Cyclic Peptides Explained: Why Some Peptides Are Rings

Published September 2026 · Patriot Labs Research Team · ~20 min read

The short answer

A cyclic peptide is a peptide whose chain is joined into a ring rather than left as an open string with two free ends. The ring is closed by a covalent bond — an amide bond between the two ends of the backbone, a disulfide bond between two cysteine side chains, or a bridge between two side chains — and that single change makes the molecule more resistant to enzymes and more rigid than the same sequence left linear.

Chemically, a cyclic peptide is made of the same amino acids and the same amide bonds as any other peptide. What differs is topology: instead of a line with a beginning and an end, the chain forms a loop. Removing the free ends and constraining the chain into a defined shape changes how enzymes attack it, how tightly it binds a target, and, in some cases, whether it can cross a membrane. Those advantages are the reason a large share of peptide medicines are cyclic rather than linear.^[1]

The rest of this guide takes the idea apart: the exact chemistry of the four ways to close a ring, the four properties a ring changes, the cyclic peptides that occur in nature, the studied compounds that happen to be rings, and how a chemist actually closes one. It is a chemistry and history explainer; it does not describe how any compound is used, and it makes no health claims.

What a cyclic peptide actually is

A cyclic peptide is a peptide in which a covalent bond connects two points of the molecule to form a ring, so that the chain no longer has both a free N-terminus and a free C-terminus exposed in the way a linear peptide does. Everything else about it — amino acids linked by amide (peptide) bonds — is ordinary peptide chemistry.

A linear peptide is written and built from an amino (N) terminus to a carboxyl (C) terminus, and those two ends stay free. When people speak of a “macrocyclic” peptide, they mean a cyclic peptide whose ring is large enough to be considered a macrocycle — conventionally a ring of twelve or more atoms — which covers essentially all cyclic peptides beyond the smallest. The words cyclic, macrocyclic and circular are often used interchangeably in the peptide literature, with circular reserved most often for peptides whose entire backbone is a closed loop.

It helps to distinguish two things a ring can enclose. A backbone ring is formed when the main chain itself is closed, so there is no true beginning or end to the sequence. A side-chain ring, such as a disulfide bridge, leaves the backbone open but ties two points of it together with a loop, the way a shoelace stays a single strand but can be tied into a bow. Many peptides combine both, and the distinction matters because backbone closure and side-chain closure protect against different enzymes, as the stability section explains.

One more piece of vocabulary appears throughout the field. A homodetic cyclic peptide is one whose ring is closed entirely by normal peptide (amide) bonds; a heterodetic cyclic peptide is one whose ring includes a different kind of bond, such as a disulfide, an ester (a lactone) or a thioether. Oxytocin, closed by a disulfide, is heterodetic; a head-to-tail peptide closed by an amide is homodetic.

The main ways a peptide is turned into a ring

There are four principal ways to close a peptide into a ring, defined by which two points are joined: the two backbone ends (head-to-tail), two cysteine side chains (disulfide), two other side chains (most often a lactam), or a side chain and one terminus. A single peptide can carry more than one of these, producing bicyclic and polycyclic architectures.

Head-to-tail (backbone / homodetic) cyclization

Head-to-tail cyclization forms an amide bond directly between the N-terminus and the C-terminus of a linear precursor, closing the whole backbone into a loop. Chemically, the C-terminal carboxyl is activated into a reactive ester — typically with a coupling reagent such as HATU or HBTU — and the N-terminal amine then attacks it to form the ring-closing amide.^[3] Because the reaction has to happen within one molecule rather than between two, it is normally run at high dilution, often submillimolar, so that the two ends of the same chain find each other before the end of one chain finds the start of another.^[3] Head-to-tail closure gives the greatest protection against exopeptidases, because it removes both free termini, and it is the dominant strategy in the therapeutic literature: analyses of cyclic-peptide research put head-to-tail closure at roughly two-thirds of reported structures.^[2]

Disulfide cyclization

Disulfide cyclization joins two cysteine residues by oxidizing their thiol (–SH) side chains into a covalent disulfide (–S–S–) bond. This is the ring found in many small peptide hormones and in a great many antimicrobial peptides, where it locks a hairpin or loop into shape. Disulfide bonds are common but conditional: they are stable in an oxidizing environment and can be reduced and reopened in a sufficiently reducing one, which is why disulfide-bridged peptides are described as environment-dependent. Of the cyclic peptide drugs approved between 2001 and 2021, disulfide closure was the single most common ring type.^[1]

