Oral Cyclic Peptides: Drug Discovery and Industry Outlook

Keywords

oral cyclic peptides; macrocyclic peptide drugs; cyclic peptide drug discovery; peptide cyclization; oral peptide bioavailability; IL-23 receptor antagonist; oral PCSK9 inhibitor; cyclic peptide manufacturing; peptide process development; peptide CDMO

Summary

The 2026 approvals of ICOTYDE™ (icotrokinra) and LIPFENDRA® (enlicitide) marked a turning point for oral cyclic peptides. The two products reached the US market four months apart and address different chronic diseases through different extracellular targets: the interleukin-23 receptor in plaque psoriasis and PCSK9 in hypercholesterolemia. Together, they show that oral peptide development is moving beyond isolated proof-of-concept programs toward a repeatable drug discovery and development strategy.

This article explains what cyclic peptides are, how their structures are classified and modified, where commercial opportunities are emerging, and which clinical programs matter most. It also examines the practical barriers that remain—from oral absorption and formulation to cyclization yield, impurity control, analytical characterization, and scale-up.

The Commercial Breakthrough: Two Oral Cyclic Peptides, Two Major Chronic-Disease Markets

In March 2026, the US Food and Drug Administration approved ICOTYDE™ (icotrokinra), an oral peptide targeting the interleukin-23 receptor, for adults and eligible adolescents with moderate-to-severe plaque psoriasis. The molecule was jointly discovered through a collaboration between Johnson & Johnson and Protagonist Therapeutics. Four months later, the FDA approved Merck’s LIPFENDRA® (enlicitide), an oral macrocyclic peptide that inhibits PCSK9, for adults with hypercholesterolemia, including heterozygous familial hypercholesterolemia.

The timing matters, but the breadth matters more. One product entered immunology; the other entered cardiovascular medicine. Both are intended for conditions that may require long-term treatment. Their approvals suggest that oral cyclic peptides are not confined to one target, one indication, or one discovery platform. The modality is beginning to look reproducible.

Peptide drugs have long faced a difficult three-way trade-off: strong biological activity, adequate stability, and convenient delivery rarely arrive together. Cyclization offers a way to rebalance those properties. By covalently constraining a peptide chain, developers can create a highly designable chemical space between conventional small molecules and large biologics. Advances in mRNA display, computational design, non-natural amino acid chemistry, formulation, and scalable synthesis are now turning that space into a practical drug development platform.

From Linear Chains to Multiple Rings: Why Conformational Constraint Changes Developability

A cyclic peptide is a peptide in which one or more covalent linkages create a closed-ring structure. The connection may join the N- and C-termini, a terminus and a side chain, two side chains, or several attachment points in a bicyclic or multicyclic architecture. Many cyclic peptides fall within an approximate molecular-weight range of 500–3,000 Da, placing them between traditional small molecules and biologics such as antibodies.[1]

Compared with a linear peptide, cyclization can provide three important benefits:

• Lower conformational entropy. Restricting the number of accessible conformations can preorganize a ligand for productive target binding and reduce the entropic penalty of complex formation.
• Greater stability. Blocking terminal residues or shielding protease-sensitive sites can improve resistance to enzymatic degradation.
• Tunable pharmacokinetics. Cyclization can redistribute polarity and lipophilicity across the molecular surface. In selected molecules, this may support membrane passage or measurable oral exposure.

Cyclization is therefore more than bending a chain into a ring. It is an engineering tool for balancing potency, selectivity, stability, exposure, and manufacturability.

That balance is particularly valuable for protein–protein interactions and other targets often described as difficult to drug. Small molecules typically perform best when they can occupy a defined pocket. Antibodies can recognize broad protein surfaces, but they are generally restricted to extracellular targets and parenteral administration. Cyclic peptides offer a larger contact surface than most small molecules while remaining far more compact than antibodies. This allows them to address part of the target space between the two modalities.[2]

Still, a ring does not automatically produce a drug. Excessive rigidity may prevent induced fit. Too much lipophilicity can damage solubility, while excessive polarity limits membrane permeability. Disulfide bonds may be unstable in reducing environments. Bicyclic and multicyclic structures add synthetic, purification, and analytical complexity. Successful programs optimize structure, biological activity, exposure, and manufacturability together—not one variable at a time.

