PeptideJournal
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Cyclic Peptides: Drug Design & Research Advances

Most peptide drugs share a structural weakness: their linear shape leaves them exposed to enzymes that chop them apart within minutes of entering the body.

Most peptide drugs share a structural weakness: their linear shape leaves them exposed to enzymes that chop them apart within minutes of entering the body. Cyclic peptides solve this problem by connecting their ends into a ring, locking in a shape that resists degradation, binds targets with unusual precision, and --- in a growing number of cases --- can even be swallowed as a pill.

With 66 cyclic peptide drugs now approved globally and a market projected to reach $4.76 billion by 2030, this molecular architecture has moved from academic curiosity to pharmaceutical workhorse. Three cyclic peptides won FDA approval in 2023 alone. And recent breakthroughs in AI-driven design, oral delivery, and screening technology are accelerating the pipeline faster than at any point in the field's history.

This article reviews the science behind cyclic peptide drug design, the approved drugs that define the class, the clinical candidates pushing its boundaries, and the technologies reshaping how these molecules are discovered.

Table of Contents

  1. What Makes Cyclic Peptides Different
  2. A Brief History: From Soil Fungi to Blockbuster Drugs
  3. FDA-Approved Cyclic Peptide Drugs
  4. The Oral Bioavailability Problem (and How It's Being Solved)
  5. Clinical Pipeline: Five Candidates to Watch
  6. Discovery Technologies: How New Cyclic Peptides Are Found
  7. AI and Computational Design
  8. The Bottom Line
  9. References

What Makes Cyclic Peptides Different

A linear peptide is a chain of amino acids with two exposed ends. Enzymes called exopeptidases recognize and attack those ends, breaking the peptide down before it can reach its target. Cyclization --- connecting the chain into a closed ring --- eliminates those vulnerable termini.

But the benefits go beyond just stability. Forming a ring constrains the peptide's shape, reducing the number of conformations it can adopt. This rigidity means it pays less of an "entropic penalty" when binding a protein target, translating to higher affinity and selectivity. The constrained backbone can also form internal hydrogen bonds that shield polar groups from the surrounding environment, improving membrane permeability.

Key advantages of cyclic vs. linear peptides:

PropertyLinear PeptidesCyclic Peptides
Enzymatic stabilityLow (minutes in plasma)High (hours to days)
Target binding affinityModerateHigh (reduced entropic penalty)
Membrane permeabilityPoorImproved (intramolecular H-bonds)
Oral bioavailabilityRareAchievable (~40% of approved cyclic drugs are oral)
Conformational flexibilityHighConstrained, predictable

This combination of properties positions cyclic peptides in a pharmacological sweet spot between small-molecule drugs and large biologics like antibodies. They bind protein surfaces too large and flat for small molecules to grip, yet they're small enough to synthesize chemically and --- increasingly --- to deliver orally.

A Brief History: From Soil Fungi to Blockbuster Drugs

The story of cyclic peptide therapeutics begins in 1970, when Sandoz (now Novartis) employees collected soil samples from Norway and Wisconsin. The fungi they isolated --- Tolypocladium inflatum and Cylindrocarpon lucidum --- produced a family of 11-amino-acid cyclic peptides called cyclosporins. One of them, cyclosporin A, turned out to be a potent and selective immunosuppressant.

Cyclosporine received FDA approval in 1983 and transformed organ transplantation. Its mechanism --- binding to the intracellular protein cyclophilin, then inhibiting calcineurin to block T-cell activation --- was also a proof of concept. A cyclic peptide weighing over 1,200 daltons could reach an intracellular target, survive the gut, and achieve 20--70% oral bioavailability. It broke every rule that said peptides couldn't be drugs.

The second landmark came from a different direction. Somatostatin, a 14-amino-acid cyclic hormone, regulates growth hormone release but has a half-life of just three minutes in the body. Researchers at Sandoz (again) truncated and modified it into an 8-amino-acid cyclic peptide called octreotide, approved in 1988. Octreotide showed a 200-fold increase in potency and a 30-fold longer half-life than its parent hormone. It became a blockbuster drug for acromegaly and neuroendocrine tumors, generating over $1 billion in annual sales and spawning analogues like lanreotide and pasireotide.

These two drugs --- one from fungal natural products, one from rational design of an endogenous hormone --- established the two main paths that cyclic peptide drug discovery would follow for decades.

