What Comes Next for Cyclic Peptide Drugs After Oral Macrocyclic Peptide Approvals?

In 2026, the development of cyclic peptide drugs reached an important turning point. Icotrokinra, developed by Johnson & Johnson and Protagonist Therapeutics, and Enlicitide, developed by Merck, were approved by the U.S. FDA in succession. These two drugs are used for psoriasis and hypercholesterolemia, respectively, and their shared feature is that they can be administered orally while acting on therapeutic targets that previously relied mainly on injectable biologics.

Peptide drugs have long been characterized by high target affinity and selectivity, but their applications have been limited by insufficient stability, membrane permeability, and in vivo exposure. The success of Icotrokinra and Enlicitide shows that, through cyclization design, unnatural amino acid modification, and continuous medicinal chemistry optimization, some cyclic peptides can overcome these limitations and become orally administered drugs with clinical value. For the different development paths of these two drugs, see the previous article “The Different Paths of Two Oral Cyclic Peptide Drugs: Icotrokinra and Enlicitide”.

However, oral administration is only one route of administration for cyclic peptides, and it does not represent the full value of this class of molecules. Cyclic peptides can form relatively stable three-dimensional structures and recognize protein surfaces through multiple amino acid side chains simultaneously. Compared with traditional small molecules, they can cover a larger molecular recognition interface; compared with antibodies, they are smaller in molecular size, can usually be produced by chemical synthesis, and allow flexible incorporation of unnatural amino acids and other chemical modifications.

These characteristics give cyclic peptides the opportunity to enter multiple different areas of drug development. From replacing some mature antibody drugs, to developing tumor-targeted radiopharmaceuticals, to exploring intracellular protein interactions, cyclic peptides are forming an emerging drug development space worthy of attention.

First Type of Opportunity: Replacing Some Existing Antibody Drugs

The most direct opportunity for cyclic peptide drugs may not be to find entirely new therapeutic targets, but to replace some antibody drugs that are already on the market.

Over the past two decades, monoclonal antibodies have achieved tremendous success in oncology, autoimmune diseases, metabolic diseases, and other fields, and they have also validated a large number of therapeutic targets with clinical value. However, antibody drugs generally need to be produced through mammalian cell culture, involving complex expression, purification, and quality control processes, requiring substantial investment in production facilities, and most require injection-based administration.

Cyclic peptides provide another option. Their molecular weights are usually far smaller than those of antibodies, and they can be produced by chemical synthesis without relying on mammalian cell expression systems. For cyclic peptides with relatively simple structures and moderate lengths, chemical synthesis offers advantages such as controllable processes, ease of incorporating unnatural amino acids, and relatively flexible production workflows. As synthesis and purification processes improve, some cyclic peptides are expected to achieve simpler production workflows and lower manufacturing costs than antibodies. However, for cyclic peptides with complex structures and many synthetic steps, the cost advantage still needs to be evaluated on a case-by-case basis.

The smaller molecular size of cyclic peptides may also bring different pharmacokinetic characteristics. Compared with antibodies, they generally exhibit faster tissue distribution and clearance, which may be advantageous in certain diseases that require access to dense tissues. At the same time, cyclic peptides can be chemically modified to adjust stability, solubility, and in vivo exposure, and some molecules can even achieve oral administration, providing patients with treatment options different from injectable antibodies.

Icotrokinra and Enlicitide are representative examples of this direction. The IL-23 and PCSK9 pathways they target have long been proven by antibody drugs to have therapeutic value, and the breakthrough of cyclic peptides lies in achieving the corresponding therapeutic effects with smaller, chemically synthesizable molecules. For the discovery and development process of Icotrokinra, see the existing article on this website, “The Birth of ICOTYDE (1): How an Oral Cyclic Peptide Began with Gastrointestinal Stability”.

Of course, cyclic peptides cannot replace all antibodies. Antibodies have long in vivo half-lives, can recognize complex protein surfaces, and can also exert specific immune effector functions through the Fc structure. Cyclic peptides generally lack these functions and may face faster in vivo clearance. Therefore, the targets best suited for replacement by cyclic peptides are those that mainly rely on high-affinity binding to block target function, do not require antibody Fc effects, and can achieve pharmacological action through a relatively limited binding interface.

For such clinically validated targets, cyclic peptide development can reduce some of the risks associated with validating an entirely new therapeutic mechanism, allowing more effort to be focused on molecule discovery, drug properties, and production processes. If they can reach a competitive level in efficacy and safety while reducing manufacturing costs or improving convenience of administration, cyclic peptides may have the opportunity to enter the existing antibody drug market.

Second Type of Opportunity: Targeted Radiopharmaceuticals

If oral administration is no longer regarded as a necessary condition for cyclic peptide development, targeted radiopharmaceuticals become another direction worthy of attention.

The basic concept of targeted nuclear medicine is to use molecules capable of recognizing tumor cells to deliver radionuclides to the target tissue. The molecule itself does not necessarily need to inhibit the function of the target protein; as long as it can bind the target with sufficiently high affinity and selectivity, it may become a component of a radiopharmaceutical for imaging or therapy.

