FDA Approved Cyclic Peptide Drugs
SummaryRecently, a paper called Cyclic Peptide Drugs Approved in Last Two Decades was published in RCS Chemical Biology. This work details the cyclic peptide drugs authorized for clinic use between 2001 and 2021 and reveals their future development trends.
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Recently, a paper called Cyclic Peptide Drugs Approved in Last Two Decades was published in RCS Chemical Biology. This work details the cyclic peptide drugs authorized for clinic use between 2001 and 2021 and reveals their future development trends.
Romidepsin is a natural dicyclic peptide discovered in Bacillus purplicum (1994), consisting of a caprolactone cyclization and a pair of disulfide bonds, produced primarily by fermentation. Romidepsin(Isodax®) is a histone deacetylase inhibitor (HDACi) approved by the FDA in 2009 as an antitumor agent for cutaneous T-cell lymphoma (CTCL) in patients who have received at least one systemic therapy. Romidepsin 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. Romidepsin was injected intravenously with a half-life of about 3.5h. Romidepsin was mainly metabolized through bile and excreted through feces in rats, with a liver clearance rate of about 20%. Since it does not rely on enzymatic degradation or liver/kidney excretion, it can be safely used in patients with varying degrees of liver/kidney damage.
Voclosporin has 11 residues, including 1 D-type amino acid, which is head and tail cyclization. The N-terminus of some amino acids are methylated by S-adenosine methionine. Volcyclosporine is obtained by optimizing cyclosporine A: By replacing the butene group on the first residue of cyclosporine A(CsA),4- [(E) -2-butenyl]-4, n-dimethyl-1-threonine (Bmt1) with 4-[(2E, 4EZ)-2, 4-pentadienyl]-4, n-dimethyl-L-threonine (E-MEPMT1), Thus, the bond with hydrophobic Cn surface was optimized and the affinity was enhanced. Therefore, the efficacy and metabolic stability of Voclosporin are better than cyclosporin A. As a novel Best-in-class calcineurin inhibitor (CNI), volcyclosporine has a synergistic and dual mechanism of action: it stabilizes renal podocytes by inhibiting CALcineurin (CN), blocking IL-2 expression and T cell-mediated immune response. Volcyclosporine has predictable pharmacokinetics, potency enhancement, and metabolic profile improvement compared to conventional CNI. 2021-01-22, volcyclosporine was approved by FDA for the treatment of lupus nephritis (LN).
Ziconotide is a synthetic ω -mviia toxin isolated from the venom of Conus Magus. It contains 25 residues, of which six amino acids are cysteine, linked by three pairs of disulfide bonds. The NMR structure shows that ω -Mviia has a stable antiparallel β -folding structure in solution. As a potent selective blocker of N-type calcium channels, ziconotide was approved in 2004 for the treatment of severe chronic pain. There is evidence that ziconotide has analgesic effects by reducing the release of pain-sensing neurotransmitters in the spinal dorsal horn. At the same time, given its limited ability to penetrate the BBB, intrathecal injections are needed to achieve optimal analgesia while minimizing potentially serious side effects.
Linaclotide is an oral peptide composed of 14 amino acids developed in the 1990s and belongs to the Cyclic Guanosine Monophosphate (cGMP) regulatory peptide family. Linaclotide is homologous to paracrine peptide hormones guanylate and uranylate, and its active conformation is stable by three intramolecular disulfide bonds. After modification, Linaclotide is a first-in-class guanylate cyclase agonist (GCCA) with a high binding affinity to the GC-c receptor even in the pH range of 5-8 (gastrointestinal pH). Linaclotide activates guanylyl cyclase-C (GC-C) receptors on the mucosal surface of the intestine, causing an increase in cGMP levels in intestinal epithelial cells, which in turn activates cGMP-dependent protein kinases and phosphorylates several downstream signal transduction molecules, including cystic fibrosis transmembrane regulatory factor (CFTR). Chloride channels are then opened to regulate chloride and water migration to the colon. Linaclotide is rarely absorbed by the intestine and acts by locally activating gC-C receptors on the intestinal epithelium. Linaclotide was rapidly degraded in mouse intestinal fluid in vitro with a half-life of 3min.
Plecanatide, 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 pH5.0(duodenum and proximal jejunum pH) bound by 2 pairs of disulfide bonds. Activation of GC-C receptors in the gastrointestinal tract stimulates intracellular production of cyclic guanosine phosphate (cGMP), which activates cGMP-dependent protein kinase G-II and cystic fibrosis transmembrane conductance regulator (CFTR), resulting in activation of ion channels, secretion of chloride and bicarbonate into the intestinal lumen, and increased and accelerated passage of small intestinal fluid. Ultimately, intestinal motility is promoted. As with most oral peptides, plecanatide is degraded by intestinal enzymes and only a very small amount of the active drug enters the systemic circulation.