Side-chain-to-side-chain cyclization (the lactam bridge)

Side-chain-to-side-chain cyclization bridges two side chains rather than the backbone. The most important version is the lactam bridge: an amide bond formed between the ε-amino group of a lysine and the carboxyl side chain of an aspartate or glutamate.^[3] In synthesis, the two partner side chains carry protecting groups that can be removed independently of the rest of the molecule (orthogonal protection), so the lysine and the acidic residue can be unmasked and coupled while everything else stays capped.^[3] Lactam bridges are the standard way to staple a short helix or turn into a fixed shape, and they are the chemistry behind several melanocortin research peptides, discussed below.

Side-chain-to-tail, and multiple rings

A fourth arrangement links a side chain to one of the termini — for example a side-chain carboxyl to the N-terminus — producing a ring that encloses part, but not all, of the backbone. Finally, these motifs combine. A peptide can carry a head-to-tail backbone ring and one or more disulfide bonds at the same time, giving a bicyclic or polycyclic structure. The naturally occurring θ-defensins and the plant cyclotides are the classic examples: a closed backbone reinforced by internal disulfides, which is about as rigid and enzyme-proof as a peptide gets.

Why cyclize: what a ring buys

Cyclization is used because a ring changes four properties of a peptide more or less at once: it resists enzymatic degradation, it is more rigid, that rigidity can raise binding affinity and selectivity, and in some cases it improves passage across membranes. No single property explains why cyclic peptides are so prominent; it is the combination.

Enzymatic stability. The most immediate gain is resistance to the enzymes that break peptides down, covered in detail in the next section. Because the great majority of peptide-degrading enzymes work from a free end, a backbone ring with no free end is largely immune to them.

Conformational rigidity. A linear peptide is a floppy chain that can adopt an enormous number of shapes. Closing it into a ring restricts that freedom, so the peptide spends more of its time in a small number of defined conformations. In binding terms, a flexible molecule pays an entropic penalty when it locks into the single shape that fits a target, because it gives up all the other shapes it could have taken; a pre-organized ring has already paid much of that cost, so binding is entropically cheaper.^[15]

Affinity and selectivity. That pre-organization tends to translate into tighter and more selective binding. It is also what lets cyclic peptides address targets that defeat conventional small molecules. Protein–protein interfaces are large, flat and shallow, and small molecules struggle to grip them; a macrocycle is big enough to lie across such a surface while still being far smaller than an antibody. One estimate holds that on the order of 20–40% of protein–protein interfaces may be addressable by macrocyclic inhibitors, which is a large expansion of what is considered druggable.^[15] This is the sense in which cyclic peptides are said to occupy a chemical space between small molecules and biologics, combining some of the specificity of a large biologic with the more tractable properties of a smaller molecule.^[2]

Membrane permeability. This one is conditional rather than automatic, and it is treated separately below, because a ring on its own does not make a peptide permeable — but a ring is the starting point that other modifications build on.

How a ring resists degradation

A cyclic peptide resists degradation mainly because the enzymes that dismantle peptides are built to work on features a ring removes. Two broad classes matter: exopeptidases, which trim residues off a free end, and endopeptidases, which cut somewhere in the middle of a chain.

Exopeptidases are the more abundant of the two, and they are the reason head-to-tail cyclization is so effective. An aminopeptidase needs a free N-terminus to grab; a carboxypeptidase needs a free C-terminus. A backbone-cyclized peptide presents neither, so an entire category of degradation simply has no place to start. This is why removing the termini — rather than any single change to the internal sequence — is often the largest single stability gain available.

