As the largest family of cell membrane surface receptors in the human body, G-protein-coupled receptors (GPCRs) are involved in the pathological processes of various major diseases, including diabetes, cardiovascular diseases, autoimmune diseases, and cancers. The development of GPCR-targeted drugs has always been a hotspot in drug research and development. Over one-third of all drugs approved by the U.S. Food and Drug Administration (FDA) target GPCRs. Peptides are substances composed of 2 to dozens of amino acids linked by peptide bonds, and to date, more than 7,000 natural peptides have been identified. These peptides function as hormones, neurotransmitters, growth factors, ion channel ligands, antibiotics, and more. In the human body, peptides are involved in many important physiological processes. For example, insulin promotes the synthesis of glycogen, fat, and proteins, playing a role in lowering blood sugar. Oxytocin promotes uterine smooth muscle contraction during childbirth and stimulates the milk ejection response in the mammary glands. Peptides, as signaling molecules, initiate specific cell signal transduction processes by binding to surface receptors such as GPCRs and ion channels. In recent years, peptide drugs have gradually attracted attention in the pharmaceutical industry due to their high biological activity, good safety profile, low production costs, and near-infinite possibilities in spatial structure, making them a new growth point in drug development. This review summarizes the successful development of marketed GPCR-targeted peptide drugs and briefly outlines the current strategies in peptide drug development and potential future directions.
The human genome encodes over 800 GPCRs, whose ligands can be small molecules such as sugars, lipids, and peptides, or large biomolecules like proteins. A common feature of GPCRs is their stereo-structure, which contains seven transmembrane α-helices, thus they are also known as 7-transmembrane receptors. The intracellular region has a G-protein (guanine nucleotide-binding protein) binding site. Based on structural similarities, GPCRs can be divided into five families: the rhodopsin-like family, secretin receptors, metabotropic glutamate receptors, adhesion receptors, and Frizzled/Taste2 receptors. In 2012, the Nobel Prize in Chemistry was awarded to American scientists Robert and Brian K. for their outstanding contributions to GPCR function and structure research. Their work promoted significant advancements in GPCR structural biology, and new GPCR structures continue to be analyzed and published, providing a deeper understanding of the complexity of GPCRs and their signal transduction.
The classic GPCR signal transduction is mediated by G-proteins, which are heterotrimeric proteins composed of three subunits: Gα, Gβ, and Gγ. The Gα subunit is a molecular switch protein with GTPase activity, while Gβ and Gγ tightly bind in a dimeric form. Gα has four subtypes: Gαs, Gαi/o, Gαq/11, and Gα12/13. Each subtype interacts with different effector proteins, which can directly or further activate downstream effectors via second messengers.
For example, with Gαs: Upon ligand binding, the GPCR undergoes a conformational change and the activated receptor binds with the G-protein trimer, leading to the exchange of GDP for GTP on the Gα subunit. The Gα subunit dissociates from the receptor and the Gβγ subunits, binding to and activating adenylate cyclase (AC), which increases the intracellular concentration of cyclic AMP (cAMP). cAMP then binds to the regulatory subunit of protein kinase A (PKA), causing the catalytic subunit to be released and enter the nucleus. This leads to the phosphorylation of cAMP response element-binding protein (CREB), which then forms a complex with CREB-binding protein (CBP) in the nucleus, activating the transcription of target genes. The dissociated Gβγ subunits can also activate downstream effectors, such as phospholipase C (PLC), which hydrolyzes phosphatidylinositol-4,5-bisphosphate (PIP2) into the second messenger inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3 stimulates the release of Ca2+ from the endoplasmic reticulum into the cytoplasm, increasing the intracellular Ca2+ concentration, while DAG activates protein kinase C (PKC), triggering the MAPK signaling pathway.
Peptides as drugs have many unique advantages: (1) A large number of natural peptides can act as ligands for cell membrane surface receptors. Peptide drugs developed based on this mechanism have clear mechanisms of action, high biological activity, and require small dosages; (2) Compared to small molecule drugs, peptide drugs do not undergo metabolism in the liver, and their metabolites are amino acids, which are almost non-toxic and generally do not accumulate in specific organ tissues, resulting in a low incidence of side effects and good safety; (3) Compared to proteins and other biological macromolecules, peptides are easy to synthesize, can be easily separated from impurities or by-products, have high purity, and their development cycle is short, with low production costs, making them suitable for medium-scale treatments. Given these favorable pharmacological properties and inherent advantages, peptide drugs have become a hotspot in new drug development in recent years. To date, more than 50 GPCR-targeted peptide drugs have been approved by the U.S. FDA, most of which are used for the treatment of metabolic diseases or cancers.
