Development of Cyclic Peptide in Therapeutics
* Please kindly note that our products and services can only be used to support research purposes (Not for clinical use).
Online Inquiry
The first administration of insulin in 1920 opened the era of therapeutic peptides, and a hundred years later, in 2023, global sales of Semaglutide exceeded 20 billion US dollars, almost forcing K drugs. Its sales far exceeded the second place Duolatopeptide, and topped the list of polypeptide sales last year.
Looking back, it was about 40 years after the first medical administration of insulin that the first hormones used in clinical practice - oxytocin and vasopressin - were synthesized. As of 2023, 114 peptides have been approved by regulators as therapeutic agents (including drugs and diagnostic tools).
Evolution of approved peptide drugs over the years. (Costa, L., 2023)
Peptides fill the molecular size gap between small molecule therapeutics (< 500 Da) and larger protein-based biologics (> 5000 Da).
Typical pharmacokinetic and compound characteristics of drug modalities compared. (Lamers, C., 2022)
To date, more than 50 cyclic peptides have been approved by different regulatory agencies, accounting for half of the approved peptide drugs. Almost all orally available peptides and highly bioactive/orally available natural products are mostly cyclized. Among them, the latest FDA approved cyclic peptide is rezafungin (trade name: REZZAYO), an oral Echinoconin antifungal cyclic peptide drug. Of the more than 60 therapeutic peptides approved by FDA and EMA in the past 20 years, two-thirds are cyclic peptides, and anti-infection is the most widely used field of cyclic peptide drugs.
Recently, Wu's research team at the Children's School of Zhejiang University constructed a CyclicPepedia cyclic peptide knowledge base containing 8,744 cyclic peptide databases. It provides a large number of cyclic peptide sequence, structure, target, biological activity, source, function and other information, the data has the characteristics of comprehensiveness and standardization, can provide a superior baseline data set for artificial intelligence, and contribute to the development of cyclic peptide therapy.
Takeda and Affymax are recalling Omontys (peginesatide) due to severe allergic reactions, and it is currently the only cyclopeptide drug to be withdrawn: Nearly 0.02% of patients (25,000) reported a fatal reaction after the first intravenous administration of Omontys, although the mechanism leading to the allergic reaction is unclear and is presumed to be due to the allergy caused by PEG, while the cyclic peptide itself is relatively safe.
Parenteral administration is a common mode, of which the intravenous route is the most common (the high molecular weight of the peptide and PSA hinder its spread into the bloodstream, making the parenteral application its most common route of administration).
The shortcomings of peptide drugs mainly focus on several aspects, including enzymatic hydrolysis, anti-intestinal pH (oral), low membrane permeability (peptides violate the five rules of Lipinksi), and pharmacokinetic properties can be improved by some molecular modification strategies, such as cyclization.
Advantages of cyclic peptides
The cyclization of peptides has a higher affinity, which can be explained by the entropy effect: since cyclic peptides are less flexible in solution than linear precursors, the entropy loss of binding to the target is lower.
A notable property of cyclic peptides compared to linear peptides is increased protection against enzymatic degradation: the limited elasticity and tension of the peptide skeleton often hinder binding to the protease active site; Moreover, peptides cycled through their terminal amino acids are protected from exopeptidases that break down peptides from the terminal.
Cyclization can promote the formation of intramolecular hydrogen bonds in peptides, reducing solvation while burying some polar surfaces, thus increasing the likelihood of membrane permeability (in order to cross the non-polar regions of the membrane, polar groups of the peptide such as the hydrogen bond donor of the peptide bond need to be de-solvated, which forms an energy barrier).
Cyclic peptides at Creative Peptides
Peptide cyclization strategy
Although cyclization can improve the pharmacokinetic properties of peptides, poor pharmacokinetic parameters are one of the main reasons for the failure of Phase I/II trials for many cyclic peptides. Nevertheless, the unique properties of cyclic peptides make them a strong capital attraction (in phase II to phase III data, peptides in particular outperformed small molecules, with a success rate of 42% compared to 29% for small molecules). Since the first peptide was synthesized by Emil Fisher in 1901, peptide synthesis methods have steadily improved. Depending on the type of constituent amino acid, cyclization can occur in four different ways: head-tail cyclization, head-side-chain cyclization, side-chain-tail cyclization, and side-chain-side cyclization.