Endopeptidases are harder to shut out, because they cut internal bonds, but rigidity helps here too. A protease active site has to bind a stretch of the substrate in an extended conformation before it can cut it; a rigid ring that will not flatten into that conformation is a poor substrate. Cyclization “imposes conformational rigidity that reduces accessibility by endopeptidases,” on top of the exopeptidase protection it provides at the ends.^[15]

The most dramatic illustration is a plant peptide. The cyclotide kalata B1 combines a head-to-tail backbone with three disulfide bonds arranged in a knot — the cyclic cystine knot. Because of that architecture, it “cannot unfold from their native conformation without breaking at least one covalent bond,” and it survives treatments that destroy ordinary peptides, including boiling and digestion by proteolytic enzymes.^[7][8] Kalata B1 is the reason cyclotides are studied as scaffolds at all: a therapeutic sequence can be grafted into one of the loops while the rigid, enzyme-proof frame holds it together.^[7] For the general chemistry of how peptides fall apart when they are not protected this way — hydrolysis, oxidation, deamidation and aggregation — see How Peptides Degrade.

Cyclization and membrane permeability

Cyclization can help a peptide cross membranes, but it does not do so on its own; the effect depends on ring size and, above all, on additional modifications such as N-methylation. Peptides are generally poor at crossing the lipid bilayer because their backbone is studded with polar amide bonds that hydrogen-bond to water and resist entering an oily membrane interior. A ring alone does not remove those polar groups.

The trick that works is to reduce the number of exposed hydrogen-bond donors and to let the molecule hide the polar ones. Backbone N-methylation — replacing an amide N–H with an N–CH₃ — “selectively blocks one hydrogen bond of the original amide NH,” lowering the energetic cost of moving the peptide out of water and into a membrane.^[12] In one reported series, N-methylation raised measured Caco-2 cell permeability from about 1×10⁻⁶ to 4×10⁻⁶ cm/s.^[11]

The textbook case is cyclosporine, a cyclic peptide with several N-methylated residues that is orally bioavailable where almost no peptide of its size is. It behaves like a molecular “chameleon”: in a nonpolar environment such as a membrane it folds so that four intramolecular hydrogen bonds form, tucking its polar groups inside and turning a hydrophobic face outward; in water those internal hydrogen bonds break and the polar groups are exposed again.^[12] That open–close switching is what lets one molecule be soluble enough in water and greasy enough to cross a membrane. Cyclosporine has a molecular weight around 1,203 Da and a reported oral bioavailability of roughly 20–70%, both far outside what the classic “rule of five” would predict for an orally available drug.^[11]

Cyclic peptides like it are the reason medicinal chemists talk about a “beyond rule of 5” space, with its own rough guideposts — for oral permeability, properties such as a molecular weight under about 1,000 Da, a limited polar surface area and a controlled number of hydrogen-bond donors.^[11] The practical point for anyone reading about peptides is that oral availability is the exception, not the rule, and it is engineered deliberately through cyclization plus backbone modification; most peptides remain poorly permeable regardless of the ring.

Cyclic peptides in nature

Nature discovered the ring long before chemists did, and many of the most familiar peptides are naturally cyclic. Surveying them shows every ring type in use and explains why the shape recurs across bacteria, fungi, plants and animals.

Hormones closed by a disulfide. Oxytocin and vasopressin are nine-residue peptide hormones, each closed into a small ring by a single disulfide bond with a short tail hanging off it. Oxytocin holds a place in the history of chemistry: Vincent du Vigneaud determined its structure and synthesized it in 1953, and the 1955 Nobel Prize in Chemistry recognized him “for his work on biochemically important sulphur compounds, especially for the first synthesis of a polypeptide hormone.”^[4] The disulfide ring was, in other words, part of the very first peptide hormone ever made in a laboratory.

Antibiotics from microbes. Bacteria and fungi produce a wealth of cyclic peptide antibiotics, many of them built on assembly-line enzymes rather than the ribosome, which is why they can contain unusual building blocks. Gramicidin S, described by Georgyi Gause and Maria Brazhnikova in 1942, is a cyclic decapeptide — cyclo(–Val–Orn–Leu–D-Phe–Pro–)₂ — that folds into an antiparallel β-sheet and contains two D-phenylalanine residues and the non-standard amino acid ornithine.^[10] Its potent activity against bacteria is offset by toxicity that confines it to topical use, a reminder that a cyclic natural product is not automatically a usable drug.^[10] Daptomycin, vancomycin and the echinocandin antifungals are other cyclic (often lipid- or sugar-decorated) peptide antibiotics.^[1]

