FDA Approved Cyclic Peptide Drugs
* Please kindly note that our products and services can only be used to support research purposes (Not for clinical use).
Online Inquiry
Cyclic peptides are peptide molecules with a cyclic structure, generally composed of 5-17 amino acids, and with a molecular weight of about 500 Da to 2000 Da. In contrast to linear peptide molecules, cyclic peptide molecules have a stable conformation.
Cellular Permeability of Cyclic Peptide
The cellular permeability of cyclic peptide is determined by five properties, including hydrogen bond potential, conformation, charge, size, and hydrophobicity. Lipinski rules are often used to predict the molecular passive diffusion into cells. Small molecules conforming to these parameters are more likely to have favorable pharmacokinetic properties. The five-rule states that the molecular weight (MW) of a drug-like molecule should be less than 500, the partition coefficient (LogP) less than 5, the hydrogen bond donor less than 5, and the hydrogen bond acceptor less than 10. Some recent work has expanded the criteria to accommodate peptides: recommendations for designing cyclic peptides include a logP between 0 and 7.5 and a PSA<200 Å2, which for cyclic peptide systems can also be achieved by modifying the backbone and side chains.
Pharmacokinetic Properties of Cyclic Peptide Drugs
Improved pharmacokinetic properties of absorption and biofilm permeability are required to reach protein targets. Cyclic peptides have a low energy barrier to adapt to the membrane environment and bind to transporters, thereby increasing passive diffusion and active transport. To further improve the PK/pharmacodynamic properties by introducing non-canonical elements; Introduction of a lipophilic side chain to greatly increase the affinity for plasma carrier proteins, thereby avoiding renal clearance and improving pharmacokinetic properties; Through alternative strategies, including combined with albumin or immunoglobulin, to prolong half-life, and to reduce dosing frequency.
Hundreds of cyclic peptides are in the preclinical research/clinical stage, and many of them have entered the late clinical stage.
FDA Approved Cyclic Peptide Drugs
At present, about 55 cyclic peptide drug molecules have been marketed, among which 26 cyclic peptide drugs have been marketed in the past 20 years, mainly from the United States, and most of them are ring-formed by disulfide bonds and amide bonds.
Before 2000, the molecular research and development of cyclic peptide drugs were mainly based on natural products. Since 2000 more have derived from the transformation of natural compounds and rationality of design, through a cyclic peptide of the whole structure to be affinity for the target protein. Among them, the modification and modification of Somatostatin, Vasopressin, Oxytocin, and other human hormones are the most popular. The research on growth hormone inhibin receptor, antidiuretic hormone 1 receptor, oxytocin receptor, and other targets is also the most extensive. Other such as Vancomycin, Echinocandin, Cyclosporine, Uroguanylin, α-MSH, and other natural products of renovation and modification with certain applications.
The discussions will be held on cyclic peptide drugs approved by the FDA over the past 20 years from different perspectives:
Targets
In the past two decades, the number of cyclic peptides acting on cell wall synthesis and β-1, 3-glucanase was the most, 10 for each, all of which were antimicrobial peptides. Followed by cyclic peptide drugs targeting the vasopressin receptor, somatostatin receptor, melanocortin receptor, and guanylate cyclase, with 3 drugs each. Finally, four cyclic peptide drugs target histone deacetylases, calcium channels, calcineurin, and membrane pore formation, respectively.
Field of Treatment
Anti-infective drugs at most, a total of 10 approved in the past 20 years, account for about 38.5% of the total; Endocrine drugs ranked second, with 8 approved, accounting for about 30.8% of the total. Followed by digestive system drugs, a total of 5 approved, accounting for about 19.2% of the total. The remaining three cyclic peptides were metabolic drugs (1), tumor/immune system drugs (1), and central nervous system drugs (1).
Type of Cyclization
At present, the classical cyclization pathways of peptide chains mainly include head and tail amidation, formation of disulfide bonds between cysteines, and amidation of side chain amines to C-terminal carboxyl groups and side chain carboxyl groups to N-terminus.
Among the 26 cyclic peptide drugs approved in the past 20 years, a total of 12 cyclic peptide drugs were cyclized by disulfide bonds, ranking first. By amide linkage cyclization of cyclic peptide drugs have nine, among them, there are five for the antifungal class medication (caspofungin, micafungin, and anidulafungin), targets for β-1, 3 - glucanase; A total of five cyclic peptide drugs were cyclized by ether bonds, and all of them were antibiotics.
