Cyclic Peptide Synthesis and Biological Applications

Cyclic peptides are macrocyclic molecules in which the N- and C-termini or side chains of amino acids are covalently linked to form a ring, conferring enhanced conformational rigidity, proteolytic stability and membrane permeability relative to their linear counterparts. Synthetic approaches encompass solid-phase and solution-phase methodologies, including macrocyclisation via head-to-tail or side-chain cyclisation, ring-closing metathesis and native chemical ligation. Mechanochemical methods and solvent-free protocols have emerged as sustainable alternatives, enabling control over stereochemistry and ring size. These synthetic advances have facilitated the rapid assembly of diverse macrocyclic libraries for screening against protein–protein interactions, enzymes and membrane receptors. In the biological realm, cyclic peptides serve as antibiotics, immunosuppressants, enzyme inhibitors and receptor modulators. Examples such as somatostatin analogues, cyclic tetrapeptides targeting histone deacetylases and peptide antibiotics illustrate the capacity of constrained backbones to enhance affinity and selectivity. Continued progress in cyclisation chemistries, stereochemical control and high-throughput screening is driving the translation of cyclic peptide scaffolds into therapeutic modalities and diagnostic probes.

Research from Nature Portfolio

A novel mechanochemical protocol employing ball-mill synthesis has been shown to yield cyclic tetrapeptides in homochiral and heterochiral forms without bulk solvents. Single-crystal X-ray diffraction and variable-temperature NMR reveal distinct conformational ensembles in different solvents, while density functional theory calculations map their energy landscapes. These cyclic tetrapeptides exhibit selective docking profiles against histone deacetylase 8 and demonstrate non-toxic behaviour in preliminary cytotoxicity assays, highlighting the potential of solvent-free cyclisation for rapid exploration of chirality–activity relationships.

Cyclic Peptide Synthesis and Biological Applications publication trend

The graph below shows the total number of articles in cyclic peptide synthesis and biological applications across all publications each year (not limited to Nature Index journals).

Technical terms

Macrocyclisation: Intramolecular cyclisation step forming the peptide ring, enhancing rigidity and metabolic stability.

Solid-phase peptide synthesis (SPPS): Sequential assembly of protected amino acids on a resin support, allowing efficient chain elongation and cyclisation.

Non-ribosomal peptide synthesis (NRPS): Enzymatic assembly of peptides independent of ribosomes, incorporating non-proteinogenic amino acids and modifications.

Marfey’s method: Chiral derivatisation of amino acids followed by liquid chromatography to determine absolute configuration.

Electrospray high-resolution tandem mass spectrometry (ESI-HRMS/MS): Analytical technique that fragments cationised peptides to obtain high-accuracy mass data for sequencing.

Mechanochemical synthesis: Solvent-free chemical reactions driven by mechanical forces, such as ball milling, to promote bond formation.

References

1. Origin and characterization of cyclodepsipeptides: Comprehensive structural approaches with focus on mass spectrometry analysis of alkali‐cationized molecular species. Mass Spectrometry Reviews (2024).
2. Occurrence of D-amino acids in natural products. Natural Products and Bioprospecting (2023).
3. Absolute Stereochemistry Determination of Bioactive Marine-Derived Cyclopeptides by Liquid Chromatography Methods: An Update Review (2018–2022). Molecules (2023).
4. Influence of heterochirality on the structure, dynamics, biological properties of cyclic(PFPF) tetrapeptides obtained by solvent-free ball mill mechanosynthesis. Scientific Reports (2024).