The fungal immunosuppressant. Cyclosporine is a cyclic undecapeptide — an 11-residue ring — produced by the soil fungus Tolypocladium inflatum. The fungus was isolated from soil in 1970, the immunosuppressive activity was recognized at Sandoz in the mid-1970s, and the drug was approved in November 1983.^[5] Its ring carries several N-methylated residues, including an unusual amino acid at position one, and those methylations are exactly what give it the chameleon behaviour described above.^[5][12]

Ultra-stable plant and animal rings. The plant cyclotides, of which kalata B1 is the prototype, are 28–37-residue peptides with a head-to-tail backbone and three disulfides forming a cyclic cystine knot; kalata B1 was first noticed because an African medicinal tea retained activity after boiling, and its cyclic structure was solved in 1995.^[7] In animals, the only known naturally backbone-cyclized peptides are the θ-defensins: RTD-1, isolated from rhesus macaque leukocytes and reported in 1999, is a small circular antimicrobial peptide assembled by joining two truncated precursor peptides end to end.^[9] That such convergent solutions arose independently in plants, fungi, bacteria and primates is the strongest possible argument that the ring is worth having.

Cyclic peptides among studied compounds

Several compounds that appear in the research-peptide literature are cyclic, and the melanocortin family is the clearest case. Understanding that they are rings explains a good deal of their reported chemical behaviour.

Melanotan II is a cyclic peptide: a shortened analogue of the natural hormone α-melanocyte-stimulating hormone (α-MSH) in which a side-chain-to-side-chain lactam bridge, between an aspartate and a lysine, closes part of the sequence into a ring. The lineage is well documented. Al-Obeidi, de L. Castrucci, Hadley and Hruby reported “potent and prolonged-acting cyclic lactam analogues of α-melanotropin” in 1989, designed with molecular-dynamics modelling; the cyclic lactam versions showed far greater melanotropic potency in laboratory melanocyte assays than the flexible linear parent, and the larger 23- and 24-membered rings showed prolonged residual activity that the smaller rings did not.^[6] That study is a textbook demonstration of the “what a ring buys” argument: the same sequence, made rigid, became both more potent and longer-lasting in the assay. The chemistry is described further in What Is Melanotan II, and the wider melanocortin comparison in Melanotan II vs PT-141.

Bremelanotide — the melanocortin peptide also known as the compound family covered in What Is PT-141 — is likewise a lactam-cyclized melanocortin peptide, and it was approved as a medicine (under the brand Vyleesi) in 2019, with the regulatory literature classifying its ring as a lactam.^[1] Setmelanotide, another melanocortin-receptor peptide, is cyclic as well; approved in 2020, it is closed by a disulfide bond.^[1] The point across all three is structural, not clinical: the melanocortin peptides are studied as rings because a rigid ring both raises potency at the receptor and slows enzymatic breakdown of an otherwise short-lived sequence.

Cyclization also sits alongside the other half-life-extension strategies. A ring resists exopeptidases; lipidation, PEGylation, albumin binding and drug-affinity-complex chemistry work by other routes. Those approaches, and how they compare with cyclization, are the subject of Peptide Half-Life Extension and What Is DAC in Peptides. Octreotide is a useful bridge between the two ideas: it is a disulfide-cyclized, D-amino-acid-containing analogue of the natural hormone somatostatin, and the combination of changes takes a reported half-life from under three minutes for somatostatin to roughly 100 minutes for octreotide.^[11]

How chemists close the ring

Most synthetic cyclic peptides are assembled as a linear chain first and then closed, and the ring-closing step is often the hardest part of the whole synthesis. The chain itself is usually built by solid-phase peptide synthesis, one protected amino acid at a time on a resin bead, the general process described in How Peptides Are Made. Cyclization is what happens after that.

For a head-to-tail ring, the C-terminal carboxyl is activated and the N-terminal amine attacks it to form the closing amide bond. The central difficulty is competition: the reactive end of one molecule is just as happy to react with the end of a different molecule, which produces dimers and longer polymers instead of the ring.^[14] The standard defence is high dilution — keeping the peptide concentration low, often submillimolar, so that any given chain is far more likely to meet its own other end than a neighbour’s.^[3] High dilution works but is awkward to scale, because it means large volumes of solvent for a small amount of product, and newer enzymatic and “self-cyclising” strategies aim to get high yields without it.^[14]

A second, subtler hazard is epimerization at the residue being activated: the chemistry that makes the C-terminus reactive can also scramble its stereochemistry, converting a fraction of the intended L-residue into the D-form and producing a diastereomeric impurity that has to be separated out. Choice of the ring-closure site and coupling reagent is used to minimize it.