The development of peptide drugs has gone through three stages: human peptide development, natural peptide development, and biotechnological development. The initial focus was on the development and utilization of human peptide hormones. Most of the currently available drugs are synthesized using this strategy, with the most typical example being insulin. In the 1980s and 1990s, researchers used recombinant DNA technology to produce high-purity biosynthetic insulin and synthesized insulin analogs by modifying the peptide chain, achieving both rapid-acting and long-acting formulations. By the end of the century, researchers expanded their scope to include natural peptides found in microorganisms, plants, and animal venoms. For example, Exendin-4, used for the treatment of type 2 diabetes and obesity, was discovered. After large-scale screening of natural peptides, peptide drug development took the inevitable path of utilizing molecular biology techniques for screening and development.
The two key foundations for developing peptide drugs using molecular biology techniques are the establishment of high-abundance peptide libraries and suitable screening strategies. In 1985, George P. Smith developed phage display technology by incorporating peptides into bacteriophage surface proteins. In 1990, Smith and Jamie K. Scott established a random peptide library by displaying random sequence peptides on the surface of bacteriophages. Phage display technology allows high-affinity peptides to be selected from high-abundance random peptide libraries (with abundance up to 109) through multiple rounds of affinity screening. DNA sequencing is used to determine the encoding information of the candidate peptides, thus linking the affinity properties of the peptide with the genetic information of the peptide. Subsequently, new techniques, such as mRNA display, ribosome display, and yeast display, emerged. Together with phage display, they have continuously developed and optimized over the past 20 years and can theoretically perform affinity-based high-throughput screening for any target protein.
In 2014, the Lerner group at the Scripps Research Institute in the U.S. successfully screened a novel GLP-1R peptide agonist, P5, as a potential drug for the treatment of type 2 diabetes. This technology uses a self-secretory signaling system in a mammalian cell line to display candidate peptide segments on the surface of mammalian cells through the platelet-derived growth factor receptor transmembrane domain (PDGFR-TM). By combining the functional reporter system for target transmembrane proteins, flow cytometry, and high-throughput sequencing, peptide agonists targeting transmembrane proteins were screened. This system, by overexpressing target transmembrane proteins in mammalian cells rather than solid-phase recombinant proteins, maintains their natural state to the maximum extent and achieves functional-based screening using the reporter system.
There are many endogenous peptide ligands for GPCRs in the human body, such as calcitonin, oxytocin, somatostatin, glucagon-like peptide, vasopressin, parathyroid hormone, and gonadotropin-releasing hormone. Modifying and altering these peptides is one of the main directions for peptide drug development. Currently, nearly 50 GPCR-targeted peptide drugs have been approved, with the main targets including glucagon-like peptide receptors, parathyroid hormone receptors, somatostatin receptors, gonadotropin-releasing hormone receptors, vasopressin/oxytocin receptors, and calcium-sensing receptors. These drugs are used to treat various diseases, including metabolic diseases, neurological disorders, and cancers. Most of the marketed peptide drugs are synthesized using chemical synthesis methods (e.g., solid-phase peptide synthesis) or genetic recombinant technology to synthesize peptide analogs and their derivatives with sequences similar to endogenous peptide ligands.
The glucagon-like peptide-1 receptor (GLP-1R) is primarily expressed in the pancreas, and its agonists have become a focus in recent years for the development of anti-hyperglycemic drugs. The natural peptide ligand for GLP-1R, glucagon-like peptide 1 (GLP-1), is a 37-amino acid peptide. After glucose intake, GLP-1 is synthesized and secreted by enteroendocrine L cells in the gut, acting on GLP-1R to increase intracellular cAMP, promoting glucose-induced insulin secretion, and inhibiting glucagon release. In addition to its unique glucose-dependent pancreatic effects, GLP-1 also exerts central effects such as reducing appetite and promoting satiety, highlighting its potential as a therapy for diabetes or obesity. The natural GLP-1 has a short half-life and is rapidly degraded by dipeptidyl peptidase IV (DPP-IV) and cleared by the kidneys, making it unsuitable for direct use as a drug. Currently, seven peptide GLP-1R agonists have been approved for the treatment of type 2 diabetes.
