Cyclopeptides (Cyclic Peptides)
Cyclopeptides or cyclic peptides, which are naturally occurring compounds with distinctive rings in their structure, are gaining popularity in both scientific and industrial fields. These peptides have high versatility and bioactivity, and therefore are promising targets in drug discovery, skincare, and diagnostics. BOC Sciences, a leading natural product provider, is the pioneer in using cyclic peptides in the most advanced biomedical applications.
What is Cyclic Peptide?
A cyclic peptide (cyclopeptide) is a peptide whose amino acids have a closed loop rather than linear peptides whose amino acids have a linear order. That structure confers special biochemical characteristics such as higher stability, resistance to enzymatic breakdown, and binding to specific biological targets, which renders them particularly valuable in therapeutic and diagnostic fields. Cyclic peptides consist of amino acids, bind together with peptide chains, and often include other modifications, like disulfide bonds, that make them more stable and bioactive.
Schematic application of natural cyclic peptides as anticancer agents. (Zhang, J.N.; et al, 2021)
Cyclic Peptides Types
Monocyclic Peptides
A monocyclic peptide is made of one loop with peptide bonds. These peptides could have different structure elements, such as a combination of hydrophobic and hydrophilic residues, that enable specific interactions with their biological partners. For instance, there is the common immunosuppressant, cyclosporin A.
Bicyclic Peptides
There are two connected loops in bicyclic peptides. They tend to be more stable and highly bioactive. They have been detected in a number of natural remedies and synthetic peptide drugs. Bicyclic peptides, for instance, as peptide ligands have been employed to modify certain protein-protein interactions that cannot be targeted with small molecules.
Bridged Cyclic Peptides
These peptides have other cross-links which can be either covalent or non-covalent. The bridge may be disulfide, other bond or some other kind of linkage, which lends the peptide structure more stability and rigidity. These peptides are useful especially for the design of drugs, which requires stability and specificity.
Macrocyclic Peptides
Macrocyclic peptides are large, cyclic peptides typically consisting of 12 or more amino acids. They often feature complex cyclic structures, including additional heteroatoms like sulfur, oxygen, or nitrogen, which contribute to their bioactivity. These peptides are widely explored in drug discovery, especially for their potential to inhibit protein-protein interactions and other challenging targets.
Sources of Cyclic Peptides
Cyclic peptides are derived from various natural sources, including plants, fungi, bacteria, and marine organisms. Each source produces peptides with distinct bioactive properties, making them suitable for specific therapeutic applications.
Cyclic Peptides from Marine Organisms
Marine organisms, such as sponges, mollusks, and marine bacteria, are rich sources of cyclic peptides. For example, peptides derived from marine fungi, like cyclosporins and decapeptides, have been used in immunosuppressive therapies and are of great interest in anti-cancer research.
Cyclic Peptides from Fungi
Fungi are another prolific source of cyclic peptides. Certain fungal species, such as Aspergillus and Penicillium, produce peptides with potent anticancer, antibacterial, and antiviral activities. Fungal cyclic peptides are often more structurally diverse compared to their bacterial counterparts, providing a broader spectrum of bioactivity.
Cyclic Peptides from Bacteria
Cyclic peptides produced by bacteria, such as bacturins and thuricin, have demonstrated antimicrobial properties, making them ideal candidates for antibiotic development. These peptides often function as natural antibiotics, targeting specific bacterial strains.
Cyclic Peptides from Plants
Plants also produce a variety of cyclic peptides, particularly those involved in defense mechanisms. For instance, plant defensins are cyclic peptides known for their ability to protect plants from pathogens, with some having potential applications in agricultural and pharmaceutical industries.
Cyclic Peptide Synthesis
The synthesis of cyclic peptides is a highly specialized field that requires both expertise in peptide chemistry and advanced technologies to achieve high purity and structural specificity. Unlike linear peptides, which are straightforward to synthesize using traditional solid-phase peptide synthesis (SPPS), cyclic peptides require additional steps to form the closed loop structure that is essential for their bioactivity. This process can be more challenging due to the need for precise cyclization, control of peptide folding, and maintaining high yield.