Disulfide and lactam rings are closed differently. A disulfide ring is formed by oxidizing two cysteine thiols, and when a peptide contains several cysteines the challenge is directing the right pairs together rather than a scrambled set, usually by protecting different cysteine pairs with different groups and oxidizing them in a controlled order. A lactam ring is formed by selectively unmasking one acidic and one basic side chain — using protecting groups removable independently of the rest — and coupling them while the backbone stays capped.^[3]

Whatever the route, the finished ring has to be verified. Because cyclization changes the molecule’s mass in a defined way — head-to-tail closure and lactam formation each release a water molecule, and disulfide formation removes two hydrogens — mass spectrometry confirms that the ring closed and that no dimer formed, while reversed-phase HPLC confirms purity and can resolve a cyclized product from its linear precursor or an epimerized side-product. What those analytical results do and do not prove is the subject of Understanding Peptide COA Testing.

Designing cyclic peptides from scratch

Beyond copying natural rings, chemists now design cyclic peptides computationally, and the ring is central to why that is possible. A cyclic backbone has far fewer accessible shapes than a linear one, which makes its structure much easier to predict and to design toward a chosen conformation.

A 2017 study from the Baker laboratory demonstrated the point at scale, computationally designing ordered peptide macrocycles and confirming that a large set of them folded into single, predictable structures — the paper describes more than 200 designs predicted to adopt single stable conformations, several verified experimentally.^[13] The work explicitly aimed to enlarge the “available starting scaffolds for both rational drug design and library selection methods.”^[13] In parallel, the cyclotide scaffolds mentioned earlier are used in reverse: rather than designing a whole new ring, a useful sequence is grafted into a loop of an existing ultra-stable cyclic frame.^[7]

The commercial context explains the effort. Industry analyses describe tens of thousands of cyclic peptides identified as having therapeutic potential and a market projected into the billions of dollars over the coming years, with research output accelerating sharply since around 2015.^[2] Macrocyclic peptides make up more than half of the cyclic-peptide structures in those analyses, with bicyclic and polycyclic forms next.^[2]

What this guide does not establish

This guide explains what cyclic peptides are and why the ring shape is used. Several things are deliberately outside its scope.

• It is chemistry and history, not clinical guidance. Where an approval year or a mechanism is given, it describes the scientific and regulatory record for that compound. Nothing here describes how any compound is used, in what amount, or in any person or animal.
• Potency figures are assay results. Statements such as a cyclic melanotropin being more potent than its linear parent refer to the specific laboratory assays reported in the cited papers — melanocyte or cell-based systems — and do not translate to any effect outside those systems.
• Permeability and half-life figures are compound- and method-specific. The Caco-2 permeability values, the cyclosporine bioavailability range and the octreotide half-life are as reported for those molecules under particular conditions; they are illustrations, not general rules for cyclic peptides.
• Market and count figures are third-party estimates. The numbers of approved cyclic peptides, identified therapeutic candidates and market size are from industry and review sources that use different definitions and cut-off dates, so they differ from one another and should be read as directional.
• Whether a specific research peptide is correctly cyclized is a testing question, not something a name guarantees. Ring identity is a claim to be checked by mass spectrometry and HPLC on the actual lot, which is why lot-specific documentation matters.

For reference on that last point: Patriot Labs is a first-responder-owned, US-based company, and every batch it sells is tested by an independent US laboratory by HPLC and mass spectrometry, with the certificate of analysis published on the product page.

Frequently asked questions

What is a cyclic peptide?

A cyclic peptide is a peptide whose chain is joined into a ring instead of being left as an open string with two free ends. The ring can be closed in several ways: an amide bond between the two ends of the backbone (head-to-tail), a disulfide bond between two cysteine side chains, or a bridge between two side chains such as a lactam. Closing the ring removes the free ends and locks the chain into a more defined shape, which usually makes a cyclic peptide more resistant to enzymes and more rigid than the same sequence left linear.