In 1992, Eng et al. isolated a natural peptide, Exendin-4, from the venom of the Gila monster. Exendin-4 shares pharmacological properties with GLP-1, such as increasing insulin secretion and lowering blood glucose levels. However, Exendin-4 differs from GLP-1 in that it has a glycine substitution for the alanine at position 2 on the N-terminus, making it resistant to DPP-IV degradation. This gives Exendin-4 a longer half-life and stronger biological activity. Exenatide, the synthetic form of Exendin-4, contains 39 amino acids and was approved by the FDA in 2005 as the first GPCR-targeted drug for the treatment of type 2 diabetes. Exenatide binds to GLP-1R, altering its conformation, activating adenylate cyclase, and increasing cAMP levels in cells. This promotes glucose-dependent insulin secretion, inhibits glucagon secretion, and enhances insulin sensitivity, resulting in blood glucose reduction. Currently, Exenatide is available in two forms: Exenatide BID (twice daily) and Exenatide QW (once weekly). Exenatide BID effectively lowers blood glucose and also helps reduce weight, making it especially suitable for treating type 2 diabetes with concomitant central obesity. However, frequent subcutaneous injections of Exenatide BID may lead to poor patient compliance. Exenatide QW, the first GLP-1R agonist to be administered once weekly, uses microsphere technology to allow slow release in the body, providing long-lasting blood glucose-lowering effects. After Exenatide QW, various other strategies have been adopted to enhance the plasma stability of GLP-1R agonists and extend their half-life. These strategies can generally be divided into two categories: one involves modifying the sequence of Exenatide to extend its plasma half-life, such as liraglutide, which omits proline at position 38 in the Exenatide sequence and adds six lysine residues and one amide group at the C-terminus. These modifications extend its plasma half-life.
Another strategy focuses on modifying the natural GLP-1, such as liraglutide, abiglutide, dulaglutide, and semaglutide. Liraglutide was approved by the FDA in 2010, where lysine at position 34 of natural GLP-1 was replaced with arginine, and a C16 palmitic acid side chain linked to glutamic acid was added at position 26 to increase its binding to plasma albumin, reduce DPP-IV degradation, and lower renal clearance. In addition to its glucose-lowering effects similar to Exenatide, liraglutide also slows gastric emptying and has shown significant efficacy in the treatment of obesity. Abiglutide and dulaglutide are both produced as fusion proteins. Abiglutide is produced through recombinant DNA technology using yeast, fused with human serum albumin, and substitutes glycine for alanine at position 2 of natural GLP-1 to resist DPP-IV degradation. Dulaglutide is produced in mammalian cell cultures and covalently linked to the human IgG4-Fc heavy chain. These modifications reduce renal clearance of these two drugs and increase the duration of their pharmacological activity.
Compared to the aforementioned GLP-1R agonists, semaglutide's major breakthrough lies in the development of long-acting formulations and oral formulations of GLP-1R agonists. In 2017, the FDA approved semaglutide injectable formulation, which can be administered once a week. Its long-acting mechanism is based on chemical modifications to its structure. In semaglutide, the amino acids at positions 8 and 34 of natural GLP-1 are replaced by 2-amino-isobutyric acid and arginine, respectively, preventing DPP-IV degradation. Furthermore, the lysine at position 26 in natural GLP-1 is acylated with stearic acid, allowing it to bind with human serum albumin. This extends its plasma half-life and prevents rapid renal clearance, significantly prolonging its circulation time in the body and allowing a half-life of up to 7 days. The oral formulation of semaglutide was approved by the FDA in 2019. It utilizes the Eligen company's macromolecule delivery technology based on absorption enhancers, where macromolecular drugs are encapsulated in lipid-like structures with multiple absorption enhancers, such as SNAC (8-(2-hydroxybenzylamino)-octanoic acid sodium), protecting the peptide drug from degradation by enzymes in the stomach.