FDA-Approved Cyclic Peptide Drugs

As of mid-2024, 66 cyclic peptide drugs have been approved globally, with 39 gaining approval since 2000. Two-thirds of all FDA- and EMA-approved peptide drugs are cyclic. Here is a snapshot of notable approvals across therapeutic areas:

Approved Cyclic Peptides by Therapeutic Area

DrugYearIndicationTypeRoute
Cyclosporine1983Organ transplant rejectionCalcineurin inhibitorOral/IV
Octreotide1988Acromegaly, NETsSomatostatin analogueSC/IM
Vancomycin1958Bacterial infectionsGlycopeptide antibioticIV/Oral
Daptomycin2003Skin infections, bacteremiaLipopeptide antibioticIV
Romidepsin2009Cutaneous T-cell lymphomaHDAC inhibitorIV
Voclosporin2021Lupus nephritisCalcineurin inhibitorOral
Pegcetacoplan2021PNH, geographic atrophyC3 inhibitorSC
Rezafungin2023CandidemiaEchinocandin antifungalIV
Motixafortide2023Multiple myeloma (mobilizer)CXCR4 antagonistSC
Zilucoplan2023Generalized myasthenia gravisC5 inhibitorSC

The 2023 Approvals in Detail

The three cyclic peptides approved in 2023 illustrate the breadth of the class:

Rezafungin (Rezzayo) is a semisynthetic echinocandin --- a cyclic lipopeptide that inhibits fungal cell wall synthesis by blocking 1,3-beta-D-glucan production. It treats candidemia and invasive candidiasis in patients with limited alternatives.

Motixafortide (Aphexda) is a 14-amino-acid cyclic peptide formed by a disulfide bridge between two cysteine residues. It blocks the CXCR4 receptor with an IC50 of approximately 1 nM and is used alongside filgrastim to mobilize hematopoietic stem cells in multiple myeloma patients before transplant.

Zilucoplan (Zilbrysq) is a 15-amino-acid synthetic macrocyclic peptide that inhibits complement component C5, preventing formation of the membrane attack complex. It is the first once-daily subcutaneous self-administered therapy for anti-AChR antibody-positive generalized myasthenia gravis.

The Oral Bioavailability Problem (and How It's Being Solved)

Most cyclic peptide drugs are injected. The reason is straightforward: these molecules are large (typically 500--2,000 daltons), polar, and violate Lipinski's "Rule of Five" --- the guidelines that predict whether a compound can be absorbed through the gut.

And yet, close to 40% of all approved macrocyclic drugs are orally bioavailable. Cyclosporine, at 1,203 daltons, achieves 20--70% oral absorption. How?

The answer lies in what researchers call "chameleonic" behavior. In aqueous environments, cyclosporine exposes its polar groups to interact with water. In lipid environments (like cell membranes), it tucks those groups away through intramolecular hydrogen bonds, adopting a compact, lipophilic shape. This shape-shifting lets it cross the intestinal wall.

Modern drug designers are engineering this property deliberately. The key strategies for improving oral peptide delivery include:

  • N-methylation: Adding methyl groups to backbone amide nitrogens reduces hydrogen bond donors and increases lipophilicity. Cyclosporine has seven N-methylated residues.
  • Intramolecular hydrogen bonding: Designing the ring so polar NH groups form internal H-bonds, hiding them from the exterior.
  • Unnatural amino acids: Incorporating gamma-amino acids (statines) or D-amino acids that maintain internal H-bonding while boosting permeability.
  • Permeation enhancers: Compounds like sodium caprate temporarily open tight junctions between intestinal epithelial cells. Merck uses this approach for its oral PCSK9 inhibitor MK-0616.
  • Backbone modifications: Replacing amide bonds with thioamides, oxazoles, or other bioisosteres to improve metabolic stability.

These tactics are producing results. Chugai's LUNA18, an 11-amino-acid cyclic peptide KRAS inhibitor, achieves 21--47% oral bioavailability across four animal species without any special formulation --- a remarkable number for a molecule of its size.

Clinical Pipeline: Five Candidates to Watch

The cyclic peptide pipeline spans oncology, cardiovascular disease, infectious disease, and rare conditions. Five programs stand out for their scientific significance and clinical progress.