Why are some peptides cyclic?

Because the ring changes four properties at once. It resists degradation, since exopeptidases need a free end to attack and a ring has none. It is more rigid, so it pays a smaller entropic penalty when it binds a target. That rigidity can raise binding affinity and selectivity. And in some cases, when combined with modifications such as N-methylation, cyclization improves passage across membranes. Nature discovered these advantages long before chemists did: many antibiotics, toxins and hormones are naturally cyclic.

What is the difference between a cyclic peptide and a linear peptide?

A linear peptide is an open chain with a free amino (N) terminus at one end and a free carboxyl (C) terminus at the other. A cyclic peptide has those ends, or two side chains, joined by a covalent bond so the chain forms a loop. The chemistry is otherwise the same amino acids and amide bonds; the difference is topology. That single change removes the free termini, reduces the number of shapes the chain can adopt, and generally increases stability and rigidity relative to the linear version of the same sequence.

Are cyclic peptides more stable than linear peptides?

Usually, yes. Exopeptidases, the most abundant peptide-degrading enzymes, chew inward from a free N- or C-terminus, and a head-to-tail cyclic peptide has neither, so it is protected from them. The conformational rigidity a ring imposes also makes it harder for endopeptidases to fit the chain into their active sites. The most extreme example is the plant cyclotide kalata B1, whose cyclic cystine-knot structure survives boiling and enzyme digestion because it cannot unfold without breaking a covalent bond.

What are the main types of peptide cyclization?

There are four main ways to close a peptide ring. Head-to-tail (backbone or homodetic) cyclization forms an amide bond between the N- and C-termini. Disulfide cyclization oxidizes two cysteine thiols into an S–S bond. Side-chain-to-side-chain cyclization bridges two side chains, most commonly a lactam between a lysine amine and an aspartate or glutamate carboxyl. Side-chain-to-tail cyclization links a side chain to one terminus. Peptides can also carry several of these bonds at once, giving bicyclic and polycyclic structures such as the cystine knot.

Is Melanotan 2 a cyclic peptide?

Yes. Melanotan II is a cyclic peptide. It is a shortened analogue of the natural hormone α-melanocyte-stimulating hormone (α-MSH) in which a side-chain-to-side-chain lactam bridge, between an aspartate and a lysine, closes part of the chain into a ring. The design traces back to the cyclic lactam melanotropin analogues reported by Al-Obeidi, Hadley, Hruby and colleagues in 1989, where the ring produced much greater potency and a longer-lasting effect in laboratory assays than the flexible linear parent. Bremelanotide (the compound also known as PT-141) is likewise a lactam-cyclized melanocortin peptide.

What was the first cyclic peptide?

Cyclic peptides were known in nature well before they were made deliberately. The antibiotic gramicidin S, a cyclic decapeptide, was described by Georgyi Gause and Maria Brazhnikova in the Soviet Union in 1942. The first chemically synthesized peptide hormone, oxytocin, which is cyclized by a single disulfide bond, was synthesized by Vincent du Vigneaud in 1953 and earned him the 1955 Nobel Prize in Chemistry. The immunosuppressant cyclosporine, a cyclic 11-amino-acid peptide from a fungus, was discovered in the 1970s and approved in 1983.

How are cyclic peptides made?

Most synthetic cyclic peptides are built as a linear chain first, usually by solid-phase peptide synthesis, and then closed. Head-to-tail closure activates the C-terminus so the N-terminus can attack it and form the ring-closing amide bond; this is normally done at high dilution so the ends of one molecule find each other rather than joining to a neighbour. Disulfide rings are formed by oxidizing two cysteine thiols; lactam rings are formed by selectively unmasking one acidic and one basic side chain and coupling them. Purity and ring identity are then confirmed by HPLC and mass spectrometry.