National and Regional Distribution
Over the previous 20 years, of the 26 approved cyclic peptide drugs, 21 were from the United States; France, Australia, Canada, Italy, and Ireland each have one approved cyclic peptide drug.
Types of Cyclic Peptide
The 26 cyclic peptide drugs approved in the past 20 years can be divided into three categories: intracellular protein targeted cyclic peptide, outer membrane protein targeted cyclic peptide, and antimicrobial cyclic peptide.
In the past 20 years, only two cyclic peptide drugs targeting intracellular protein targets have been approved: romidepsin and voclosporin. The development of wear can reach target cells in the cell membrane cyclic peptide, which is extremely challenging. Unlike small molecules that can enter cells by passive diffusion, peptide molecules larger than 1000Da have special physical properties, mechanisms of action, and cell penetration, and modifications suitable for enhancing small molecule ADMET are not suitable for developing cyclic peptides. Currently, several theories for the design of such peptides, including passive diffusion, endocytosis, and carrier-mediated transport (CPPs), are limited in many aspects. For example, CPPs can bind to several extracellular receptors and realize active import, but it needs to be achieved by introducing specific elements in the peptide chain, which will affect the conformation of the peptide molecule and further reduce its binding affinity with the target.
Of the 26 approved cyclic peptide drugs, about 50% target outer membrane protein targets that interact primarily with G protein-coupled receptors (GPCR). At present, most GPCR-targeted therapeutic agents are small molecules. Peptides (≤50 amino acids) are endogenous GPCR ligands, and the development of their therapeutics is feasible. The goal of developing peptide therapies based on endogenous ligands is to retain and exploit their natural properties of high affinity, selectivity, and potency, and to improve adverse pharmacokinetic properties such as short half-life, rapid degradation, and high clearance. Among them, because of the natural linear peptide short half-life seriously hindered the development of peptide treatment, therefore, prolonging half-life is one of the main goals of drug development.
Over the previous 20 years, six anti-bacterial and three anti-fungal cyclic peptides have been approved for clinical use. These cyclic peptides were developed from natural metabolites that evolved in organisms. The high potency and low toxicity of cyclic peptide are well suited for the development of antibacterial agents against targeted microbial proteins with no or low similarity to human proteins. Daptomycin is a cyclic lipopeptide antibiotic isolated from Streptomyces rosebospora. It contains 13 residues, of which 2 are unnatural amino acids and 10 amino acids form a lactone ring through the side chain and C-terminus of Thr4. Telavacin is a semitransynthetic vancomycin derivative, which is based on the structure of vancomycin, obtained by chemical modification of the amino group of the sugar group by the introduction of an aliphatic chain and the introduction of a methylamine phosphate methyl group to the seventh aromatic amino acid. Dalbavancin is the second generation of semisynthetic fat sugar peptide antibiotics, strengthens its effect more than vancomycin, and inhibits the synthesis of bacterial cell walls. Oritavancin, a vancomycin analogue derived from chlororimonin A, differs from the addition of a lipophilic N-4(4 '-chlorophenyl) benzyl side chain, which has a heptapeptide core identical to the structure of vancomycin and has the same glycosylation modification as chloramphenicol.
Conclusion
At present, we mainly start from the backbone of natural products and chemically modify it to develop new cyclic peptide drugs. However, the natural backbone structure cannot cover a broader sequence and conformation space, so the de novo design of cyclic peptide drugs based on the target structure will also be a promising research direction in the future.
References
- Zhang H, Chen S. Cyclic peptide drugs approved in the last two decades (2001–2021)[J]. RSC Chemical Biology, 2022, 3(1): 26-31.
- Howard Jr J F, Vissing J, Gilhus N E, et al. Zilucoplan: an investigational complement C5 inhibitor for the treatment of acetylcholine receptor autoantibody–positive generalized myasthenia gravis[J]. Expert Opinion on Investigational Drugs, 2021, 30(5): 483-493.
- Hoy S M. Motixafortide: First Approval[J]. Drugs, 2023, 83(17): 1635-1643.
- Ham Y Y, Lewis II J S, Thompson III G R. Rezafungin: a novel antifungal for the treatment of invasive candidiasis[J]. Future Microbiology, 2021.