Solid-Phase Peptide Synthesis (SPPS)
SPPS is the most widely employed technique for the synthesis of both linear and cyclic peptides. The process involves sequential addition of amino acids to a solid support, where the peptide chain is constructed step-by-step. For cyclic peptides, the final linear peptide is cyclized either chemically (via cross-linking agents like disulfide bonds) or enzymatically (using cyclases).
Template-Assisted Synthesis
In some cases, the synthesis of cyclic peptides is facilitated using a template, which guides the formation of the cyclic structure. This method is particularly useful for peptides that require specific spatial arrangements, such as those with non-natural amino acids or complex cyclic motifs.
Peptide Cyclization via Chemical Reactions
To close the peptide loop, cyclization reactions are often employed. These include disulfide bond formation, lactamization (amide bond formation), or click chemistry, which allows for the incorporation of diverse chemical groups into the cyclic structure. Chemical cyclization methods offer high yield and the ability to control the structure of the final peptide.
Cyclic Peptides Examples
Cyclosporine A
One of the most famous cyclic peptides, Cyclosporine A is a cyclic undecapeptide that has revolutionized organ transplantation medicine. It is produced by the fungus Tolypocladium inflatum and is primarily used as an immunosuppressant to prevent organ rejection in transplant recipients.
Gramicidin S
Gramicidin S is a well-known cyclic peptide with significant antimicrobial properties. It was first isolated from Bacillus brevis and has been widely studied due to its broad-spectrum activity against bacteria, including both Gram-positive and Gram-negative species. Gramicidin S has inspired the design of synthetic antimicrobial peptides and continues to serve as a model for developing new agents against antibiotic-resistant pathogens.
Tyrocidine
Tyrocidine is a cyclic decapeptide with a similar structure to gramicidin S but with differences in the composition of amino acids. Like gramicidin S, tyrocidine is an antimicrobial agent that disrupts bacterial membranes by embedding into the lipid bilayer, leading to leakage of ions and macromolecules. It is particularly effective against Gram-positive bacteria.
Bacitracin
Bacitracin is a well-established cyclic peptide antibiotic that has been widely used in the treatment of bacterial infections. It is produced by Bacillus subtilis and is particularly effective against Gram-positive bacteria. Bacitracin consists of a cyclic peptide with a core structure containing a sequence of amino acids such as leucine, threonine, and tyrosine. The peptide ring is closed via a thiazoline ring structure, which contributes to its antimicrobial activity.
Cyclic Citrullinated Peptide
Cyclic citrullinated peptides (CCPs) are a specific class of cyclic peptides that have gained importance in clinical diagnostics, particularly for autoimmune diseases like rheumatoid arthritis (RA). CCPs are generated through the post-translational modification of arginine residues into citrulline by the enzyme peptidyl arginine deiminase.
Cyclic Peptide vs Linear Peptide
| Comparison | Cyclic Peptides | Linear Peptides |
|---|
| Structure | Cyclic peptides are characterized by their closed-loop structure, which can be formed through various chemical linkages, such as peptide bonds, disulfide bridges, or even lactam bonds. | A linear peptide consists of a series of amino acids arranged in a specific sequence, typically without any intramolecular covalent bonding, aside from the peptide bonds between the amino acids. |
| Stability | Cyclic peptides, owing to their rigid structure and closed-loop design, are significantly more stable than their linear counterparts. Their circular shape prevents them from being easily recognized and degraded by proteases, which contributes to a longer half-life and improved stability in biological systems. | Due to their unstructured nature, linear peptides are more susceptible to enzymatic degradation, particularly by proteases, which break down peptide bonds. This makes linear peptides relatively unstable in biological systems, limiting their use in clinical or therapeutic applications unless modified. |
| Binding Affinity | Cyclic peptides typically exhibit higher binding affinity and specificity for their targets due to their rigid structure. The closed-loop design allows them to adopt a specific three-dimensional conformation that is ideal for binding to particular receptors or enzymes. This makes them highly effective in applications that require precise molecular recognition. | Linear peptides generally exhibit good bioactivity, though their flexibility can sometimes limit their ability to achieve a high degree of specificity in binding interactions. They may require a specific conformation to interact optimally with their targets, which can sometimes lead to lower binding affinity and specificity compared to cyclic peptides. |
