Discovery and optimization of peptide macrocycles

ABSTRACT

Introduction: Macrocyclic peptides are generally more resistant to proteolysis and often have higher potency than linear peptides and so they are excellent leads in drug design. Their study is significant because they offer potential as a new generation of drugs that are potent and specific, and thus might have fewer side effects than traditional small molecule drugs.

Areas covered: This article covers macrocyclic drug leads based on nature-derived cyclic peptides as well as synthetic cyclic peptides and close derivatives. The natural peptides include cyclotides, sunflower-derived peptides, theta-defensins and orbitides. Technologies to make engineered cyclic peptides covered here include cyclization via amino acid linkers, CLIPS, templates, and stapled peptides.

Expert opinion: Macrocyclic peptides are promising drug leads and several are in clinical trials. The authors believe they offer key advantages over traditional small molecule drugs, as well as some advantages over protein-based ‘biologics’ such as antibodies or growth factors. These include the ability to penetrate cells and attack intracellular targets such as protein-protein interactions as well as to hit extracellular targets. Some macrocyclic peptides such as cyclotides offer the potential for production in plants, thus reducing manufacture costs and potentially increasing opportunities for their distribution to developing countries at low cost.

KEYWORDS:

• Cyclic peptides
• cyclotides
• drug design
• kalata B1
• peptide macrocycles
• stapled peptides

Article highlights

• Naturally occurring cyclic peptides are ultra-stable and can be used as scaffolds for the delivery of introduced bioactive epitopes.

• Peptide macrocyclization is an effective strategy to enhance the pharmacological properties of bioactive peptides.

• Several alternative and complementary technologies exist to make peptide macrocycles.

• Some peptide macrocycles have the ability to penetrate cells to inhibit intracellular protein-protein interactions.

• The factors underlying the membrane-penetration mechanism(s) of peptides are still not well understood, but are being actively investigated.

• Several peptide macrocycles are now in Phase 1 and 2 clinical development.

This box summarizes key points contained in the article.

Acknowledgments

We thank Ashley Cooper for proof reading the manuscript.

Declaration of interest

The authors have 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

Work in our laboratory on peptide macrocycles is funded by grants from the Australian Research Council (ARC; DP150100443), the National Health and Medical Research Council (APP1084965), and a GlaxoSmithKline Award for Research Excellence. DJ Craik is an ARC Australian Laureate Fellow (FL150100146). AM White is grateful for financial support from an Australian Postgraduate Award and the E.M.A and M.C. Henker Postgraduate Medical Research Scholarship.