Form and function in cyclic peptide natural products: a pharmacokinetic perspective

Area of Science:

• Natural Product Chemistry
• Medicinal Chemistry
• Pharmacology

Background:

• Natural products, especially cyclic peptides, possess complex structures distinct from synthetic drugs.
• These molecules can access biological targets beyond conventional enzyme active sites and receptors.
• Many cyclic peptides exhibit cell permeability via passive diffusion and some are orally bioavailable, like cyclosporine A.

Purpose of the Study:

• To review cyclic peptide natural products from a structure-pharmacokinetic (PK) perspective.
• To identify knowledge gaps regarding the structure-PK relationships of cyclic peptides.
• To explore the potential of cyclic peptides as scaffolds for modulating challenging biological targets, such as protein-protein interactions.

Main Methods:

• Literature review focusing on the structural properties and pharmacokinetic behavior of cyclic peptides.
• Analysis of existing data on cell permeability and metabolic clearance for cyclic peptide natural products.
• Discussion of trends and challenges in understanding the 'drug-likeness' of these complex molecules.

Main Results:

• Cyclic peptides often fall outside traditional 'drug-likeness' parameters due to their size and complexity.
• Their unique structural features allow targeting of biological spaces inaccessible to conventional small molecules.
• Systematic studies on the relationship between cyclic peptide structure and PK properties, particularly oral bioavailability, are lacking.

Conclusions:

• Cyclic peptides represent a promising chemical space for drug discovery, offering potential for novel therapeutic agents.
• Understanding their structure-PK relationships is crucial for designing orally bioavailable and cell-penetrant cyclic peptide drugs.
• Further investigation is needed to fully leverage cyclic peptides for modulating difficult biological targets and creating 'rule-breaking' molecules.