Cyclic peptides are emerging as one of the most promising classes of therapeutic agents due to their exceptional structural stability, enhanced cell permeability, and strong resistance to proteolytic degradation. These unique properties position them at the forefront of modern peptide drug development.

Core Advantages and Market Position of Cyclic Peptides

Compared with traditional linear peptides, cyclic peptides form a closed-ring structure through head-to-tail or side-chain cyclization. This rigid conformation improves target binding selectivity and affinity, while significantly enhancing metabolic stability by resisting enzymatic degradation.

As of May 2024, cyclic peptides account for 46% of the 105 approved therapeutic peptides worldwide, highlighting their growing dominance as a mainstream strategy in peptide drug research.

Diverse Origins: From Natural Discovery to Rational Design

Natural Sources

Cyclic peptides are widely found in nature, including:

• Plants: e.g., SFTI-1 from sunflower seeds
• Bacteria: e.g., Tyrocidine
• Marine organisms: sponges and cyanobacteria

Notably, cyclic peptides isolated from cyanobacteria exhibit antibacterial and antiviral activities. In addition, marine fungi-derived peptides such as Simplicilliumtide K have demonstrated potent activity against HSV-1.

New Biosynthetic Mechanisms

A groundbreaking study published in Nature Chemistry by a research team from Shanghai Jiao Tong University revealed that pseudo-kinases (e.g., TvaE) in bacteria can directly catalyze peptide cyclization, forming thioether crosslinks.

This discovery challenges the traditional view that pseudo-kinases lack catalytic function and opens new pathways for enzyme-mediated cyclic peptide synthesis.

Synthesis Technologies: From Time-Consuming to Rapid Manufacturing

Historically, complex synthesis limited the scalability of cyclic peptides. However, recent innovations are transforming the field:

Automated “Molecular Printing”

A team from Zhejiang University developed the CycloBot platform, combining intelligent automation with a diaminonicotinic acid linker.

• Reduces synthesis time from 4 days to 27 minutes
• Achieves yields up to 93%
• Enables high-throughput screening
• Identified antimicrobial cyclic peptides ~100× more potent than penicillin

Enzyme-Free Biochemical Production

A novel enzyme-free approach uses cyanation and intramolecular ammonolysis to generate seamless cyclic peptides (orbitides) directly from recombinant or natural proteins.

This method significantly lowers production costs and expands applications beyond pharmaceuticals into agriculture and materials science.

Screening and Discovery Platforms for Challenging Targets

mRNA Display Technology

mRNA display enables ultra-large libraries (up to 10¹⁵ variants) for high-throughput screening.

Recent research reported in Acta Pharmaceutica Sinica B demonstrated the integration of sulfonyl fluoride warheads into mRNA display, leading to the discovery of covalent cyclic peptides targeting Nectin-4. These were further developed into highly effective peptide-drug conjugates (PDCs).

DNA-Encoded Libraries (DEL)

A study published in JACS Au by researchers from the Shanghai Institute of Materia Medica constructed a cyclic peptide library of 100 million compounds.

Key findings include:

• Single cyclization strategies may produce false positives
• Cross-analysis using multiple cyclization methods significantly improves screening accuracy

Expanding Applications: From Functional Tags to Covalent Drugs

Affinity Tags

Cyclic peptides can function as molecular tags fused to proteins, supporting:

• Protein purification
• Intracellular delivery (e.g., cell-penetrating peptides)
• Enhanced biological activity

Covalent Therapeutics

Using reactions such as SuFEx (Sulfur Fluoride Exchange), cyclic peptides can form irreversible covalent bonds with target proteins, enabling highly specific and durable therapeutic effects.

Case Study: Macrocyclic Peptides Targeting PD-1/PD-L1

BMS-986189 is a macrocyclic peptide inhibitor of the PD-1/PD-L1 interaction, with an IC50 of 1.03 nM, demonstrating strong potential in cancer therapy.

• In preclinical studies (2 mg/kg, subcutaneous, single dose), it effectively inhibited signaling in L2987 lung cancer xenografts
• Maintained PD-L1 target engagement for up to 24 hours in PD-L1-positive tissues

Radiotracer Innovation: [18F]BMS-986229

Using copper-mediated click chemistry, researchers developed [18F]BMS-986229, a PET imaging tracer with picomolar affinity for PD-L1.

Key findings include:

• Binding ratio of 8:1 in PD-L1-positive vs. negative tumors
• >90% specific binding in NSCLC and primate spleen tissues
• High signal-to-noise ratio in PD-L1-positive tissues
• ~5× higher uptake in PD-L1-positive tumors vs. controls in mouse models
• Up to 97% target occupancy for PD-L1 inhibitors

Compared with antibody- or adnectin-based tracers, this macrocyclic peptide radioligand demonstrates superior imaging performance. Clinical studies are currently underway to evaluate its application in non-invasive PD-L1 expression assessment.

Conclusion

Cyclic peptides are rapidly reshaping the landscape of drug discovery. With advances in biosynthesis, automated production, and high-throughput screening, they are overcoming traditional limitations and unlocking new therapeutic possibilities.

From oncology to infectious diseases and beyond, cyclic peptides are poised to become a