Diverse peptide cyclization methods. (A) Cyclization in solution; (B) Cyclization by native chemical ligation; (C) Cyclization by Ser/Thr ligation approach; (D) Cyclization by KAHA ligation approach; (E) Cyclization by Staudinger's ligation approach; (F) On-resin cyclization; (G) Enzyme-mediated cyclization; (H) CyClick cyclization; (I) Cyclization by formation of a triazene bond; (J) Cyclization of propargylated peptides through imine formation mediated by gold. (Costa, L., 2023)
Head-to-tail cyclization: For head-to-tail cyclic peptides, macrocyclization involves lacamidation of the amino and carboxylate groups at the two ends of the linear precursor. In addition to the two ends, the side chain amino group of Lys, the side chain carboxylic acid group of Asp or Glu, the hydroxyl group of Ser and Thr, and the sulfhydryl group of Cys are also common functional groups involved in macrocyclization reactions, resulting in the other three types of cyclic peptides. In addition to peptide cyclization using functional parts present in the terminal and side chains of the peptide, functional groups installed on the N-α atoms of the main chain may also be involved. This non-classical N-backbone peptide cyclization relies on the use of functionalized n-alkylated amino acids.
Head-to-side chain cyclization: Head-to-side chain cyclization involves the connection of the n-terminal amino group to the side chain group, which can enhance structural diversity and specificity, and is suitable for the design of cyclic peptides with specific functions.
Side chain to tail cyclization: Side chain to tail cyclization by connecting side chain groups and C-terminal carboxyl group to form a ring structure, can significantly improve the stability of the peptide, but due to the reactivity of side chain groups, synthesis may be more complex and the yield is low.
Side chain to side chain cyclization: Side chain to side chain cyclization is the formation of a ring structure by the joining of two side chain groups, allowing for the design of highly diverse peptide molecules, despite the complexity of the reaction and the possibility of higher side reactions.
Other strategies to optimize peptide
Improve the membrane permeability
Peptide products easily exceed Lipinski's rule, and most oral peptides in the literature are < 1200 Da in size (molecular size greatly limits paracellular transport). N-methylation, including cyclization, and intramolecular hydrogen bonding are the main chemical modifications. N-methylation increases the number of cis-peptide bonds by reducing the energy difference between cis-peptide and trans-peptide bonds. It also reduces the number of free NH groups in the peptide skeleton that can participate in H bonding, thereby reducing the energy loss to solvation prior to membrane passage.
Increase the protease stability
Some natural amino acid residues are more susceptible to enzyme action, such as aspartate (Asp), aspartamide (Asn), and methionine (Met). Peptide amide bonds are recognized and cleaved by many proteases and peptidases, which are particularly effective for linear peptide sequences and unaltered free amino and carboxyl termini. Peptide stability can be improved by chemical modification of the N-terminal (N-methylation produces A peptide skeleton that is barely recognized by peptidase, and cyclosporin A has N-methylation on its main chain), such as acetylation. Non-protein amino acids (not found in the human genetic code) are not recognized by human proteases and can increase the proteolytic stability of therapeutic peptides.
Most peptidases recognize L-amino acids (most eukaryotic peptides are composed of this form), so exchanging L-amino acids with the corresponding D-amino acids can make the corresponding peptides more stable, such as despressin (8-D-arginine instead of 8-L-arginine).
Prolonging the cyclic half-life
PEGylation has been shown to be an effective strategy for prolonging the in vivo half-life of therapeutic peptides. PEGylation also reduces phagocytosis and removes its conjugates from the bloodstream, and its large hydrodynamic radius, in particular, interferes with renal filtration and prolonging the half-life. In addition to PEG, natural degradable polymers such as hyaluronic acid (HA) and hydroxyethyl starch (HES) have successfully established conjugates with peptides. At this point, consider the possibility of Peginesatide-like allergic events.
Steric hindrance of peptides with macromolecules may interfere with the therapeutic compound's interaction with the target, thereby reducing efficacy. Conjugates of large molecules such as polyethylene glycol are harmful to health due to hypersensitivity and complement activation (up to 25% of the population has anti-PEG antibodies).
Of course, increasing the stability of proteases can increase the half-life of peptide drugs, and octreotide, which contains fewer amino acids and contains D-configurational tryptophan (Trp) residues, is 200 times more potent and has a 30-fold increase in half-life compared to somatostatin.
Related services at Creative Peptides
Conclusion
With the emergence of Simeiglutide peptide oral technology, artificial intelligence + peptides, new delivery systems, conjugation technology, the layout of peptide drug companies are also more favored by the capital, is the current pharmaceutical winter one of the few strong items, the indications of peptide drugs in the fields including anti-infection, anti-tumor and cardiovascular disease everywhere. New peptide innovative drugs are gradually emerging, and the development of the peptide industry is expected to enter a period of rapid growth. Looking forward to the vast future of peptide drugs, the development of cyclic peptides is obvious to all. Cyclic peptides, mainly used for anti-infection, have gradually entered the multi-direction of tumor and conjugated drugs, which surely have a bright future ahead.
References
- Costa, L., et al. Cyclic peptides in pipeline: what future for these great molecules? Pharmaceuticals. 2023, 16(7): 996.
- Lamers, C. Overcoming the shortcomings of peptide-based therapeutics. Future Drug Discovery. 2022, 4(2): FDD75.
