Enhancing the therapeutic potential of peptide toxins

ABSTRACT

Introduction: Peptide toxins are potent and often exquisitely selective probes of the structure and function of ion channels and receptors, and as such are of significant interest to the pharmaceutical and biotech industries as both therapeutic leads and pharmacological tools. Their progression as clinical candidates, however, faces many of the challenges that are common to peptide drugs generally.

Areas covered: The attributes of peptide toxins as therapeutic leads are outlined, as well as some of the limiting factors that have hampered the clinical development of many promising candidates. Strategies to overcome or circumvent these limitations are described, and their applications to peptide toxins from cone snails, sea anemones and scorpions are exemplified.

Expert opinion: Peptide toxins have exceeded their promise as valuable pharmacological tools but have yet to yield the anticipated bounty of therapeutic leads. As the number of new peptides identified in venom transcriptomes and proteomes expands rapidly, screening approaches that capture those with genuine therapeutic potential are required, along with methods for enhancing the stability, pharmacokinetics and pharmacodynamics of these peptides.

KEYWORDS:

• Cone snail
• sea anemone
• scorpion
• proteolysis
• disulfide
• cyclisation
• PEGylation
• delivery
• pharmacokinetics
• pharmacodynamics

Article highlights

• As potent and often exquisitely selective ligands for ion channels and other receptors, peptide toxins are of significant interest to the pharmaceutical and biotech industries as therapeutic leads and pharmacological tools.

• Modifications are often required to achieve the desired target selectivity. These modifications can be achieved using structure-guided design, high-throughput screening or a combination of both.

• The progression of peptide toxins as clinical candidates faces many of the challenges that are common to peptide drugs generally, including disulfide scrambling, susceptibility to proteolysis, short plasma half-lives and lack of oral bioavailability.

• Strategies for overcoming or circumventing these potential limitations are illustrated for several peptide toxins, including cone snail toxins that block nicotinic acetylcholine receptors or voltage-gated sodium channels, as well as sea anemone and scorpion toxins that block the voltage-gated potassium channel Kv1.3 and are potential therapeutics for autoimmune diseases.

• Pharmacokinetic, pharmacodynamics and distribution studies are a key component of the development pipeline, and need to be engaged early on in the assessment of clinical potential.

• The venoms of marine and terrestrial organisms continue to yield novel and interesting peptides, and they remain highly promising as a source of future drug candidates. More efficient approaches are required for identifying genuine therapeutic leads from among the rapidly growing profusion of venom peptides.

This box summarizes key points contained in the article.

Acknowledgments

I thank my many outstanding collaborators, past and present, for their contributions to the progression of peptide toxins as therapeutics, some of which are described in this article. In particular, I would like to thank Mike Pennington and Nick Barlow for their helpful comments and suggestions and Eleanor Leung and Eric Tarcha for their assistance with figures.

Declaration of interest

This author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

The work from the author’s laboratory was supported by a fellowship from the Australian National Health and Medical Research Council and grants from the National Health and Medical Research Council (grant no.’s 1059060, 1042481 & 1093450) and Australian Research Council (grant no.’s LP120100414 & LP150100621).