biodiscovery. In addition, efficient utilisation of venom toxins in drug design and development cannot be achieved without recognition of the true biochemical, ecological, morphological, and pharmacological diversity of venoms and associated venom systems. A major limitation of the use of venom proteins thus far has been the very narrow taxonomical range studied. Entire groups of venomous animals remain virtually ignored. Those that have been examined have apparently been selected due to their medical significance or ease of collection, rather than as a result of their ecological or evolutionary uniqueness.

Venom is defined as “a secretion, produced in a specialised gland in one animal and delivered to a target animal through the infliction of a wound (regardless of how tiny it may be), which contains molecules that disrupt normal physiological or biochemical processes in the victim so as to facilitate feeding or defence by the producing animal”.⁴ This definition encompasses creatures normally considered venomous (e.g., scorpions, snakes, and spiders) as well as animals that have not been traditionally recognised as such (e.g., leeches, ticks, and vampire bats). Acknowledgement of the evolutionary analogy of the recruitment and use of toxins in all these animals increases the number of known independent occasions in which venom has evolved independently. In addition, this acknowledgement improves our understanding of the factors underlying the evolution of venoms and their associated proteins while also drawing attention to the vast pool of unstudied toxins. Venom has been a key innovation in the evolutionary history of an incredibly diverse range of animals. Even using the traditional definition of venom, venom systems are believed to have evolved independently on at least 20 occasions in extant lineages (Figure 1.1). Intriguing fossil evidence has also led to speculation about the possibility of extinct venomous lineages represented by the theropod dinosaur Sinornithosaurus⁵ and the extinct pantolestid mammal Bisonalveus browni.⁵ If lineages such as ticks, leeches, vampire bats, etc. are rightfully recognised as venomous, the number of independent evolutionary events in which venom has arisen increases to over 30.

Figure 1.1 Schematic tree of venomous life in the animal kingdom. Coloured branches indicate lineages that include members with venom systems. Phylogeny based on the tree of life presented in Pennisi.¹⁴⁵ Note that a number of animal lineages have been pruned from the tree. Adapted from ref. 34.

The evolutionary selection pressure upon defensive venoms (e.g., those of fish and bees) is largely directed at the development of streamlined venom that has the primary action of immediate, intense localised pain.^6–8 In contrast, predatory venoms are shaped by a classic co-evolutionary arms race, where evolving venom resistance in prey and the evolution of novel venom composition exerts reciprocal selective pressures on one another in a situation that conforms to the Red Queen hypothesis of Van Valen.⁹ Powerful purifying selection pressures acting on predatory venoms for millions of years have resulted in highly complex modern venom arsenals that consist of potent compounds with exquisite target specificity. Variation in venom composition is not only observed between different lineages, but also between the closely related species within a clade.¹⁰ Intraclade differences in venom composition often arise as a result of the evolution of prey-specific toxins in species with specialised diets.^11–13 Significant variation in venom profile has even been demonstrated within individual species with widespread geographical distributions.^14,15 Venom can also vary intraspecifically as the result of numerous other factors, including sibling differences¹⁶ and ontogenic changes in prey preference¹⁷ or behaviour. In Sydney funnel-web spiders (Atrax robustus), juvenile male spiders and female spiders of all ages have similar insecticidal predatory venoms, whilst sexually mature males (who stop feeding and leave the burrows in search of females) have a vertebrate-specific defensive venom.¹⁸ It is this adaptive complexity and innovation that makes predatory venoms ideal candidates for the discovery of therapeutic lead compounds.

The majority of venom components have evolved to target physiological systems reachable by the bloodstream. In particular, the neurological and haemostatic systems have been convergently targeted via a myriad of innovative pathways (Figure 1.2).⁴ A consistent feature of venom proteins is a stable molecular scaffold of cross-linked cysteines¹⁹ (see Chapter 2 for further details of disulfide-rich toxin scaffolds); this characteristic appears to facilitate modification of non-structural residues, which in turn facilitates protein neo-/sub-functionalisation. A remarkable degree of convergence exists not only in terms of toxin molecular scaffolding, but also in target specificity and bioactivity.⁴ The superimposition of sequences from functionally convergent toxins reveals tremendously useful information regarding structure–function r...

Table of contents

• Cover image
• Title page
• Copyright
• Preface
• Contents
• Chapter 1 Seeing the Woods for the Trees: Understanding Venom Evolution as a Guide for Biodiscovery
• Chapter 2 The Structural Universe of Disulfide-Rich Venom Peptides
• Chapter 3 Venoms-Based Drug Discovery: Proteomic and Transcriptomic Approaches
• Chapter 4 Venoms-Based Drug Discovery: Bioassays, Electrophysiology, High-Throughput Screens and Target Identification
• Chapter 5 Reptile Venoms as a Platform for Drug Development
• Chapter 6 The Molecular Diversity of Conoidean Venom Peptides and their Targets: From Basic Research to Therapeutic Applications
• Chapter 7 Scorpion Venoms as a Platform for Drug Development
• Chapter 8 Therapeutic Applications of Spider-Venom Peptides
• Chapter 9 Case Study 1: Development of the Analgesic Drugs Prialt® and Xen2174 from Cone Snail Venoms
• Chapter 10 Case Study 2: Transforming a Toxin into a Therapeutic: the Sea Anemone Potassium Channel Blocker ShK Toxin for Treatment of Autoimmune Diseases
• Chapter 11 Engineering Venom Peptides to Improve Their Stability and Bioavailability
• Chapter 12 Manufacturing of Venom-Derived Therapeutic Peptides
• Subject Index