| Pharmacokinetics | The stability of cyclic peptides not only extends their half-life but also improves their pharmacokinetic properties. Their reduced susceptibility to enzymatic breakdown allows for better bioavailability, even in the harsh biological environments of the gastrointestinal tract or bloodstream. | The pharmacokinetics of linear peptides are often hindered by their susceptibility to enzymatic degradation, which can limit their bioavailability. In some cases, linear peptides require modification or the use of delivery systems to protect them from premature breakdown and improve their effectiveness. |
| Applications | Cyclic peptides, due to their enhanced stability and high specificity, are increasingly being explored in drug discovery, particularly in areas such as cancer treatment, autoimmune diseases, and infectious diseases. Their ability to specifically target receptors and enzymes makes them excellent candidates for targeted therapies. | Linear peptides have been extensively studied for their potential in drug development, particularly as enzyme inhibitors, receptor ligands, or antimicrobial agents. However, due to their relative instability, they often require modification to improve their pharmacological properties. |
Applications of Cyclic Peptides
Cyclic Peptides for Drug Development
Cyclic peptides hold great promise as therapeutic agents due to their high specificity, stability, and ability to target challenging proteins. In drug development, these peptides are being explored for their ability to bind to protein-protein interfaces, enzyme active sites, and other biological targets that are difficult for traditional small molecules to interact with. Cyclic peptides can serve as scaffolds for the development of new classes of drugs, particularly in oncology, immunology, and neurology.
Cyclic Peptides in Skin Care
Cyclic peptides are increasingly being incorporated into cosmetic formulations due to their ability to improve skin hydration, promote collagen synthesis, and exhibit antioxidant properties. Peptides like palmitoyl pentapeptide-4 and acetyl hexapeptide-8 have been shown to reduce the appearance of fine lines and wrinkles, enhancing skin elasticity and reducing signs of aging. These peptides function by promoting skin cell regeneration and providing deep hydration, making them valuable in both anti-aging and skin rejuvenation products.
Cyclic Peptides in Cancer Therapy
Cyclic peptides have proven particularly effective in cancer therapy due to their ability to specifically target cancer cells while minimizing damage to surrounding healthy tissues. These peptides can be engineered to recognize overexpressed receptors or specific tumor antigens, allowing for targeted drug delivery and enhancing the efficacy of chemotherapy. BOC Sciences, with its advanced peptide synthesis capabilities, is actively engaged in the development of novel cyclic peptide-based therapeutic agents for cancer treatment.
Advantages of BOC Sciences' Cyclic Peptides
Cyclic peptides derived from natural products represent an exciting and rapidly growing area in the field of peptide chemistry and drug development. BOC Sciences offers a range of high-quality cyclic peptides derived from natural sources.
- Enhanced Bioactivity and Specificity: Cyclic peptides from natural sources often show superior bioactivity due to their evolutionary optimization for interacting with biological targets. BOC Sciences' peptides exhibit high specificity and potent biological effects.
- Rigorous Quality Control: Each batch of cyclic peptides is subjected to rigorous quality control procedures, ensuring that they meet the highest standards of purity and functionality. This includes structural verification, biological testing, and stability analysis, guaranteeing that each peptide performs as expected in the intended applications.
- Comprehensive Applications: From drug discovery to diagnostics, the cyclic peptides offered by BOC Sciences are applicable in a variety of therapeutic and research contexts. These peptides are used in areas such as cancer therapy, immunology, and infectious disease research, contributing to the advancement of targeted therapies and precision medicine.
- Customization and Optimization: BOC Sciences offers expert support for formulation development, biosynthesis optimization, and application guidance, assisting clients in achieving their research and product development goals.
Reference
- Zhang, J.N.; et al. Natural Cyclopeptides as Anticancer Agents in the Last 20 Years. Int. J. Mol. Sci. 2021, 22(8): 3973.
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