Cyclic Peptide Classification: Topology and Bond Chemistry

Cyclic peptides can be grouped into five practical topological classes:

• Head-to-tail cyclization. The N-terminal amine and C-terminal carboxyl group form an amide bond that closes the peptide backbone. This widely used format can increase global rigidity and resistance to exopeptidases. It also has the deepest record of clinical validation.
• Head-to-side-chain or side-chain-to-tail cyclization. A terminal group is connected to the side chain of a residue such as lysine, aspartic acid, or glutamic acid. The approach constrains a selected region while retaining some backbone flexibility.
• Side-chain-to-side-chain cyclization. Common linkages include disulfides, lactams, thioethers, and click-chemistry products. These bonds can stabilize a preferred secondary structure or orient key pharmacophores.
• Bicyclic or multicyclic peptides. Two or more connections create several loops. The added constraint can improve selectivity and allow separate regions to handle target recognition, biological effect, or payload attachment.
• Hybrid cyclization. A single molecule combines more than one linkage type. Hybrid designs can deliver highly preorganized structures, but development and manufacturing become more demanding.

Bond chemistry provides another classification. Homodetic cyclic peptides contain only conventional amide bonds within the ring. Heterodetic peptides include at least one non-alpha-amide linkage involving a side chain. Cyclic depsipeptides replace one or more amide bonds with ester bonds. Cyclosporine A is a familiar homodetic macrocycle, while bacitracin and microcystins contain heterodetic connections. Natural products such as romidepsin illustrate still more complex ring chemistry.

From an industry perspective, head-to-tail macrocycles remain the most established structural category. Bicyclic and multicyclic peptides are less numerous, but their stronger conformational control and ability to separate functions across loops make them increasingly relevant to highly selective ligands and targeted conjugates. A recent Journal of Medicinal Chemistry review identified 46,574 cyclic peptide–related substances in the dataset it analyzed, with macrocyclic peptides concentrated mainly in the approximate 1,000–2,500 Da range.[1]

Chemical Modification Is a Core Design Layer, Not a Finishing Step

Cyclization addresses part of the stability and conformational problem. Most candidates still need additional chemical engineering to improve exposure, selectivity, or processability.

N-methylation is one of the most important strategies. Methylating backbone amide nitrogens reduces hydrogen-bond donors, may decrease protease recognition, and can promote intramolecular hydrogen bonding. In the right molecular context, these effects improve membrane permeability and oral bioavailability. The Journal of Medicinal Chemistry analysis identified N-methylation as the most common modification in its cyclic peptide dataset.[1]

D-amino acids and other non-natural residues can redirect local conformation, reduce recognition by natural proteases, and expand side-chain chemistry. Amide-to-ester substitutions offer another route to adjusting polarity and hydrogen-bonding behavior. For oral macrocycles, the goal is no longer simply to maximize rigidity. Developers increasingly seek chameleonic behavior: the molecule exposes polar groups in water to maintain solubility, then temporarily shields them through intramolecular hydrogen bonds in a lipid environment to support membrane passage.

Lipidation, glycosylation, and PEGylation address different pharmacokinetic needs. Lipidation may increase membrane interaction, albumin binding, or receptor selectivity. Glycosylation can improve solubility, stability, and tissue recognition. PEGylation may reduce renal clearance and extend systemic exposure. In bicyclic peptide drug conjugates and radioconjugates, linker design and conjugation-site selection must also account for payload release, plasma stability, tissue penetration, and target internalization.[3]

There is no universal combination. Moving a modification by one residue may alter cyclization yield, isomer ratios, chromatographic behavior, and the impurity profile. That is why medicinal chemistry and CMC development are closely connected in cyclic peptide programs. Early attention to the synthetic route, purification strategy, analytical methods, and scale-up risk reduces expensive redesign later.

