Cyclic Peptides
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Creative Peptides provides several cyclic peptides. Besides, we can provide a wide range of cyclic peptide synthesis.
So far, small molecule drugs and biologics have been highly regarded in the early stages of drug research and development. Despite their respective advantages as drug molecules, such as the oral availability and cell membrane penetration of small molecules acting on intracellular targets, and the higher specificity of biologics, their applications still have limitations. In many aspects, they cannot perfectly complement each other. Small molecules can only interact with targets that have rigid and hydrophobic patches or grooves. Additionally, the binding regions of small molecules on target proteins are usually highly conserved, and low selectivity inevitably leads to many side effects. Selecting and evolving kinase inhibitors with high selectivity for specific targets has always been a challenge in small molecule development.
On the other hand, large molecule drugs inherently cannot penetrate cell membranes, and their use is restricted to membrane or extracellular targets. Moreover, many large molecule drugs are produced through cell culture methods, making it difficult to avoid heterogeneity due to post-translational modifications and other derivatizations. Lastly, they cannot be taken orally and typically need to be administered intravenously. Therefore, large molecules are prone to degradation and neutralization in the bloodstream, and can even cause serious immunogenicity.
As a result, peptide molecules, which fall between small and large molecules in terms of structure and functionality, have attracted increasing attention in recent years, especially cyclic peptides, bringing hope for the development of new drugs.
Advantages of Cyclic Peptides
1. Reduced conformational flexibility due to cyclization significantly improves metabolic stability, binding affinity, and specificity for target proteins. Smaller cyclic peptides, such as those with fewer than 10 amino acids, are relatively resistant to protease degradation.
2. Medium-sized cyclic peptides (6-15 amino acid residues, 500-2000 Da) are typically 3-5 times the size of small molecule drugs, allowing them to bind to larger surface areas on target proteins. Thus, cyclic peptides have the ability to encompass the unique affinity and specificity of proteins, even targeting proteins without any binding pockets, similar to the binding strength and specificity of biologics like monoclonal antibodies.
3. Cyclic peptides exhibit enormous structural diversity. For instance, an octapeptide using only 20 natural amino acids from human protein sources can generate approximately 2.5x10^10 different cyclic peptide molecules. Introducing non-proteinogenic amino acids (e.g., D-amino acids, β-/γ-amino acids, non-natural amino acids), N-methylation of amide bonds, altering size, and changing the way of cyclization can further increase diversity. In fact, various types of cyclic peptide compound libraries, ranging from billions to trillions and even quadrillions (10^14) of cyclic peptide molecules, have been generated. This level of structural diversity far surpasses human antibody libraries and theoretically allows for the discovery of highly potent and specific cyclic peptide ligands for any protein target.
4. Compared to proteins, cyclic peptide molecules retain some characteristics of small molecules, such as stability, low risk of immune reactions, ease of synthesis, and low production costs.
5. Cyclic peptides can possess cell-penetrating properties, allowing them to target intracellular proteins, including those involved in protein-protein interactions (PPIs).
Classification of Cyclic Peptides
Cyclic peptides can be classified based on the types of bonds forming the ring. Generally, they can be divided into homocyclic peptides and heterocyclic peptides. Homocyclic peptides consist of rings composed only of regular peptide bonds (i.e., between the α-carboxyl group of one residue and the α-amino group of another residue), such as cyclosporin A. Heterocyclic peptides contain at least one non-α-amide bond, for example, in microcystins and bacteriocins, where a bond exists between the side chain of one residue and the α-carboxyl group of another residue.
Additionally, cyclic peptides can be further classified based on the location of the cyclic structure in the peptide. There are four main types: head-to-tail, head-to-side chain, side chain-to-tail, and side chain-to-side chain cyclization.
Application of Cyclic Peptides
Drug Therapy
Cyclic peptide molecules possess certain metabolic stability, cell-penetrating properties, and high specificity for target binding. They find applications in various disease treatment areas, including anti-infection (antibacterial, antifungal, antiviral), anticancer, platelet aggregation inhibition, antihypertensive, tyrosine kinase inhibition, cyclooxygenase inhibition, lipoxygenase inhibition, estrogen-like activity, immunosuppression, etc. These molecules can target extracellular membrane proteins such as GPCRs and ion channels, as well as intracellular membrane proteins such as PPIs.
1. Antibacterial (Antibiotics)
There is a series of natural products and analogs used as antibiotics since 1948, such as bacitracin, polymyxin B, streptomycin, vancomycin, daptomycin, enopeptin, valinomycin, vancomycin, teicoplanin, dalbavancin, oritavancin, and telavancin.
