Strategies for transitioning macrocyclic peptides to cell-permeable drug leads

- Peptides are a highly versatile class of promising drug candidates.
- Peptides can be both passively and actively cell permeable.
- It is now possible to develop cell permeable peptides.
- Artificial amino acid incorporation contributes to more drug-like peptides.
- Optimisation of sequences can enhance protease resistance and residence time.

The ready availability of potent peptide binders for any desired target highlights their potential impact as therapeutic agents. Despite their versatility, however, peptides tend to display unfavourable pharmacological properties, such as low bioavailability, high renal clearance and proteolytic degradation rates, and low cell permeability. Fortunately, an increasing number of promising strategies to produce novel peptides and furnish pre-existing scaffolds with more drug-like properties are now becoming available. These strategies include incorporation of non-proteinogenic amino acids, tag appendage to existing peptides and grafting onto scaffolds already possessing desirable pharmacokinetic properties. As a consequence, a variety of promising bioactive macrocyclic peptides have recently been discovered highlighting the promise of this class of molecules as future medicines.

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