Market Outlook: Value Is Moving from Individual Assets to Platforms

Cyclic peptide innovation is shifting from academic exploration to asset creation. According to the Journal of Medicinal Chemistry review, patent activity exceeded publication output in 2023–2024, while drug-focused patent filings also rose sharply.[1] The pattern points to stronger commercial competition around discovery platforms, enabling chemistry, oral delivery, and targeted conjugates.

Third-party estimates cited in the review project that the global cyclic peptide market could grow from approximately US$3.16 billion in 2024 to more than US$5.3 billion by 2032, representing a compound annual growth rate of roughly 6.5%–6.7%.[1] These figures should be treated as directional rather than definitive. Market reports do not always use the same boundaries for natural cyclic peptides, stapled peptides, bicyclic conjugates, and cyclic peptide antibiotics.

The more durable commercial logic lies in high-value clinical assets and reusable technology. A validated display or conformational-design platform can generate ligands against several difficult targets. The same targeting peptide may also be adapted to carry a cytotoxic payload, an immune agonist, or a radionuclide. Once a platform produces clinical evidence, later programs may benefit through faster discovery, stronger partnership value, and recurring demand for specialized development and manufacturing.

Three business models now stand out: Merck’s orally available macrocyclic peptides, Protagonist Therapeutics’ oral peptide platform, and Bicycle Therapeutics’ bicyclic peptide conjugates. Each creates value differently, but all depend on the same principle: a well-designed constrained peptide can become more than a single molecule. It can become an expandable product engine.

Therapeutic Landscape: Oncology Leads, While Immunology and Cardiometabolic Disease Accelerate

In the 2020–2025 dataset reviewed in the Journal of Medicinal Chemistry article, oncology was the largest therapeutic area for cyclic peptide research. Infectious and inflammatory diseases followed. Autoimmune, cardiovascular, metabolic, and neurodegenerative indications accounted for smaller shares but showed clear expansion.[1]

Oncology attracts cyclic peptide developers for two reasons. First, constrained peptides may bind protein surfaces involving RAS, MDM2/MDMX, or beta-catenin–TCF4 that are difficult for conventional small molecules to cover effectively. Second, short peptides can serve as compact targeting ligands for cytotoxic or radioactive payloads. Their tissue penetration and clearance can be tuned in ways that differ from antibodies. Zelenectide pevedotin, which uses a Nectin-4-binding bicyclic peptide to deliver a cytotoxic payload, is a representative example.

Infectious disease has a long history of cyclic peptide medicines, including vancomycin, bacitracin, and polymyxins. Current research extends that legacy into drug-resistant bacteria, viral protein interfaces, and engineered natural-product scaffolds. In inflammation and autoimmune disease, complement C3 inhibitors, IL-23 receptor antagonists, and locally acting gastrointestinal peptides demonstrate the range of possible approaches.

Cardiovascular and metabolic disease are emerging as important value pools. PCSK9 has historically been addressed by injectable monoclonal antibodies and siRNA therapies. The approval of enlicitide shows that a macrocyclic peptide can inhibit a large extracellular interaction surface through an oral dosage form. The commercial implication is significant: cyclic peptides may compete in common chronic diseases with large patient populations, not only in indications with few alternatives.

From Pipeline to Product: The Cyclic Peptide Programs to Watch

As of August 2026, the most important development is not simply a larger pipeline. Several distinct cyclic peptide strategies have crossed meaningful clinical or regulatory milestones at the same time.

Three themes emerge. First, ICOTYDE and LIPFENDRA validate oral cyclic peptides in two different chronic-disease markets. Second, once-weekly subcutaneous rusfertide shows that the value of cyclic peptides is not limited to oral delivery. Third, bicyclic conjugates and intracellular PPI inhibitors are extending the modality into oncology. Zelenectide pevedotin also offers a useful caution: an elegant platform still needs rigorous control groups, appropriate endpoints, and a convincing benefit–risk profile.

