Peptide drugs offer many advantages over other drugs. They are simple to tolerate, can interact with large protein surfaces, and have stereochemistry that is easy to insert. Peptides can be used to bind to many, sometimes unsteady, surfaces of proteins that regulate PPI.
What is Cyclic Peptide?
Cyclic peptides are peptide chains with a cyclic structure. They typically consist of 5-14 amino acids and a molecular weight of 500-2000 Da. Cyclic peptides have many advantages over linear peptides. Linear peptides can be unstable and vulnerable to intracellular proteolysis. Because they have the free acid (and also free amine) at both ends, they are polar. Cyclization increases intramolecular hydrocarbon bonds within the rings structure, and decreases external hydrogen bonding ability of molecules. This decreases the polarity as well as membrane permeability of the compound, compared to its precursor. Two b-turn local secondary structures are formed by cyclization, which decreases the polar surface area of the compound and generally increases cell permeability.
End-to-end, cephalic, or side-chain -to-side chain reactions can all be used to produce cyclic peptides. Cycling can improve the stability of the peptide chains, which increases binding affinity to target proteins and decreases non-specific binding because there are fewer conformations. Reduced conformational flexibility can increase the likelihood that molecules will fit into the protease catalytic sites and decrease proteomic resistance. Intervention in protein-protein interaction (PPI) is a way to improve the efficiency of peptide chains.
Chem. Eur. J. 2021, 27, 1487-1513
Cell Permeability of Cyclic Peptides
There are two routes that allow cyclic amino acids to enter cells: the passive transport pathway and the carrier-mediated transportation pathway. The passive diffusion pathway is required to allow cyclic peptide molecules (1000Da), to enter cells. Transporters can recognize some peptide-based drugs and introduce them into the cells. Some enter cells via PepT1 and PepT2 transporters. These receptors are found in the stomach (absorption), as well as the kidney (excretion), which are vital for oral bioavailability and elimination, as well cellular penetration of peptide drug peptides. The Endocytic Sac membrane is very similar to that of the cell membrane. Non-passive permeable substances might not be able to escape the endosome and lysosome into the cytoplasm. Peptide drugs need to be lighter and more philic in order to increase cell permeability. Cyclic peptide drugs can meet these needs. First, control the sequence lengths of cyclic-peptide molecules to regulate their molecular weight requirements. Side chains can be modified by injecting unnatural amino acids or creating disulfide bonds, among other things. or main chains (n-methylation, etc. To increase hydrophobicity or cell permeability of cyclic peptide drug molecules, an unnatural hydrophobic group can be added. Cyclic amino acids can be optimized for their hydrophilic and hydrophobic properties by ensuring the framework is symmetric.
Chem. Eur. J. 2021, 27, 1487-1513
FDA approved Cyclic Peptide Drugs
Targeting intracellular proteins
- Romidepsin
Romidepsin is a natural bicyclic amino acid protein found in Chromobacterium VIolaceum (1994). It contains a head to tail lactone cycle as well as a pair of disulfide bonds. These were formed mainly by fermentation. FDA approved Romidepsin in 2009 as a histone-deacetylase inhibitor. It is used for the treatment of cutaneous T-cell lymphoma (CTCL). It reduces disulfide to 2 mercaptols in the intracellular matrix. This chelates zinc at the active zinc sites of histone Acetylase. It inhibits histone acetylase, and causes apoptosis.
- Voclosporin
Voclosporin contains 11 residues. This includes 1 D type amino acid, which is head and tail cyclization. S-adenosine-methionine can methylate the N-terminus of certain amino acids. Volcyclosporine can be made by optimizing CyclosporinA. Voclosporin is much more stable and efficient than cyclosporin. Voclosporin (CNI) is a novel and best-in-class inhibitor of calcineurin. It works by a dual mechanism. It stabilizes the kidney podocyte by blocking CALcineurin (CN), blocking IL-2, and T-cell-mediated immunity response.
Extramembrane Protein Targeting Cyclic Drugs
- Ziconotide
Conus Magus’ venom contained Ziconotide which is a synthetic omega MVIIA xin. It contains 25 residues. The cysteine is composed of six amino acids and one cysteine. Three pairs of disulfide bonds link them. Ziconotide is a strong selective blocker of N-type calcium channels that was approved in 2004 for severe chronic pain.
- Linaclotide
Linaclotide is an oral peptide that is made up of 14 amino acids. It was developed in the 1990s and is part of Cyclic Guanosine Monphosphate’s (cGMP) regulatory peptide family. Linaclotide was approved by the FDA in 2012 to treat irritable bowel syndrome-C.