References

1. Zhang, H., & Chen, S. (2022). Cyclic peptide drugs approved in the last two decades (2001–2021). RSC Chemical Biology, 3(1), 18–31. doi:10.1039/D1CB00154J. https://pubs.rsc.org/en/content/articlehtml/2022/cb/d1cb00154j
2. CAS (Chemical Abstracts Service). Trends for cyclic peptides in drug discovery (CAS Insights report). https://www.cas.org/resources/cas-insights/cyclic-peptides
3. Creative Peptides. Head-to-Tail vs Side-Chain Cyclization in Peptide Engineering. https://www.creative-peptides.com/resources/head-to-tail-vs-side-chain-cyclization-in-peptide-engineering.html
4. The Nobel Prize in Chemistry 1955 — Vincent du Vigneaud, “for his work on biochemically important sulphur compounds, especially for the first synthesis of a polypeptide hormone.” NobelPrize.org. https://www.nobelprize.org/prizes/chemistry/1955/vigneaud/facts/
5. Moore, D. The cyclosporine story (discovery of ciclosporin from Tolypocladium inflatum; isolated 1970, immunosuppressive activity mid-1970s, FDA approval November 1983). davidmoore.org.uk. https://www.davidmoore.org.uk/sec04_01.htm
6. Al-Obeidi, F., de L. Castrucci, A. M., Hadley, M. E., & Hruby, V. J. (1989). Potent and prolonged-acting cyclic lactam analogues of α-melanotropin: design based on molecular dynamics. Journal of Medicinal Chemistry, 32(12), 2555–2561. doi:10.1021/jm00132a010
7. Weidmann, J., & Craik, D. J. (2016). Discovery, structure, function, and applications of cyclotides: circular proteins from plants. Journal of Experimental Botany, 67(16), 4801–4812. doi:10.1093/jxb/erw210
8. Colgrave, M. L., & Craik, D. J. (2004). Thermal, chemical, and enzymatic stability of the cyclotide kalata B1: the importance of the cyclic cystine knot. Biochemistry, 43(20), 5965–5975. doi:10.1021/bi049711q
9. Tang, Y. Q., Yuan, J., Ösapay, G., et al. (1999). A cyclic antimicrobial peptide produced in primate leukocytes by the ligation of two truncated α-defensins. Science, 286(5439), 498–502. doi:10.1126/science.286.5439.498
10. Gramicidin S (structure cyclo(–Val–Orn–Leu–D-Phe–Pro–)₂; discovered by G. F. Gause and M. Brazhnikova, 1942). Wikipedia. https://en.wikipedia.org/wiki/Gramicidin_S
11. WuXi AppTec DMPK. Cyclic Peptides: FDA-Approved Drugs and Their Oral Bioavailability and Metabolic Stability Tactics. https://dmpkservice.wuxiapptec.com/articles/403-cyclic-peptides-fda-approved-drugs-and-their-oral-bioavailability-and-metabolic-stability-tactics/
12. Li, Y., Li, W., & Xu, Z. (2021). Improvement on Permeability of Cyclic Peptide/Peptidomimetic: Backbone N-Methylation as A Useful Tool. Marine Drugs, 19(6), 311. doi:10.3390/md19060311
13. Hosseinzadeh, P., Bhardwaj, G., Mulligan, V. K., et al. (2017). Comprehensive computational design of ordered peptide macrocycles. Science, 358(6369), 1461–1466. doi:10.1126/science.aap7577. https://www.bakerlab.org/2017/12/15/new-article-science-exploring-peptide-landscape/
14. Jia, X., Chin, Y. K. Y., Zhang, A. H., et al. (2023). Self-cyclisation as a general and efficient platform for peptide and protein macrocyclisation. Communications Chemistry, 6, 48. doi:10.1038/s42004-023-00841-5
15. Intavis Peptide Services. Closing the Loop: How Cyclic Peptides Are Reshaping Therapeutics. https://intavispeptides.com/en/insights/31

For related reading, see What Are Peptides? for the basics of amino acids and amide bonds, Peptide Half-Life Extension for how cyclization compares with lipidation and PEGylation, How Peptides Are Made for the solid-phase synthesis that precedes ring closure, How Peptides Degrade for the chemistry a ring protects against, and What Is Melanotan II for a cyclic lactam research peptide in depth.

All Patriot Labs products are sold strictly for in-vitro research and laboratory use only. Not for human or veterinary consumption. This guide is educational and describes the chemistry and history of cyclic peptides in general terms; it is not medical advice, does not describe how to use any product, and makes no claim about the effects of any compound.