Oral Delivery Has Broken Through, but the Hard Work Is Not Over

Oral delivery is the most closely watched—and least forgiving—frontier in cyclic peptide development. Most cyclic peptides remain larger and more polar than conventional oral small molecules. They may carry many hydrogen-bond donors and acceptors and face degradation by gastrointestinal proteases, entrapment in mucus, limited epithelial permeability, efflux transport, and first-pass metabolism. Cyclization can improve stability, but it does not guarantee absorption.

Current solutions fall into three layers:

• Molecular design: N-methylation, D-amino acids, amide-to-ester substitutions, lipidation, and chameleonic conformational behavior.
• Formulation and excipients: lipid-based systems, enteric coatings, protease inhibitors, and permeation enhancers.
• Delivery devices: gastrointestinal microneedles and self-orienting delivery systems.

A clinically viable product must balance sequence, conformation, formulation, dose, dosing conditions, and cost of goods. Optimizing only permeability is not enough.

The success of ICOTYDE and enlicitide does not mean the oral barrier has disappeared. It raises the standard for every program that follows. Candidates will need to show acceptable food effects, manageable interpatient variability, long-term safety, practical tablet burden, adherence, and a commercially realistic manufacturing cost. For many cyclic peptides, an injectable, inhaled, ophthalmic, topical, or gut-restricted product may still be the better therapeutic design.

The Next Scale-Up Challenge: Moving from a Feasible Synthesis to a Robust Process

As clinical validation increases, competition is extending from discovery technology into CMC execution and supply reliability. Common development risks include aggregation of the linear precursor, competition between cyclization and oligomerization, incorrect disulfide pairing, epimerization, deletion or truncation sequences, and difficult purification when the product and its impurities have similar physicochemical properties. Multicyclic peptides, stapled peptides, and peptide conjugates add further complexity through attachment-site variants, isomers, and payload distribution.

A sustainable cyclic peptide development model requires three capabilities early in the program:

• Process selection. The sequence, ring size, and linkage chemistry should guide the choice of solid-phase, liquid-phase, or hybrid synthesis. Cyclization concentration, orthogonal protecting groups, reagent addition, and reaction order require systematic optimization.
• Analytical characterization. Orthogonal methods are needed to confirm sequence, stereochemistry, linkage position, ring topology, and impurity identity.
• Integrated scale-up. Process chemistry, analytical development, quality, and manufacturing teams should work together before the route is locked. The goal is a controlled transition from milligram-scale screening material to gram, kilogram, and GMP production.

This is the rationale behind ChemExpress’s integrated peptide platform. Its capabilities include solid- and liquid-phase peptide synthesis, Fmoc chemistry, purification, analytical development, and quality management for peptides containing approximately 3–80 amino acids, from milligram to kilogram scale. For cyclic peptides, available approaches include TATA cyclization, one to three disulfide pairs, click cyclization, lactam rings, click/disulfide bicyclic formats, and stapled peptides. Quality work can focus on the issues that matter most to development teams: confirming sequence and topology, identifying critical impurities, and controlling process-related residues.

The practical advantage of integrating design and manufacturing is straightforward. Teams can determine earlier whether a promising molecule can be synthesized reproducibly, purified efficiently, characterized unambiguously, and scaled without repeatedly redesigning the process. That reduces avoidable delays between hit validation, candidate selection, and clinical supply.

Conclusion: Cyclic Peptides Have Entered a Period of Clinical Validation

Cyclic peptides are not substitutes for small molecules or antibodies. They are a distinct modality that fills part of the capability gap between them. The rise in patent activity, the approvals of oral IL-23 receptor and PCSK9 inhibitors, the late-stage progress of a hematology program, and the expansion of bicyclic conjugates and radioligands all point in the same direction: the field is moving from proving that cyclic peptides can work to showing that they can become reliable products.