Pasireotide is a hexapeptide with a cyclic head and tail. Compared with octreotide and ranretide, pasireotide has a higher binding affinity for somatostatin receptors SSTR1, SSTR3, and SSTR5. The binding affinity of pasireotide to SSTR1 was 30 and 19 times that of octreotide and lanreotide, respectively. The binding affinities of SSTR3 and SSTR3 were 5 and 9 times as high as those of SSTR3 and SSTR3, respectively. The binding affinities of SSTR5 and SSTR5 were 39 and 106 times, respectively. Paretide was approved by EMA and FDA for the treatment of Cushing's disease in 2012 and by FDA for the treatment of acromegaly in 2014.
Lanreotide is the first sustained-release, long-acting somatostatin octapeptide similar, 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 weak affinity for central receptors. Lanreotide has a good specific effect on growth hormone secretion and gastrointestinal hormone secretion and is more active than natural somatostatin, and the effect duration is longer. In addition, the inhibitory effect on growth hormone secretion was more selective than that on insulin secretion, and it inhibited intestinal exocrine, digestive hormone, and cell proliferation mechanism.
Vasopressin, which was discovered in 1928 and whose sequence was elucidated in 1951, is an antidiuretic hormone with nine amino acids derived from the cyclization of the disulfide bond between Cys4 and Cys9. Vasopressin is encoded by proneurotin II mRNA in the human body and has the affinity to activate vasopressin V1a, V2, and V1b as well as oxytocin receptors. Vasopressin induces vasoconstriction by activating the V1 receptor, thereby promoting antidiuretic activity and procoagulant activity on vascular smooth muscle. Vasopressin has shown a huge advantage over other drugs in treating septic shock by increasing blood pressure.
Terlipressin 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-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.
Bremelanotide is a synthetic peptide molecule consisting of seven amino acids cycled between side chains Asp2 and Lys7 to form the lactam analog of α -melanocyte-stimulating hormone (α-MSH). Bremelanotide was originally developed as a potential tanning agent but was unexpectedly found to have activatory and evocative effects. Bremelanotide is a non-selective melanocortin receptor agonist targeting MC3 and MC4 receptors. Activation of the G protein-coupled MC receptor enhances intracellular cAMP, calcium mobilization, and receptor internalization, and activates the dopamine terminal of the medial preoptic region (MPOA). The release of dopamine (DA) mediates a variety of physiological effects, including the activation of sexual arousal. 2019-06-21 Bremelanotid is approved by the U.S. Food and Drug Administration (FDA) for the treatment of systemic hyposexual desire disorder (HSDD) in premenopausal women with a half-life of 2.7hr by subcutaneous injection before anticipated sexual activity.
Setmelanotide is a disulfide cyclized octapeptide that preferentially stimulates melanocortin 4 receptor (MC4R) with an EC50 value of 0.2 nM. It and Terlipressin are the only two approved cyclitide drugs developed from natural linear hormones to lock part of the cyclic conformation by introducing a cyclization bridge. It is these locked sequences that bind to the target. Setmelanotide is effective in reducing obesity in individuals caused by POMC, PCSK1, or LEPR deficiency. Genetic variations in these proteins damage the MC4R pathway, which regulates hunger and energy expenditure. As an MC4R agonist, Setmelanotide is designed to restore impaired MC4R pathway activity, thereby reducing hunger and weight loss.
Daptomycin is a cyclic lipopeptide antibiotic isolated from Streptomyces rosiana. It contains 13 residues, 2 of which are non-natural amino acids, and 10 of which form lactone rings through the side chain and C-terminal of Thr4. Supporting genetically altered decanoic acid phosphatidyl glycerol depend on the way inserted in the cell walls of gram-positive bacteria, gathered up to Joe toxin produced in the goal of the bacterial cell membrane hole curvature and disrupt cell membranes, ion leakage and membrane potential loss caused, which makes proteins, DNA and RNA synthesis is restrained, ultimately induce cell apoptosis. Daptomycin has a half-life of about 8hr in adult patients and is excreted through urine.
Telavacin is a semi-synthetic vancomycin derivative, which is based on the vancomycin structure and is obtained by chemical modification by introducing an aliphatic chain to the amino group of the sugar group and a phosphoric methylamine methyl to the seventh aromatic amino acid. Through modification, the binding force with the cell membrane and affinity with the antibacterial target is enhanced, and telavacin is a fast bactericidal antibiotic for injection. Telavacin interferes with the polymerization and cross-linking of peptidoglycan by binding to the D-Ala-D-ALA terminal of peptidoglycan in growing cell walls, thereby inhibiting the synthesis of cell walls in gram-positive bacteria. In addition, it can directly act on the bacterial cell membrane, causing rapid depolarization of bacterial cell membrane potential, and increasing the permeability of the cell membrane, to rapidly play the antibacterial function.