1. Enlicitide Decanoate (MK-0616) --- Oral Cholesterol Reduction

Developer: Merck | Target: PCSK9 | Phase: 3 (CORALreef program)

This oral macrocyclic peptide may become the first pill-form PCSK9 inhibitor, replacing injections like evolocumab and alirocumab. Discovered through mRNA display screening, MK-0616 binds PCSK9 with a Ki of 5 picomolar --- extraordinarily potent. Its oral bioavailability is just 1--2%, but because it is so potent, a standard oral dose still works.

Phase 3 results from the CORALreef Lipids trial, presented at the American Heart Association Scientific Sessions 2025 and published in JAMA, showed a 55.8% reduction in LDL cholesterol at week 24 compared to placebo (p<0.001). A post-hoc reanalysis put that figure at 59.7%. The CORALreef HeFH trial in familial hypercholesterolemia patients showed a 59.4% LDL-C reduction. Adverse events were comparable to placebo. The CORALreef program includes more than 19,000 participants across multiple Phase 3 studies, including a cardiovascular outcomes trial.

Industry projections estimate peak annual sales could reach $5 billion.

2. LUNA18 --- Oral KRAS Inhibitor for Solid Tumors

Developer: Chugai/Roche | Target: Pan-RAS (KRAS, NRAS, HRAS) | Phase: 1

LUNA18 is an 11-amino-acid cyclic peptide that blocks the interaction between RAS proteins and their activators. Discovered using Chugai's mRNA display platform for "beyond Rule of Five" molecules, it shows a protein-protein interaction IC50 below 2 nM, a KRAS-G12D binding affinity of 43 picomolar, and a cellular IC50 of 1.4 nM.

What makes LUNA18 exceptional: it reaches an intracellular target while being taken as an oral capsule. KRAS-G12D mutations affect an estimated 180,000 patients in the US and Europe. The Phase 1 trial (NCT05012618) enrolled 195 patients with locally advanced or metastatic solid tumors.

3. Zosurabalpin --- First New Antibiotic Class in Decades

Developer: Roche | Target: LPS transport (LptB2FGC complex) | Phase: 1 (Phase 3 planned)

Carbapenem-resistant Acinetobacter baumannii (CRAB) is classified as a critical-priority pathogen by the WHO. No new antibiotic class has entered clinical practice for this organism in over 50 years. Zosurabalpin, a fully synthetic tethered macrocyclic peptide, changes that.

Its mechanism is novel: it blocks the LPS transport machinery in the bacterial inner membrane, causing toxic accumulation of lipopolysaccharide intermediates that kills the bacterium. In vitro, it showed potent activity against multidrug-resistant isolates with MICs of 0.06--0.5 micrograms/mL. Phase 1 trials in 64 healthy participants demonstrated safety at IV doses from 10 mg to 2,000 mg. Roche planned to initiate Phase 3 in late 2025 or early 2026.

4. BT8009 --- Bicycle Toxin Conjugate for Cancer

Developer: Bicycle Therapeutics | Target: Nectin-4 | Phase: 1/2

Bicycle Toxin Conjugates (BTCs) represent an innovative twist on peptide-drug conjugates: small, constrained bicyclic peptides deliver cytotoxic payloads directly to tumor cells. BT8009 targets Nectin-4, a receptor overexpressed in urothelial carcinoma and other solid tumors. Phase 1/2 data show preliminary anti-tumor activity with an acceptable safety profile.

5. Lonodelestat (POL6014) --- Cystic Fibrosis

Developer: Santhera Pharmaceuticals | Target: Neutrophil elastase | Phase: 2

Lonodelestat is a 13-amino-acid synthetic cyclic peptide discovered through Polyphor's PEM (Peptide Epitope Mimetic) technology. It is a potent, selective inhibitor of neutrophil elastase, an enzyme that drives lung damage in cystic fibrosis. It is administered by inhalation directly to the lungs.

Discovery Technologies: How New Cyclic Peptides Are Found

Two display technologies dominate cyclic peptide discovery, and both have matured dramatically in the past five years.

mRNA Display and the RaPID System

The Random nonstandard Peptides Integrated Discovery (RaPID) system, developed by Hiroaki Suga's laboratory at the University of Tokyo, combines genetic code reprogramming with mRNA display. The FIT (Flexible In vitro Translation) system uses engineered ribozymes called flexizymes to load non-standard amino acids --- including N-methylated, D-configured, and beta-amino acids --- onto tRNAs. This lets researchers build libraries of more than 10 trillion (10^12) unique macrocyclic peptide sequences and screen them against a target protein in a single experiment.

