Design and discovery of bioactive peptides and proteins in venomous animals

Novel toxins from Australia’s venomous creatures as a platform for drug discovery

Peptide chemistry has enormous potential to aid in the understanding of fundamental physiology. As a consequence, it is at the forefront of new drug development, and peptide drugs are emerging as new candidates for vast numbers of ailments.

Professor Paul Alewood said that one such ailment familiar to many of us is pain, in particular chronic neuropathic pain.

“There are very few drugs that have much effect on chronic pain,” said Professor Alewood.

“Although they tend to work well with acute and inflammatory pain, drugs like paracetamol, aspirin and morphine simply do not target the sensory nerves involved in chronic pain.”

Professor Alewood’s group focuses on the discovery and development of peptide drugs that target chronic pain, with a major source of inspiration coming from our local venomous creatures.

Research overview

“Venom from ‘dangerous’ marine animals like cone shells and sea snakes contains thousands of small complex peptides that target sensory nerve receptors, many of which are important in chronic pain transmission.

“The way animal venom affects human pain receptors on sensory nerves is helping us to identify new receptors. And molecules that target such receptors are prime candidates for drug development.”

While finding new pain drug candidates is the group’s primary focus, the nature of peptide toxins often leads to interesting molecules with potential to be used in fields such as inflammation, cardiology, infectious diseases and cancer.

“New technology is being developed to speed up the toxin discovery process.

"We’re calling the new approach venomics, which is integrating aspects of transcriptomics (gene sequencing), proteomics (mass spectrometry sequencing) and bioinformatics, to help interpret the data sets.

“Venomics has revolutionised the field by yielding the identity of thousands of novel peptide toxins within weeks, not years or decades,” said Professor Alewood.

Research projects

Many organisms including insects, snakes, spiders, molluscs, frogs, fish and some mammalian species have evolved venom as either a defence mechanism or as a primary weapon for the capture of their prey. The plethora of biologically active molecules that constitute venom is used to disrupt or control essential organ systems in the envenomed animal and most venomous species present an incredibly rich and yet untapped polypeptide (ie toxins) libraries – based on recent advance proteomic analyses in our labs we estimate that the cone snails alone have greater than 1,000,000 uncharacterised bioactive peptides called conotoxins.

These toxins possess highly conserved cysteine frameworks with multiple disulfide bonds that give rise to well-defined three-dimensional structures. Each venom is composed of a complex mixture of neurotoxins that target GPCRs, ion-channels, proteases and transporters that act in either the central or peripheral nervous systems. Their high degree of protease stability plus high potency combined with exquisite selectivity provides a valuable source of research tools for pharmacologists, neurochemists and physiologists, often with significant applications in drug discovery.

Importantly, next generation sequencing and advanced mass spectrometry have sped up the discovery process and we are well positioned to find new drug targets using high-throughput screening technologies that will enable us to understand the broad physiology and pharmacology of these peptidic molecules.

Our current research is focused on developing new chemistry to match the discovery and characterisation.

  • New methods using mass spectrometry and gene technology to accelerate discovery of toxin sequences
  • Discovery of peptide toxins that target specific pain receptors
  • New regioselective synthesis and selenochemistry to accelerate control of toxin folding
  • New fast and efficient chemistry to enhance the development of structure activity relationships
  • New cyclisation strategies to enhance toxin stability and drug delivery
  • Design and synthesis of water soluble fluorescent tags suitable for conjugation (eg using ‘click’ chemistry or metathesis) with appropriately tagged toxins
  • Development of therapeutic peptide dendrimers to understand Gut-CNS and pain signalling
  • Oxytocin and vasopressin research and development of lead molecules for breast cancer.

Research training opportunities

Research title: Venom peptides that target chronic pain

Summary of research interests: Our research focuses on identifying bioactive molecules from Australia’s venomous animals that have the potential to create drugs that will play important roles in finding treatments for chronic pain, heart disease, inflammation, irritable bowel syndrome, and breast cancer. Although venom peptides (also called toxins) when delivered by an animal sting or bite can have a devastating effect, many are useful in treating human disease and the potential to expand this class of new drugs is huge. Specifically, we are interested in the discovery and total synthesis of potent and selective venom peptides from Australia’s venomous animals; the chemical synthesis of proteins and bioactive peptides; the development of new synthetic and analytical chemistry; and protein structure and function.

Traineeships, honours and PhD projects include

  • Discovery and characterisation of new conotoxins that are likely to target human receptors involved in chronic pain
  • Determination of the structure-function relationships of natural and designed bioactive molecules including the discovery, isolation and characterisation of venom peptides from snakes, spiders, cone snails, platypus, ticks and scorpions, their role in human health and uncovering new pain pathways in chronic pain.

Contact: Professor Paul Alewood

+61 7 3346 2982

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Prof Paul Alewood

Professor Paul Alewood

Group Leader, Chemistry and Structural Biology Division
Investigator, Centre for Pain Research

  +61 7 3346 2982
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  • Mr Alun Jones

    Mass Spectrometry Facility Manager
    Institute for Molecular Bioscience