Cyclic peptides have several characteristics suitable for this purpose. They can recognize cell-surface proteins through relatively fixed three-dimensional structures, and they can also improve stability and molecular properties through unnatural amino acid modifications. Compared with antibodies, smaller cyclic peptides can generally be cleared from the blood more rapidly and may enter certain tumor tissues more quickly. This characteristic has potential value for radiopharmaceuticals that require control of radioactive exposure in normal tissues.

However, faster clearance is not always better. The drug must remain in the tumor for a sufficient length of time to generate an effective imaging signal or therapeutic effect. At the same time, many peptide-based radiopharmaceuticals are prone to accumulation in the kidneys, so the difference in radioactive distribution between tumor and normal tissues often determines the value of a candidate molecule more than binding affinity alone.

Compared with oral cyclic peptides, radiopharmaceutical development has another practical advantage: it usually uses injection-based administration and does not need to solve the problem of intestinal absorption. Researchers can focus on optimizing target recognition, in vivo stability, tissue distribution, and clearance characteristics. This does not mean that radiopharmaceuticals are easier to develop, because radionuclides, chelators, and linkage strategies all affect the properties of the final molecule, but it enables cyclic peptides to deliver value along another drug development path.

For cell-surface proteins that have clearly established tumor-associated expression but lack suitable targeting ligands, discovering cyclic peptides through high-throughput screening and then developing them into radiopharmaceuticals may be a research and development path worth investing in.

Third Type of Opportunity: Oral Cyclic Peptides in Chronic Diseases

The approvals of Icotrokinra and Enlicitide have also led people to reassess the value of oral cyclic peptides in the treatment of chronic diseases.

For psoriasis, hypercholesterolemia, and other diseases requiring long-term treatment, patients may need to receive drug therapy continuously for several years or even longer. Oral drugs can reduce the inconvenience associated with injections and may also make it easier for some patients to initiate and adhere to treatment.

But oral administration does not necessarily mean superiority over injection. The dosing intervals of modern antibody drugs can reach several weeks or even several months, whereas oral cyclic peptides may need to be taken daily, and some may also be subject to restrictions related to diet and timing of administration. Therefore, whether future oral cyclic peptides can truly replace injectable biologics will still depend on their overall competitiveness in efficacy, safety, convenience of administration, and price.

From the perspective of drug development, chronic diseases have an important characteristic: many therapeutic targets have already undergone long-term clinical validation, and efficacy endpoints are also relatively well defined. For cyclic peptide developers, this means that they can search for new molecular formats around mature targets without simultaneously bearing all of the risks associated with validating an entirely new target.

The development process of Enlicitide demonstrates how oral activity can be obtained from a high-affinity cyclic peptide through multiple rounds of medicinal chemistry optimization. This process has been described in detail in the previous article on this website, “From mRNA Display Hit to Enlicitide (1): The Story Begins with a Screen”.

In the future, immune-inflammatory diseases, cardiovascular and metabolic diseases, and other diseases requiring long-term treatment may still be important application areas for oral cyclic peptides. However, the truly valuable opportunity is not simply to convert an injectable drug into an oral one, but to provide patients with a more reasonable dosing approach and therapeutic choice while maintaining effective treatment.

Fourth Type of Opportunity: Intracellular Protein Interactions

The currently successful oral cyclic peptide drugs mainly act on extracellular or cell-surface proteins. After entering the blood, the drug can contact the target and exert its effect without further crossing the cell membrane.

However, a large number of proteins with important therapeutic value in the human body are located inside cells, including molecules involved in tumor growth, cell signaling, and regulation of protein function. Many protein-protein interactions lack the deep pockets to which traditional small molecules can readily bind, making it difficult to develop effective inhibitors for a long time.

Cyclic peptides have potential advantages in this area. They can form relatively large molecular recognition surfaces and obtain relatively stable three-dimensional structures through cyclization and unnatural amino acid modifications. If they can enter cells, they may be able to intervene in certain protein interactions that are difficult for traditional small molecules to regulate effectively.

However, cell permeability remains the most important obstacle in this direction. Cyclic peptides typically contain multiple peptide bonds and polar groups, making it difficult for them to cross cell membranes. Although molecular properties can be improved through N-methylation, D-amino acids, and other structural modifications, these methods do not follow universally applicable rules. The same modification may produce completely different effects in different cyclic peptides.

Cyclosporine provides an important insight. It can adjust its molecular conformation in different environments and reduce exposed polar surface area through intramolecular hydrogen bonding and other mechanisms, thereby gaining unusual membrane permeability. How to extend this conformational modulation capability to artificially designed cyclic peptides remains an important research direction.

If cyclic peptides with cell permeability can be designed more reliably in the future, their potential target range will expand significantly. However, effective intracellular exposure depends not only on membrane permeability, but is also affected by factors such as efflux transport, metabolic stability, and intracellular distribution. Therefore, although this direction has substantial room for development, it is still quite far from becoming a generally applicable drug development approach.