RaPID was the platform behind MK-0616's discovery. Merck screened massive mRNA display libraries to identify lead cyclic peptides that bound PCSK9, then optimized them through structure-based drug design. The system has also yielded inhibitors of SARS-CoV-2 main protease and numerous other targets.

Phage Display

Phage display uses bacteriophages to present cyclic peptide libraries on their surface. While library sizes are smaller than mRNA display (typically 10^7--10^9), phage display benefits from decades of optimization and broad accessibility. Recent innovations include cyclization through cysteine-acryloyl lysine linkages, which produce cell-penetrating macrocycles with 4--6-fold stronger target binding than their linear counterparts.

A 2024 advance --- multiplexed phage display of macrocyclic organo-peptide hybrids (MOrPH-PhD) --- combined non-canonical amino acid cyclization modules to generate structurally diverse, genetically encoded peptide macrocycles that target RNA structures, opening a frontier beyond traditional protein targets.

AI and Computational Design

Artificial intelligence is reshaping cyclic peptide drug design at every stage, from structure prediction to sequence optimization to de novo scaffold generation.

AfCycDesign: AlphaFold Meets Cyclic Peptides

In May 2025, researchers published AfCycDesign in Nature Communications --- a modified version of AlphaFold2 engineered specifically for cyclic peptides. The key innovation was a cyclic relative positional encoding that teaches the neural network the first and last residues are neighbors, enforcing the ring constraint during structure prediction.

The results were striking. AfCycDesign generated over 10,000 structurally diverse cyclic peptide designs predicted to fold correctly with high confidence. X-ray crystal structures for eight experimentally tested designs matched the computational models with sub-angstrom accuracy (RMSD < 1.0 angstroms). The team then used these scaffolds to design binders with nanomolar IC50 values against MDM2 and Keap1 --- two validated cancer targets.

Generative AI for Peptide Optimization

A 2026 study in Chemical Communications described PepThink-R1, a chain-of-thought reasoning model for cyclic peptide optimization that combines supervised fine-tuning with reinforcement learning. Unlike black-box generative models, PepThink-R1 explains why it makes specific sequence modifications --- for instance, substituting an amino acid to improve metabolic stability while preserving target binding.

A parallel 2025 review in the Journal of Medicinal Chemistry cataloged the computational toolkit now available for cyclic peptide design, including molecular dynamics simulations of membrane permeability, machine learning models for predicting oral bioavailability, and graph neural networks for structure-activity relationship mapping.

What AI Cannot Yet Do

AI tools still struggle with accurately predicting the "chameleonic" conformational switching that governs membrane permeability in macrocycles. Predicting oral bioavailability from structure alone remains unreliable. And training data for cyclic peptides is thin compared to small molecules or proteins, limiting model accuracy. These gaps are closing, but wet-lab validation remains indispensable.

The Bottom Line

Cyclic peptides have matured from a handful of natural products into a deliberately engineered drug class spanning immunology, oncology, cardiology, and infectious disease. The field's trajectory is defined by three converging trends:

Oral delivery is becoming real. MK-0616 demonstrated in Phase 3 that an oral cyclic peptide can reduce LDL cholesterol as effectively as injectable PCSK9 inhibitors. LUNA18 showed that a cyclic peptide can reach an intracellular oncology target via an oral capsule with meaningful bioavailability. These are not edge cases --- they signal a shift in what peptide drugs can do.

Discovery is accelerating. mRNA display libraries of 10^12+ members, combined with AI-driven structure prediction and design tools like AfCycDesign, are compressing timelines from target identification to clinical candidate. Researchers can now computationally generate thousands of novel cyclic peptide scaffolds, predict their structures with atomic accuracy, and design binders for specific targets --- all before synthesizing a single molecule.

The approved portfolio keeps growing. Three cyclic peptides gained FDA approval in 2023. The pipeline includes candidates against KRAS mutations, complement-mediated diseases, multidrug-resistant bacteria, and cancer. With 66 cyclic peptides approved globally and hundreds more in clinical trials, this molecular class has earned its place alongside natural and synthetic peptides as a foundational drug modality.

For researchers and clinicians, the practical message is clear: cyclic peptides are no longer a niche curiosity. They are a growing part of the therapeutic toolkit, with unique advantages in stability, selectivity, and --- increasingly --- oral bioavailability that neither small molecules nor antibodies can match.

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