Dalbavancin is the second generation of semi-synthetic lipopeptide antibiotics, which is more potent than vancomycin and can inhibit the synthesis of the bacterial cell wall. The vancomycin family of natural antimicrobial glycopeptides is a highly modified heptapeptide in which five amino acids remain unchanged and amino acids 1 and 3 are highly differentiated. The heptapeptide core is used to bind the C-terminal D-ALa-D-ALA of the peptidoglycan chain and derive side chain, functional groups, to improve the properties of peptide molecules. The carboxyl terminus of dabavanacin was acylated and saponified to improve its antibacterial activity against Staphylococcus, especially coagulase-negative staphylococcus. The formation of lipophilic branched chains and dimers improved tissue penetration and affinity to bacterial cell membranes. By specifically binding d-Ala-D-ALA on bacterial cell wall peptidoglycan, dalbavancin inhibits the extension and cross-linking of bacterial cell wall peptidoglycan and prevents cell wall synthesis to play a bactericidal role. The precursor glycopeptides of dabavanacin are prepared by fermentation of selected Nonomuraea strains followed by carboxylamidation and saponification. The resulting tabavan is a composite mixture of five subtypes, about 90% of which are B0. Compared with vancomycin and teicoranin, dabavanacin has a wider antibacterial spectrum, stronger antibacterial activity, good tolerance, long half-life (about 1W), fewer side effects, and other advantages, providing a new choice for the treatment of gram-positive bacterial infection.
Olivan vancomycin analog, derived from chlorophorin A, differs in the addition of lipophilic N-4(4 '-chlorophenyl) benzyl side chain, which has the same heptaeptide core structure as vancomycin and has the same glycosylation modification as chloramphenicol. The structural changes improved the activity of Olivacin against Vancomycin-sensitive enterococcus (VSE) and Vancomycin-resistant enterococcus (VRE). Lipophilic side chains in Olivans anchor compounds to cell membranes through hydrophobic interactions, while stabilizing olivans dimers. Olivaxin also binds d-ALa-D-ALA in Gram-positive bacteria to inhibit transglycosylation during peptidoglycan synthesis. Olivacin is stable in the body and the excretion form remains unchanged. Olivaxin has a long half-life of 393 hr, reducing the frequency of administration in the treatment of acute bacterial skin and skin structure infections (ABSSSI).
- Caspofungin, Micafungin and Anidulafungin
Caspofungin, micafungin, and anidulafungin all belong to the cyclic hexaliphatic peptide family. They share the same cyclic peptide core structure and are cyclized by amidation between the n-end of the side chain of the first lysine residue and the c-end of the peptide chain, and all target the 1,3-β -glucan synthase in the cell wall for the synthesis of glucan. All three antifungal agents have clinical efficacy against invasive candidiasis and other forms of systemic mycosis. Among them, carpofen is a semi-synthetic analog of pneumococcin B0, a natural lipophilic cyclic peptide isolated from the fungus Glarea lozoyensis in 1985. It is mainly metabolized in the liver and plasma. It is slowly metabolized into inactive metabolites by hydrolysis and/or n-acetylation, and only about 1.4% is excreted in urine as the prototype.
Micafungin is a semi-synthetic analog of the natural cyclic hexapeptide-fr901379. The n-terminal palmityl group has been enzymically deacylated and chemically reacylated to become the best n-acyl isooxazole analog (with heterocyclic structure, which can reduce blood sugar, pain, inflammation, kill harmful bacteria, and control/reduce the harm of HIV, etc.). Micafennet has poor oral bioavailability with a half-life of about 15hr and is metabolized mainly through enzymatic modification of the side chain and excreted through feces.
Anidulafungin is also a semi-synthetic echinocenin-like cyclic hexapeptide, which is semi-synthesized by removing the linoyl side chain twice through acylation and then in three steps including reacylation with tribenyl. Anidulafungin can inhibit β-(1,3) -glucan synthase noncompetitively and has good clinical efficacy. Its oral bioavailability is low, 2-7%, requiring extragastric administration with a half-life of 27hr. Most of the active ingredients are metabolized into linear peptides through ring-opening hydrolysis, 10% remain prototyped, and 30% and 1% are excreted through feces and urine, respectively.
As a unique molecular class, cyclic peptides have attracted increasing attention, among which natural peptides are the main sources of approved cyclic peptides in the last century. In the past 20 years, the main trend of cyclic peptide drug discovery was to optimize the natural isolated cyclic peptides to improve the potency, stability, and pharmacokinetic properties of cyclic peptide drugs.
In the future, cyclic peptides are expected to surpass small molecules and antibodies in some applications in the pharmaceutical industry, among which oral cell-penetrating peptides will be one of the most important hotspots of cyclic peptides research. At the same time, the reduction of production costs will facilitate the development of cyclic peptide drugs.
References: Cyclicpeptide drugs approved in the last two decades (2001–2021)