Fifth Type of Opportunity: Molecular Glues and Targeted Protein Degradation

In addition to directly inhibiting protein function, cyclic peptides may also be used to alter interactions between proteins and even induce degradation of specific proteins. PROTAC and molecular glues, which have attracted attention in recent years, provide new drug design concepts for this direction.

PROTAC molecules typically use two binding units to recognize the target protein and an E3 ubiquitin ligase, respectively, thereby directing the target protein into the cell’s protein degradation pathway. Cyclic peptides can serve as the target-protein recognition unit, making them especially suitable for exploring proteins for which conventional small-molecule ligands are difficult to obtain. Molecular glues, by contrast, alter the formation of protein complexes by stabilizing or inducing interactions between proteins, and some can also promote target protein degradation. The rich three-dimensional structures and modifiability of cyclic peptides provide new possibilities for the discovery of such molecules.

However, these applications are still at a relatively early exploratory stage. Cyclic peptides not only need to recognize the target protein, but also must enter cells and form protein complexes with the intended function. For cyclic peptide–based PROTAC molecules, the additional linker structure may further increase molecular weight and polarity, making drug development more difficult. Therefore, molecular glues and protein degraders represent long-term directions worth exploring for cyclic peptides, but they remain at a considerable distance from a mature drug development path.

What technical capabilities are needed to realize these opportunities?

Whether replacing existing antibody drugs, developing targeted radiopharmaceuticals, or exploring intracellular protein–protein interactions, cyclic peptide drug R&D faces a common challenge: how to identify candidates with genuine drug development value from among large numbers of molecules capable of binding the target.

High affinity is only the starting point. Different types of cyclic peptide drugs have distinctly different requirements for molecular properties. Inhibitors intended to replace antibodies need sufficient in vivo exposure and duration of action; targeted radiopharmaceuticals place greater emphasis on tumor uptake, normal-tissue distribution, and clearance rate; while intracellular inhibitors and protein degraders must also address issues such as cell permeability and the formation of functional protein complexes. Therefore, cyclic peptide development cannot focus only on achieving higher binding affinity; instead, molecules must be optimized in a targeted manner according to their specific intended use.

Non-natural amino acids provide important chemical tools for this type of optimization. By modifying side-chain structures, stereochemistry, and backbone conformation, researchers can adjust the stability, solubility, and in vivo distribution of cyclic peptides while maintaining target-binding capability. The practical workflow of one round of mRNA Display selection explains how high-throughput technologies can discover high-affinity ligands from extremely large molecular libraries, providing a starting point for subsequent medicinal chemistry optimization; for more on the relationship between non-natural amino acids and high-throughput screening, see “Why Is mRNA Display Especially Suitable for Non-Natural Amino Acids and Cyclic Peptide Discovery?”.

As the chemical space of cyclic peptides continues to expand, artificial intelligence and computational design may also play an increasingly important role. However, what is truly valuable is not simply generating more sequences, but integrating screening, synthesis, structural analysis, and experimental results to gradually build predictive capabilities for cyclic peptide binding ability and drug-like properties. Especially for cyclic peptides containing non-natural amino acids, high-quality experimental data remain insufficient, and how to continuously accumulate and use these data will directly affect the efficiency of future molecular design. Regarding this direction, the website already has an article titled “How Can mRNA Display Data Be Combined with AI Peptide Design?”.

Therefore, the key to the next stage of cyclic peptide drug development is not merely having a particular screening technology or computational model, but being able to connect high-affinity ligand discovery, non-natural amino acid chemistry, drug-property optimization, and experimental validation to form an R&D system suitable for different types of drugs.

Where Is the Next Opportunity for Cyclic Peptide Drugs?

The approvals of Icotrokinra and Enlicitide demonstrate that artificially designed cyclic peptides can not only recognize protein targets that are difficult for conventional small molecules to address, but also acquire clinically valuable drug properties through systematic chemical optimization. However, oral administration is only one application form of cyclic peptides. Their broader value lies in their ability to use relatively small and flexibly modifiable molecular structures to achieve target recognition and functional modulation that previously relied mainly on antibodies or other complex biologic drugs.

In the future, replacing some mature antibody drugs and developing targeted radiopharmaceuticals may be the first directions to generate practical industrial value; meanwhile, intracellular protein–protein interactions, molecular glues, and targeted protein degradation are expected to further expand the application scope of cyclic peptides. The technical barriers faced by different directions are not the same, but all of them need to start from high-affinity ligands and, through chemical modification and experimental optimization, transform molecules into drugs with genuine therapeutic value.

The success of orally administered cyclic peptides is only a starting point. The more important opportunity for cyclic peptide drugs is to use their unique molecular recognition capabilities, advantages in chemical synthesis, and designability to open up new drug space between conventional small molecules and antibodies. Future competition will no longer be only about how many high-affinity cyclic peptides can be discovered, but about who can more effectively develop these molecules into drugs with clinical value, manufacturing feasibility, and commercial competitiveness.