Cyclic peptides are usually produced by end-to-end, cephalic, or side-chain-to-side-chain cyclization reactions. Introducing cyclization can make the conformation of the peptide chain more stable, thereby increasing the binding affinity to the target protein and reducing nonspecific binding due to fewer alternative conformations. Reduced conformational flexibility reduces the chance of molecules fitting to protease catalytic sites and improves proteomic resistance. Intervention in protein-protein interaction (PPI) by forming larger interaction surfaces to improve peptide chain efficacy.<\/p>\n
Chem. Eur. J. 2021, 27, 1487-1513<\/p>\n There are three pathways by which cyclic peptides enter cells: passive diffusion pathway, carrier-mediated transport pathway, and endocytosis pathway. The passive diffusion pathway usually requires good amphiphilicity and low molecular weight (<1000Da) of cyclic peptide molecules to enter cells. Some peptide-based drugs are recognized by transporters and subsequently introduced into cells, and some cyclic peptides enter cells through PepT1 and PepT2 transporters. However, these receptors are expressed primarily in the gut (absorption) and kidney (excretion), so they are important for oral bioavailability and elimination of peptide drugs but are unlikely to be involved in the cellular penetration of target tissues. Moreover, the membrane of the endocytic sac is similar to the cell membrane, and non-passive permeable molecules may not be able to effectively escape the endosome and lysosome into the cytoplasm. In order to enhance the cell permeability of peptide drugs, it is necessary to improve the molecular weight and amphiphilicity of drugs. Cyclic peptide drugs, however, are flexible enough to meet these needs. First, controlling the sequence length of the cyclic peptide molecule can control the molecular weight requirements. Secondly, by modifying the side chains of amino acids (introducing unnatural amino acids, forming disulfide bonds, etc.) or main chains (n-methylation, etc.), introducing unnatural hydrophobic groups can enhance the hydrophobicity of cyclic peptide molecules, thus improving the cellular permeability of cyclic peptide drug molecules. Furthermore, the hydrophilic and hydrophobic properties of cyclic peptides can be further optimized according to the symmetry of the framework (d-type amino acids).<\/p>\n Chem. Eur. J. 2021, 27, 1487-1513<\/p>\n Romidepsin<\/a> is a natural bicyclic peptide discovered in Chromobacterium violaceum (1994), containing a head-to-tail lactone cyclization and a pair of disulfide bonds, mainly produced by fermentation. Romidepsin, a histone deacetylase inhibitor (HDACi), was approved by the FDA in 2009 for cutaneous T-cell lymphoma (CTCL) that has received at least one systemic therapy, primarily as an antineoplastic drug. It is a prodrug in which disulfide is reduced to two mercaptols in the intracellular matrix that chelates zinc ions at the zinc-dependent active site of histone deacetylase (HDAC), thereby inhibiting histone deacetylase and inducing apoptosis.<\/p>\n Voclosporin has 11 residues, including 1 D-type amino acid, which is head and tail cyclization. The N-terminus of some amino acids is methylated by S-adenosine methionine. Volcyclosporine was obtained by optimizing cyclosporin A<\/a>. Voclosporin has better efficacy and metabolic stability than cyclosporin A. As a novel best-in-class calcineurin inhibitor (CNI), voclosporin has a synergistic and dual mechanism of action: it stabilizes renal podocyte by inhibiting CALcineurin (CN), blocking IL-2 expression and T cell-mediated immune response.<\/p>\n Ziconotide<\/a> is a synthetic omega-MVIIA toxin isolated from the venom of Conus Magus. It contains 25 residues, of which six amino acids<\/a> are cysteine<\/a>, linked by three pairs of disulfide bonds. As a potent selective blocker of N-type calcium channels, Ziconotide was approved in 2004 for the treatment of severe chronic pain.<\/p>\n Linaclotide<\/a> is an oral peptide composed of 14 amino acids developed in the 1990s and belongs to the Cyclic Guanosine Monophosphate (cGMP) regulatory peptide family. In 2012, linaclotide was approved by the FDA for the treatment of irritable bowel syndrome with constipation (IBS-C).<\/p>\n Pukanatide is an oral guanylate cyclase C(GC-C) agonist developed by Synergy that regulates acid and base ions in the gastrointestinal tract, inducing fluid transport into the gastrointestinal tract and increasing peristalsis. Pukanatide, a 16-amino acid analog of uranyin, is produced by replacing Human uranyin Asp3 with Glu3 and binds to guanylate cyclase C(GC-C) receptors at pH 5.0 (duodenum and proximal jejunum pH) bound by 2 pairs of disulfide bonds. On 2017-01-19, Plcanatide was first approved by the FDA for the treatment of gastrointestinal disorders such as constipated irritable bowel syndrome (IBS-C) and chronic idiopathic constipation (CIC).<\/p>\n Pasireotide<\/a> is a second-generation analog of somatostatin<\/a>, a naturally occurring inhibitory hormone that blocks the release of several other hormones by interacting with the somatostatin receptor (coupled to G protein), including growth hormone, thyroid-stimulating hormone (TSH), insulin, and glucagon<\/a>. Compared with other somatostatin analogs, paretide has a 40-fold increase in affinity for somatostatin receptor 5. Pasireotide is a head-to-tail cyclized hexapeptide. Pasireotide has a higher binding affinity to the somatostatin receptors SSTR1, SSTR3, and SSTR5 than octreotide<\/a> and lanreotide.<\/p>\n Lanretide<\/a> is the first sustained-release, long-acting somatostatin octapeptide analog, which is produced by cyclization of a disulfide bond between cysteine and cysteine, and binds stronger to somatostatin receptors on adenohypophysial cells than octreotide. Studies have shown that lanreotide mainly acts through somatostatin receptor-2 and somatostatin receptor-5, with a strong affinity for peripheral somatostatin receptors and a weaker affinity for central receptors.<\/p>\n Vasopressin, discovered in 1928 and its sequence elucidated in 1951, is an antidiuretic hormone with nine amino acids, cyclized by a disulfide bond between Cys4 and Cys9.<\/p>\n Terisopressin<\/a> is a synthetic, long-acting vasopressin analog that acts on the vasopressin receptors V1a, V1b, and V2. It is a prodrug that is degraded in vivo by endopeptidase to form lysine<\/a>-vasopressin by removing the trisglycine residue at the N-terminal of the cyclic peptide, which is the main active metabolite and is further degraded in the liver, kidney, and other tissues. As a result, teripressin acts slowly but has a longer duration, with a half-life of 6hr, which is longer than that of vasopressin (10min), and is safer with fewer side effects.<\/p>\n Bremelanotide<\/a> is a synthetic peptide molecule consisting of seven amino acids cycled between side chains Asp2 and Lys7 to form the lactam analog (\u03b1-MSH) of the alpha-melanocyte-stimulating hormone.<\/p>\n Setmelanotide<\/a> is a disulfide-cyclized octapeptide that preferentially agonizes the melanocortin 4 receptor (MC4R) with an EC50 of 0.2 nM.<\/p>\n![\"\"](\"https:\/\/www.creative-peptides.com\/blog\/wp-content\/uploads\/2022\/04\/Chem.-Eur.-J.-2021-27-1487-1513-300x169.png\")
<\/a><\/p>\nCell Permeability of Cyclic Peptides<\/h2>\n
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<\/a><\/p>\nFDA-Approved Cyclic Peptide Drugs<\/h2>\n
Cyclic peptide drugs targeting intracellular proteins<\/h3>\n
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Cyclic peptide drugs targeting extramembrane proteins<\/h3>\n
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Antimicrobial Cyclic Peptides<\/h3>\n
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