The glucagon-like peptide-2 receptor (GLP-2R) is primarily distributed in gastrointestinal tissues and regulates the gastrointestinal system via cAMP-dependent signaling pathways, enhancing nutrient absorption. The natural peptide ligand for GLP-2R, glucagon-like peptide 2 (GLP-2), is a gut-derived peptide composed of 33 amino acids, secreted by enteroendocrine L cells. GLP-2 is rapidly degraded by DPP-IV, and its half-life is very short, only 7 minutes. Teduglutide is a GLP-2 analogue synthesized using recombinant DNA technology. It was approved by the FDA in 2012 as a designated drug for the treatment of adult short bowel syndrome (SBS) that requires parenteral nutrition support. SBS is a rare, potentially life-threatening malabsorption disease caused by congenital defects, disease-induced absorption impairments, or extensive surgical resection leading to the loss of most intestinal function. When SBS patients' ability to absorb nutrients, electrolytes, and water is insufficient to meet the body's needs, parenteral nutrition support is required. In Teduglutide, the alanine at position 2 of natural GLP-2 is replaced with glycine to resist DPP-IV degradation and extend the plasma half-life. Teduglutide exerts biological effects through its action on GLP-2R to regulate the gastrointestinal system, reduce gastric emptying and secretion, and promote the growth, proliferation, and repair of small intestinal mucosal epithelial cells, thus increasing small bowel absorption and reducing diarrhea.
Table.1 Glucagons and glucagon-like peptides (GLP-1 / GLP-2) at Creative Peptides.
CAT# | Product Name | M.W | Price |
---|---|---|---|
10-101-158 | Albiglutide | 3283.6 | Inquiry |
R2090 | Exendin-4 | 4187 | Inquiry |
10-101-159 | Dulaglutide | 3314.6 | Inquiry |
10-101-16 | Exenatide | 4187 | Inquiry |
10-101-325 | Semaglutide | 4113.57 | Inquiry |
10-101-285 | Teduglutide | 3752.1 | Inquiry |
10-101-18 | Glucagon | 3482.7 | Inquiry |
10-101-351 | Retatrutide | 4731 | Inquiry |
10-101-46 | GLP-1 (7-37) Acetate | 3355.71 | Inquiry |
10-101-59 | Liraglutide | 3751 | Inquiry |
10-101-83 | Exendin (9-39) Acetate | 3369.8 | Inquiry |
10-101-85 | GLP-1 (7-36) amide Acetate | 3297.68 | Inquiry |
G05001 | Glucagon (22-29), human | 1038.2 | Inquiry |
G05002 | Glucagon (19-29), human | 1352.5 | Inquiry |
G05003 | Glucagon (1 - 18) | 2148.3 | Inquiry |
G05006 | [Des - His1, Glu9] - Glucagon (1 - 29), amide | 3358.7 | Inquiry |
G05007 | [Des-His1,Glu9] Glucagon | 3359.6 | Inquiry |
G05008 | Glucagon, human | 3482.6 | Inquiry |
G05009 | Glucagon (1 - 29), bovine, human, porcine, FAM- - labeled | 3841.1 | Inquiry |
G05010 | Oxyntomodulin / Glucagon 37 | 4421.9 | Inquiry |
G16002 | Glucagon - Like Peptide 1, GLP - 1 (7 - 36), amide, human | 3297.7 | Inquiry |
G16003 | (Ser8)-GLP-1 (7-36), amide, human | 3312.7 | Inquiry |
The parathyroid hormone 1 receptor (PTH1R) is primarily expressed in the kidneys and bones and exists in two different high-affinity conformations: the G protein-independent conformation (R0) and the G protein-dependent conformation (RG). Ligands with higher affinity for the R0 conformation mainly activate β-inhibitory protein signaling pathways, leading to receptor internalization and triggering long-term signaling responses. In contrast, ligands with higher affinity for the RG conformation primarily activate G protein-mediated cAMP-dependent signaling pathways, triggering transient signaling responses. Parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHrP) are important regulators in bone metabolism. PTHrP contains an N-terminal sequence homologous to PTH. Both hormones act on PTH1R to regulate bone metabolism via the cAMP-dependent PKA signaling pathway. However, PTH mainly regulates calcium homeostasis and bone resorption, while PTHrP is a key peptide that promotes bone formation.