- Plecanatide
Pukanatide is an oral guanylate cyclase C agonist that Synergy developed. It regulates the acid and base ions in the gastrointestinal tract. This stimulates fluid transport to the gastrointestinal system and improves peristalsis. Pukanatide, a 16-amino acid analogue of uranyin, is also available. It is produced by replacing Human uranyin Asp3 with Glu3 and binds guanylate cyclase C receptors at pH5.0. This pH corresponds with the duodenum and proximal Jejunum pH, and is bound by two pairs of disulfide bonds. FDA approved Plcanatide on the first day in 2017. It is a treatment for chronic idiopathic diarrhea and constipated irritable stool disorder (IBS).
- Pasireotide
Pasireotide is a second-generation analog of somatostatin. It blocks the release of many hormones by interfacing to the somatostatin (coupled with G proteins), such as growth hormone (TSH) and glucose. Paretide has a 40-fold higher likelihood of binding to the somatostatin receptors than other analogues. Pasireotide is a head to tail cyclized, hexagonal hexapeptide. Pasireotide can bind more strongly to the somatostatin receptors, SSTR1, SSTR3 and SSTR5 than Octreotide and lanreotide.
- Lanreotide
Lanretide is the first long-acting and sustained-release somatostatin analogue. It is made by cyclization of a disulfide linking between cysteine and cysteine. It is more compatible with somatostatin receptors of the adenohypophysial cells than octreotide. Research has shown that lanreotide is primarily able to act through the somatostatin receptor-2 or 5, with stronger affinity for the peripheral receptors than the central receptors.
- Vasopressin
Vasopressin was first discovered in 1928. In 1951, the sequence of its amino acids was discovered. Vasopressin, an antidiuretic hormone, contains nine amino acids. It cycles through the disulfide bonds between Cys4 and Cys9.
- Terlipressin
Terisopressin is a synthetic vasopressin analogue that acts on V1a and V1b. Endopeptidase is used in vivo to degrade the prodrug and form lysinevasopressin. Trisglycine is the main active metabolite at the nterminal cyclic proteine. The vasopressin receptors (V1a, V1b, and V2) are then activated. Although Teripressin has a longer half-life, it is slower than vasopressin. It’s safer and has fewer side effects.
- Bremelanotide
Bremelanotide is a synthetic peptide molecule consisting of seven amino acids cycled between side chains Asp2 and Lys7 to form the lactam analogue (a-MSH) of alpha-melanocyte-stimulating hormone.
- Setmelanotide
Setmelanotide is a disulfide cyclic octapeptide that preferentially antagonizes melanocortin4R (MC4R) with an EC50 value 0.2 nM.
Antimicrobial Cyclic Peptides
- Daptomycin
Daptomycin is a cyclic lipopeptide antibiotic that was isolated from Streptomyces rosea. It contains 13 residues. 2 are not natural amino acids. 10 can form lactone rings using the side chain or Cterminal of Streptomyces roseiana.
- Telavacin
Telavancin is a semi-synthetic Vancomycin derivative that is based on the vancomycin structure. Chemical modification can be used to introduce methylamine methyl phosphate to the seventh amino acid and an aliphatic link for the sugar amino group. Teravanin is a rapid, bactericidal antibiotic which can be injected. It has a modified affinity and binding force with the cell membrane.
- Dalbavancin
Dalbavancin is a second-generation semisynthetic, semisynthetic lipoglycopeptide antibacterial. It is more potent than vancomycin and inhibits the formation of bacterial cell walls. It is also more efficient. Vancomycin belongs to a group of natural antimicrobial pentapeptides. Five amino acids remain the same, while amino acids 1 to 3 are highly different. The core of the heptapeptide is used to bind the C-terminal D.Ala.D.Ala from the Peptoglycan chain. To enhance the properties of the peptide, functional groups can also be derived from side chains.
- Oritavancin
Oritavancin, a semi-synthetic second-generation lipoglycopeptide, is known as Oritavancin. It is an analogue of vancomycin, chloroeremomycin. It is very similar to vancomycin, and has a core of the heptapeptide.
- Anidulafungin, Micafungin, and Caspofungin are some examples
Anifengin (micafengin), capofungin, and micafengin all belong to the cyclic hexaliphatic family. All three share the same cyclic core structures of a peptide. They are cyclized by amidation between the end chain for the first Lysine residue (n -end) or the c-end of the peptide chain. They all target the 1,3-b -glucan synthase in the cell wall to synthesize glucan. All three antifungal agents have been clinically proven to be effective against invasive candidiasis and other forms of systemic mycosis.
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