The next stage of competition will not be defined by the ability to make a ring alone. Developers must identify the right topology, conformational behavior, and route of administration for a specific target, then translate that design through scalable, well-characterized, regulatory-ready manufacturing. The market opportunity is open. The technical barriers that will separate durable platforms from individual experiments are only beginning to take shape.

Frequently Asked Questions

1. What is the main advantage of a cyclic peptide over a linear peptide?

Cyclization restricts conformational freedom. This can preorganize the peptide for target binding and shield sites that would otherwise be vulnerable to proteases. The result may be better potency, selectivity, and stability. The trade-off is that excessive rigidity or lipophilicity can reduce solubility or prevent productive binding. Every ring must therefore be designed around the target and intended route of administration.

2. Why are oral cyclic peptides so difficult to develop?

They face both biological and pharmaceutical barriers. The gastrointestinal tract contains proteases, mucus, epithelial tight junctions, efflux transporters, and first-pass metabolic systems. Cyclic peptides are also typically larger and more polar than conventional oral drugs. Successful programs combine molecular design with formulation, dose selection, and a manufacturable process. Oral exposure alone is not enough; variability, food effects, tablet burden, safety, and cost must also support the target product profile.

3. Which cyclization strategy is best for drug discovery?

There is no single best method. Head-to-tail cyclization is well established and often improves global rigidity. Side-chain linkages can preserve useful backbone flexibility. Disulfides are efficient but may be unsuitable in reducing environments. Lactam, thioether, click, stapled, and bicyclic designs offer different stability and geometry. Selection should consider the binding epitope, ring size, required flexibility, formulation, synthetic yield, impurity risk, and scale-up route.

4. What should a development team evaluate before scaling a cyclic peptide?

The team should first confirm sequence, stereochemistry, ring topology, and linkage position. It should then assess precursor aggregation, competing oligomerization, epimerization, deletion sequences, disulfide scrambling, purification behavior, and process-related residues. A route that works at milligram scale is not automatically suitable for clinical supply. Early alignment between process chemistry, analytical development, quality, and manufacturing is usually the fastest way to expose scale-dependent risks.

5. When is an integrated peptide development partner most useful?

An integrated partner is most useful when discovery decisions begin to affect CMC risk—often earlier than teams expect. Support may include cyclization screening, non-natural amino acid incorporation, route comparison, impurity identification, analytical characterization, purification, and scale-up. ChemExpress can connect these activities within one peptide platform, including multiple cyclic, bicyclic, disulfide, click, lactam, and stapled formats. The value is not simply outsourcing synthesis; it is obtaining development material and process knowledge that can carry a candidate toward GMP production.

References

[1] Thite T, Iyer KA, Jain P, et al. Cyclic Peptides in Modern Drug Discovery: Trends and Therapeutic Directions. Journal of Medicinal Chemistry. 2026.

[2] Sunny EA, Sadanandan S. Macrocyclic Peptides as Protein–Protein Interaction Modulators: A Review. Organic & Biomolecular Chemistry. 2026.

[3] Hu K, et al. Cyclic Peptide Radiopharmaceuticals: A Concise Review. ChemMedChem.2026.

[4] Merck. US FDA approval announcement for LIPFENDRA® (enlicitide). July 16, 2026.

[5] Johnson & Johnson. US FDA approval announcement for ICOTYDE™ (icotrokinra). March 18, 2026.

[6] Johnson & Johnson. Icotrokinra Phase IIb ANTHEM-UC Week 28 results. October 27, 2025.

[7] Takeda; Protagonist Therapeutics. FDA acceptance and Priority Review of the rusfertide NDA. March 2, 2026.

[8] Bicycle Therapeutics. Initial Duravelo-2 data presented at the 2026 ASCO Annual Meeting. May 21, 2026.

[9] Bicycle Therapeutics. Fourth Quarter and Full Year 2025 business update. March 17, 2026.