Teriparatide is a 34-amino acid PTH analogue and the first peptide drug approved by the FDA to regulate bone metabolism. It mainly acts on the R0 conformation of PTH1R, promoting the binding of β-inhibitory proteins, leading to internalization. This sustained regulation of cAMP levels activates downstream signaling pathways, mediating long-term signaling responses and accelerating bone resorption.
Abaloparatide is the first developed PTHrP analogue, consisting of 34 amino acids. It was approved by the FDA in 2017 for the treatment of postmenopausal osteoporosis. Abaloparatide primarily acts on the RG conformation of PTH1R, triggering a transient increase in cAMP levels and mediating short-term signaling responses. Its ability to promote bone formation exceeds that of bone resorption. Although both Teriparatide and Abaloparatide target the same receptor, PTH1R, the differences in their conformational preferences lead to distinct activation of downstream signaling pathways. As a result, Abaloparatide demonstrates superior efficacy in treating postmenopausal osteoporosis compared to Teriparatide. This highlights the importance of considering conformational preferences when developing peptide drugs targeting GPCRs.
Table.2 Parathyroid Hormones and Related Peptides at Creative Peptides.
CAT# | Product Name | M.W | Price |
---|---|---|---|
P03001 | Parathyroid Hormone (1-34), human, C-Terminal | 4604.3 | Inquiry |
P03002 | pTH (73-84) (human) | 1273.45 | Inquiry |
P03003 | Parathyroid Hormone (70-84), human | 1587.8 | Inquiry |
P6924 | Teriparatide | 4118 | Inquiry |
P03004 | Parathyroid Hormone (69-84), human | 1716.9 | Inquiry |
10-101-172 | Abaloparatide | 3961 | Inquiry |
P03005 | pTH-Related Protein (1-16) (human, mouse, rat) | 1790.01 | Inquiry |
P03006 | Parathyroid Hormone (28-48), human | 2148.4 | Inquiry |
P03007 | pTH (64-84) (human) | 2231.49 | Inquiry |
P03008 | [Asn76] Parathyroid Hormone (64-84), human | 2231.5 | Inquiry |
P03009 | (Tyr27)-pTH (27-48) (human) | 2311.58 | Inquiry |
P03011 | pTH-Related Protein (67-86) amide (human, bovine, dog, mouse, ovine, rat) | 2409.72 | Inquiry |
P03012 | Parathyroid Hormone (13-34), human | 2808.3 | Inquiry |
P03013 | Parathyroid Hormone (44-68), human | 2836.1 | Inquiry |
P03014 | (Tyr43)-pTH (43-68) (human) | 2999.29 | Inquiry |
P03015 | Parathyroid Hormone (39-68), human | 3285.7 | Inquiry |
P03017 | [Tyr34] Parathyroid Hormone (7-34), amide, bovine | 3496.1 | Inquiry |
P03018 | pTH (18-48) (human) | 3505.07 | Inquiry |
The somatostatin receptor (SSTR) family includes SSTR1-5, which are widely distributed in the central nervous system, pituitary, and many peripheral organs. The natural ligand for somatostatin receptors, somatostatin (SST), binds to the receptor to induce cAMP-dependent signaling pathways, inhibiting the release of various tumor-promoting hormones and growth factors, thereby suppressing cancer cell proliferation or inducing cancer cell apoptosis. Somatostatin has a high affinity for its receptor but a very short half-life in plasma, only 1-3 minutes. A synthetic octapeptide derivative of natural somatostatin, octreotide, is used to treat neuroendocrine tumors and acromegaly. By introducing D-amino acids, octreotide's plasma half-life is extended to 72-113 minutes and selectively binds to somatostatin receptor subtype 2 and subtype 5. Upon binding to somatostatin receptors, octreotide mediates signaling pathways through PLC, generating the second messenger IP3 and activating L-type Ca2+ channels, thereby inhibiting growth hormone production. Pasireotide is another somatostatin receptor agonist, approved by the US and EU for the treatment of Cushing's syndrome. Pasireotide has a higher affinity for somatostatin receptor 5 and can inhibit the secretion of adrenocorticotropic hormone (ACTH), reducing cortisol secretion in patients with Cushing's syndrome.
Table.3 Somatostatin & analogs at Creative Peptides.
