Cyclic peptides are peptides whose chain is closed into a ring, a shape that makes them more stable and selective than straight-chain peptides. The quick answer: more than 40 cyclic peptide drugs were in clinical use by 2017, with about one new one reaching the market each year,[1] including recent approvals such as zilucoplan (2023) for myasthenia gravis.[6] A new oral ring-shaped peptide, enlicitide, cut LDL cholesterol by 56 percentage points vs placebo in a 2,909-person phase 3 trial.[9]
This page is part of our peptide basics hub. For how peptides are made and modified in general, see natural vs synthetic peptides.
Bottom line
- Established: cyclization improves stability and target binding, and dozens of cyclic peptide drugs are approved.[1][2]
- Established: most approved cyclic peptides come from nature, such as antibiotics and hormone analogs.[1]
- New: cyclic peptides discovered in the lab, not in nature, are now reaching approval and late-stage trials.[5][8]
- Still hard: most cyclic peptides can’t be taken by mouth.[3]
Why make a peptide into a ring?
A linear peptide is floppy and has two exposed ends. Enzymes in the gut and blood attack those ends and the loose middle quickly. Closing the chain into a ring:[1][2]
- Locks the shape, so the peptide spends more time in the form that binds its target, improving potency and selectivity.
- Hides the ends from enzymes called exopeptidases, which trim peptides from the tips.
- Allows larger contact surfaces than small-molecule drugs, so cyclic peptides can block protein-protein interactions that pills usually can’t.
Rings can be closed in several ways: a normal peptide bond joining head to tail, a disulfide bridge between two cysteines, or a chemical “staple.” Chemists add further tweaks, such as N-methylation (adding small methyl groups to the backbone), to help peptides cross cell membranes. Cyclosporine, a naturally N-methylated ring of 11 amino acids, is the textbook example of a cyclic peptide that works as a pill.[3]
Approved cyclic peptide drugs
| Drug | What it does | Origin |
|---|---|---|
| Cyclosporine | Suppresses the immune system after transplants (oral) | Fungus |
| Daptomycin | Antibiotic for Gram-positive infections | Bacterium[4] |
| Polymyxin B, colistin | Last-resort antibiotics | Bacteria |
| Octreotide, lanreotide | Mimic the hormone somatostatin; used in acromegaly and some tumors | Human hormone analog |
| Bremelanotide (PT-141) | Treats low sexual desire in premenopausal women | Melanocortin hormone analog |
| Zilucoplan | Blocks complement C5 in myasthenia gravis; FDA-approved October 2023 | Synthetic macrocycle[5][6] |
| Pegcetacoplan | Blocks complement C3 in paroxysmal nocturnal hemoglobinuria | Cyclic peptide linked to polyethylene glycol[7] |
Most of these, as a 2017 review noted, are derived from natural products such as antimicrobials or human hormones.[1] Antibiotic examples are covered in our antimicrobial peptides research guide. The unapproved tanning peptide Melanotan II and the supplement cyclic glycine-proline are also ring-shaped, but they lack the trial evidence behind approved drugs.
How new cyclic peptides are found
For most of the 20th century, cyclic peptide drugs came from screening soil microbes and fungi, or from copying human hormones and making them sturdier. That still accounts for the bulk of the approved list.[1]
Newer methods build rings to order. In display technologies, scientists create libraries of trillions of different peptide rings, each tagged with the genetic code that made it. The library is washed over a target protein, the rings that stick are kept, and their codes are read to reveal their sequences. Repeating this several times enriches the best binders.[2] Chemists then refine the winners, swapping in unnatural amino acids, adding methyl groups or fatty tails, and shrinking the ring, to improve stability and absorption.[3][8]
These approaches let researchers target proteins that nature never evolved a peptide for, such as PCSK9. A 2017 review predicted that rings designed this way would soon reach clinical use,[1] and the late-stage results below suggest that prediction is coming true.
Key studies
Zilucoplan (RAISE). Zilucoplan is a self-injected macrocyclic peptide that blocks complement C5, part of the immune system that damages nerve-muscle junctions in myasthenia gravis. In 174 adults with antibody-positive generalized myasthenia gravis, it improved daily-living scores by 4.39 points at 12 weeks vs 2.30 with placebo. The most common side effect was bruising at the injection site (16% vs 9%).[5]
Pegcetacoplan (PEGASUS). Pegcetacoplan is a cyclic peptide attached to polyethylene glycol (PEG), which slows its removal from the body. In patients with paroxysmal nocturnal hemoglobinuria who remained anemic on eculizumab, pegcetacoplan raised hemoglobin by an average 3.84 g/dL more than eculizumab at 16 weeks, and 85% vs 15% no longer needed transfusions. Injection-site reactions (37% vs 3%) and diarrhea (22% vs 3%) were more common.[7]
Enlicitide, an oral macrocycle. PCSK9 is a protein that raises LDL (“bad”) cholesterol. Existing PCSK9 blockers are injected antibodies or RNA drugs. Merck researchers used mRNA display, a method that screens huge libraries of peptide rings, to find a lead, then engineered it into the oral macrocyclic peptide MK-0616 (enlicitide).[8] In the CORALreef Lipids phase 3 trial of 2,909 adults with or at risk of heart disease, 20 mg daily lowered LDL cholesterol by 57.1% at 24 weeks vs a 3.0% rise with placebo. Adverse events were similar between groups.[9] It was not listed in FDA’s approved-drug database when we checked in October 2026.
Limitations
- Oral delivery is still rare. Most cyclic peptides are injected, and engineering oral activity takes heavy chemical modification.[3]
- Cost and manufacturing: complex rings can be expensive to make.
- Strong lab binding is only a first step: many display-discovered rings bind well in a test tube but fail on stability or safety.[2]
What’s next
The field is shifting from natural ring peptides to rings designed from scratch, discovered with display libraries and refined with structure-based design.[1][8] Enlicitide’s outcome trial and regulatory review will show whether oral macrocycles can compete with injected drugs. For other ways peptides are being engineered, see peptide-drug conjugates and cell-penetrating peptides.
Questions to discuss with a clinician
- Is the peptide drug I’ve been prescribed cyclic, and does that affect how it’s taken or stored?
- Would an oral option be available or suitable for me?
- What side effects should I watch for with complement-blocking peptides?
- How is a “cyclic” supplement different from an approved cyclic drug?
