Structure and Application of Knottin, Orbitides, Multicyclic Peptides

It seems that human beings can no longer be satisfied with cyclic peptides. With the deepening of the exploration and research of cyclic peptides, cyclic peptides have also been gradually subdivided. By classifying from the perspective of amide bonds, homocyclic peptides and heterocyclic peptides can be obtained. It can be classified from the source to obtain plant-derived cyclic peptides, synthetic cyclic peptides, marine-derived natural cyclic peptides, and semi-synthetic cyclic peptides modified by disulfide bonds on natural cyclic peptides. It can be divided into single loop, double loop, or multi-loop type according to the number of main links.

Fig.1 Representative structure of plant cyclic peptides. (Daly, Norelle L., and David T. Wilson., 2021)

Table 1 Representative cyclic peptides at Creative Peptides.

Knottin peptides

The knotted peptide, with a length of about 30-50 amino acids, is able to form three pairs of disulfide bonds. One pair of disulfide bonds can pass between the other two pairs of disulfide bonds, thus forming a structural image.

Fig.2 The FDA-approved knottin peptide drug Linaclotide.

Ordinary cyclic peptides also have good resistance to enzymatic hydrolysis. Compared with ordinary cyclic peptides, Kenottin is more stable, not only resistant to enzymatic hydrolysis, but also resistant to acid, base and high temperatures. At present, this cyclic peptide structure is also used in many disease fields, such as tumor immunity, chronic pain treatment, etc., and has not been systematically studied in the field of skin. However, Knottin has already made discoveries in the field of antimicrobials. For example, one of the structures, Psacotheasin, has significant antifungal properties and has no hemolytic effect on human red blood cells, so it is a good antibacterial ingredient that can be extended to the field of scalp care.

Orbitides

Orbitides are cyclic peptides that do not contain any disulfide bonds or unnatural amino acids. The first orbitides Evolidine was isolated from tropical rainforest plants in the 50s of the 20th century, and the sequence was determined and confirmed. Orbitides are head- and tail-linked cyclic peptides and are a very representative type of cyclic peptides.

Orbitides are found in many natural plants, such as Asteraceae and flaxseed. Different orbitides may exhibit different biological activities, such as antitumor activity, antibacterial activity, anti-inflammatory, anticoagulant, antimalarial and other effects. Among them, orbitides, which have antibacterial and anti-inflammatory activities, can also be introduced from the field of drugs to the field of skin care products.

Fig.3 Structure of orbitide.

In addition, due to the spatial structure of Orbitides, this structure can also be used as a carrier for some drugs. For example, PLP-53 is an Orbitides extracted from the seeds of Ratibida columnifera (Dogwood in the family Rutaceae) and consists of 16 amino acids. Its cavity structure, the charge of different groups, and the hydrophilic and hydrophobic properties of different sites allow it to carry drugs. In addition, it is also a development idea to use Orbitides as scaffolds to embed bioactive sequences into them.

Multicyclic peptides

Polycyclic peptides are also part of the large family of cyclic peptides. They typically have a stable three-dimensional structure, higher conformational rigidity, and metabolic stability, exhibiting unique high efficiency in inhibiting protein-protein interactions (PPIs).

Fig.4 The famous dicyclic peptide Empaveli, which active ingredient is Pegcetacoplan.

An interesting peptide oligomer with antimicrobial properties was used as a functional monomer and made into single, bicyclic and tricyclic peptides by a dynamic hydrazone condensation reaction. After the formation of polycyclic rings, its antibacterial effect has also been improved to a certain extent.

References

1. Hwang, Bomi, et al., Antifungal properties and mode of action of psacotheasin, a novel knottin-type peptide derived from Psacothea hilaris. Biochemical and Biophysical Research Communications 400.3 (2010): 352-357.
2. Fisher, Mark F., et al., An orbitide from Ratibida columnifera seed containing 16 amino acid residues. Journal of natural products 82.8 (2019): 2152-2158.
3. Reuther, James F., et al., A versatile approach to noncanonical, dynamic covalent single-and multi-loop peptide macrocycles for enhancing antimicrobial activity. Journal of the American Chemical Society 140.10 (2018): 3768-3774.
4. Daly, Norelle L., and David T. Wilson. Plant derived cyclic peptides. Biochemical Society Transactions 49.3 (2021): 1279-1285.