CAT# | Product Name | M.W | Price |
---|---|---|---|
R1574 | Octreotide | 1019.2 | Inquiry |
R1683 | Somatostatin | 1637.9 | Inquiry |
10-101-169 | Pasireotide | 1047.2 | Inquiry |
10-101-289 | Somatostatin-28 | 3148.6 | Inquiry |
10-101-32 | Somatostatin Acetate | 1637.9 | Inquiry |
10-101-169 | Pasireotide | 1047.2 | Inquiry |
10-101-26 | Octreotide Acetate | 1019.2 | Inquiry |
10-101-44 | Vapreotide Acetate | 1191.4 | Inquiry |
M34140635H | [Nal3]Octreotide acetate | 1069.3 | Inquiry |
M34140636H | TETA-Octreotide acetate | 1433.7 | Inquiry |
M34140637H | NOTA-Octreotide trifluoroacetate | 1304.5 | Inquiry |
M34140643H | DOTA-Lanreotide acetate | 1481.7 | Inquiry |
M34140653H | [Tyr3,Lys5(Boc)]octreotide acetate | 1135.36 | Inquiry |
M34140655H | [Lys5(Boc)]lanreotide acetate | 1196.44 | Inquiry |
O1003 | ([ring-D5]Phe3)-Octreotide | 1024.3 | Inquiry |
S07018 | (D-2-Nal5,Cys6·11,Tyr7,D-Trp8,Val10,2-Nal12)-Somatostatin-14 (5-12) amide | 1180.4 | Inquiry |
S07043 | Vapreotide | 1131.4 | Inquiry |
The gonadotropin-releasing hormone receptor (GnRHR) is mainly expressed in the pituitary and reproductive system-related tissues. Its natural peptide ligand, gonadotropin-releasing hormone (GnRH), is a decapeptide neurohormone secreted by the hypothalamus that plays an important role in reproductive regulation.
Table.4 GnRHR related peptides at Creative Peptides.
CAT# | Product Name | M.W | Price |
---|---|---|---|
G2001 | GnRH Associated Peptide (GAP) (1-13), human | 1492.5 | Inquiry |
G2002 | GnRH Associated Peptide (GAP) (1-13), rat | 1506.6 | Inquiry |
G2003 | GnRH Associated Peptide (GAP) (1-24), human | 2732.9 | Inquiry |
G2005 | GnRH Associated Peptide (GAP) (25-53), human | 3284.7 | Inquiry |
M34140611H | GnRH Triptorelin | 1311.45 | Inquiry |
R1393 | GnRH-I | 1182.32 | Inquiry |
OPO-011 | sGnRH-A | 1282.4 | Inquiry |
R1483 | LGnRH-III, lamprey | 1259.3 | Inquiry |
10-101-04 | Antide | 1591.3 | Inquiry |
10-101-166 | Gonadorelin | 1182.3 | Inquiry |
Leuprolide is a gonadotropin-releasing hormone analogue and receptor agonist, approved by the FDA in 1985 for the treatment of hormone-responsive cancers such as prostate cancer and breast cancer. It is also used to treat other estrogen-dependent diseases, such as endometriosis and uterine fibroids. Leuprolide primarily associates with GPCR via the Gαq/11 pathway, activating PLC and releasing IP3 and DAG, which induces PKC activation. This stimulates the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary, ultimately transiently increasing serum estradiol and testosterone levels through the normal hypothalamic-pituitary-gonadal axis. The regulation of the hypothalamic-pituitary-gonadal axis relies on the pulsatile secretion of GnRH from the hypothalamus. As a result, prolonged treatment with Leuprolide leads to decreased receptor sensitivity to GnRH, which is the primary mechanism of Leuprolide's action. This ultimately reduces the secretion of LH and FSH and leads to gonadal dysfunction, significantly lowering estradiol and testosterone levels, which distinguishes it from other GPCR agonists.