2. Antifungal
Several cyclic peptide drugs for antifungal purposes have been introduced, including caspofungin, micafungin sodium, anidulafungin, and rezafungin.
3. Antiviral
Cyclic peptide drugs targeting HIV, such as palivizumab, golimumab, and fostamatinib, have been approved.
4. Targeting Intracellular Membrane Proteins
Two cyclic peptide drugs targeting intracellular membrane proteins have been approved: romidepsin and voclosporin.
5. Targeting Extracellular Proteins like GPCRs
Peptide inhibitors based on somatostatin modification, including octreotide, lanreotide, and pasireotide. Melanocortin agonists like bremelanotide and setmelanotide. Targeting chemokine receptor with motesanib.
6. Targeting Ion Channel Proteins
Ziconotide, a synthetic ω-conotoxin (ω-MVIIA), is a potent and selective blocker of N-type calcium channels. It was approved in 2004 for the treatment of severe chronic pain by reducing the release of neurotransmitters in the spinal dorsal horn.
Disease Diagnosis
Since 1994, five tumor diagnostic reagents based on somatostatin analogs have been developed, such as Indium In-111 Pentetreotide, Lutetium Lu 177 dotatate, Edotreotide gallium Ga-68, and Dotatate Copper Cu-64.
Fluorescent cyclic peptides serve as excellent chemical scaffolds for constructing molecular imaging optical reagents. Besides possessing good physicochemical properties, they can be modified with various organic fluorescent groups, generating useful probes for specific protein (receptor or enzyme) bioassays.
The RGD motif (arginine-glycine-aspartate sequence) has a long history in integrin transmembrane receptor targeting research.
Target Research
Protein-protein interactions (PPIs) play a crucial role in many biological and biochemical processes, including intracellular signaling and metabolism. Currently, there are 930,000 human PPIs identified, and targeting these interactions in drug development poses significant challenges. However, cyclic peptides demonstrate advantages in structure, stability, and cell-penetrating properties when targeting such interactions.
Various methods are employed for studying PPI targets, such as using display technologies to screen high-throughput cyclic peptide compound libraries, studying the potential affinity molecules of target proteins, employing high-throughput virtual screening (HTVS) to identify candidate drug molecules from large compound libraries, and integrating deep learning (DL for protein structure prediction) and HTVS techniques, as seen in AlphaFold2.
Drug Delivery
Cyclic cell-penetrating peptides (cCPPs) are a relatively new class of peptides with enormous potential in delivering therapeutic drugs intracellularly. They aim to treat challenging diseases, including multidrug-resistant bacterial infections, cancer, and HIV.
Cell-penetrating peptides can be classified based on origin, physicochemical properties, or conformational differences. Based on origin, they can be protein-derived, chimeric, or synthetic. Based on conformation, they can be linear CPPs or cyclic CPPs. Based on physicochemical properties, they can be cationic CPPs, hydrophobic CPPs, amphipathic CPPs, etc.
1. Commonly Used Efficient CPPs
For most CPPs, the efficiency of cell entry is low (<5%). Examples include CPP1, CPP9, and CPP12, with cell entry efficiencies of 20%, 62%, and 120%, respectively. High cell entry efficiency characteristics for CPPs include cyclic peptides, the presence of arginine and hydrophobic residues, and small ring sizes (≤9 aa). Some naturally occurring cyclic peptide scaffolds, such as SFTI-1, MCoTI-II, and Kalata B1, are commonly used for drug delivery.
2. Main Methods for CPPs Grafting
Cyclic CPPs can be grafted in five different ways for endocytic delivery: external loop, internal loop, double loop, reversible cyclization, and non-covalent complexation.
3. Deliverable "Cargo"
Deliverable "cargo" includes drug molecules, proteins, phosphorylated peptides, siRNA, fluorescent molecules, or other bioactive molecules.
Self-Assembling Cyclic Peptide Supramolecular Materials
Some cyclic peptides can assemble into tubular structures to form supramolecular cyclic peptide nanotubes, including α-peptides, β-peptides, α,γ-peptides, and cyclic peptides based on δ- and ε-amino acids.
These cyclic peptide molecules self-assemble into nanotubes through intermolecular hydrogen bonding. They find applications in biological areas such as ion channels, lipid interactions, and membrane embedding.
In addition to their applications in drug therapy, disease diagnosis, target research, drug delivery (such as molecular probes, PDC, etc.), cosmetics, supramolecular materials, etc., cyclic peptides also have various applications in industries such as catalysts, coatings; in biotechnology, such as separation and purification of biomolecules, biosensors; in the food and health supplement fields, such as functional ingredients.