In the treatment of hormone-sensitive prostate cancer, the initial increase in testosterone levels induced by Leuprolide may exacerbate prostate cancer symptoms, prompting researchers to further develop gonadotropin-releasing hormone receptor antagonists. In 2008, the FDA approved Degarelix, a gonadotropin-releasing hormone receptor antagonist, for the treatment of advanced prostate cancer. Degarelix binds reversibly to the gonadotropin-releasing hormone receptor, downregulates intracellular cAMP levels, and inhibits cAMP-dependent GPCR signaling pathways, thereby reducing the release of gonadotropins and inhibiting testosterone release to prevent the growth and worsening of prostate cancer. By introducing P-ureido-phenylalanine at positions 5/6 in the peptide chain, Degarelix extends the duration of action while avoiding hypersensitivity reactions caused by histamine release. Studies suggest that Degarelix is superior to Leuprolide in the treatment of advanced prostate cancer.
Vasopressin receptors (VRs) include V1AR, V1BR, and V2R. V1AR is mainly expressed in the liver, vascular smooth muscle, and platelets, promoting vasoconstriction and platelet aggregation. V1BR is primarily expressed in the pituitary, promoting the release of adrenocorticotropic hormone (ACTH). V2R is mainly expressed in the renal collecting ducts and plays a role in antidiuretic effects. Oxytocin receptors (OTRs) are mainly distributed in the uterus and mammary glands. Both vasopressin and oxytocin are nonapeptides, exerting their effects mainly by binding to their respective receptors. The mechanisms of action of V1AR, V1BR, and oxytocin receptors are similar, mainly through coupling with Gαq/11 to stimulate PLC activity, releasing IP3 and DAG, and inducing calcium release from the endoplasmic reticulum. In contrast, V2R mainly couples with Gαs, activating adenylate cyclase (AC) to produce cAMP, which then activates protein kinase A (PKA).
Carbetocin is a synthetic oxytocin analogue, where the hydroxyl group on the phenolic ring of natural oxytocin is replaced by a methyl group, and the amino and sulfur groups on cysteine residues are replaced by hydrogen and methylene, respectively. These modifications extend the duration of carbetocin's action. Carbetocin binds to oxytocin receptors in uterine smooth muscle, inducing rhythmic uterine contractions, increasing contraction frequency and strength, and is used to control postpartum hemorrhage.
Desmopressin is a synthetic nonapeptide compound, approved by the FDA in 2017 for the treatment of central diabetes insipidus. It has the strongest effect on V2R, promoting renal vasodilation by increasing cAMP levels in renal collecting duct epithelial cells, thereby exerting an antidiuretic effect. Compared to natural vasopressin, desmopressin has significantly enhanced antidiuretic effects while reducing smooth muscle effects, avoiding the adverse effects of hypertension.
Table.5 Vasopressin related peptidesat Creative Peptides.
Calcium-sensing receptors (CaSR) are widely distributed in tissues and organs involved in regulating calcium homeostasis, such as the parathyroid glands, gastrointestinal tract, kidneys, and bone tissue. Elevated blood calcium levels activate CaSR, inhibiting the secretion of parathyroid hormone (PTH). Conversely, decreased blood calcium levels suppress CaSR activity, promoting the secretion of PTH. Secondary hyperparathyroidism (SHPT) is a common chronic complication of chronic kidney disease (CKD), characterized by parathyroid gland hyperplasia, elevated PTH levels, and mineral metabolism abnormalities such as calcium and phosphate imbalance. These mineral imbalances lead to severe complications such as skeletal disease, soft tissue calcification, vascular calcification, and cardiovascular issues.
Velcalcetide (Etelcalcetide) is a novel long-acting CaSR agonist, approved by the FDA in 2017 for the treatment of secondary hyperparathyroidism in adult patients undergoing hemodialysis. Velcalcetide directly binds and activates the CaSR on the parathyroid glands, stimulating PLC to cleave PIP2 into the second messengers IP3 and DAG, thereby inhibiting PTH secretion from the parathyroid glands.
G protein-coupled receptors are crucial drug targets, playing key roles in various physiological and pathological processes. Peptide drugs have emerged as a promising strategy for targeting GPCRs due to their high specificity, low toxicity, and excellent safety profile. However, the complexity of GPCRs and limitations in screening technologies continue to challenge peptide drug development. With advancements in display technologies, functional screening, and structural optimization, the discovery of peptide drugs targeting GPCRs is reaching new frontiers. In the future, the integration of high-throughput screening, computational design, and intracellular functional validation is expected to accelerate the development of GPCR-targeting peptide therapeutics, offering more precise and effective treatment solutions for various diseases.
References
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