Synthesis, Modification, and Applications of Therapeutic Peptides

Therapeutic peptides consist of short amino acid chains as drugs that usually possess molecular weights between 500 and 5000 Da. Natural hormones like insulin, oxytocin, and vasopressin sparked the initial research into peptides and their physiological roles in humans. In 1921 scientists successfully synthesized insulin which became the first therapeutic peptide to mark a groundbreaking achievement in drug development. Since more than 80 peptide drugs have received global approval, peptide drugs have become a significant focus in pharmaceutical research.

Between 1950 and 1990 research into bioactive peptide hormones and their receptors together with improved protein purification and synthesis methods supported the creation of peptide drugs. Researchers successfully developed synthetic peptides including oxytocin, vasopressin, and recombinant insulin before the 20th century ended. In the 21st century scientific developments in structural biology and recombinant biopharmaceuticals along with new synthetic techniques strengthened peptide drug development systems.

The last two decades have seen regulatory approval for 33 non-insulin peptide drugs which treat diseases such as HIV and type 2 diabetes along with chronic pain. The therapeutic applications of peptide drugs have expanded to cover numerous medical fields. The worldwide peptide drug market exceeded $70 billion in 2019 while numerous additional peptide drugs continued through clinical testing.

Development of Therapeutic Peptides

Peptide Drug Development

Natural Peptides/Hormones in Human Body

The history of peptide drug development began with the use of naturally occurring hormones and peptides, which had well-researched physiological functions, to treat diseases caused by hormone deficiencies, such as type 1 or type 2 diabetes, where insulin is needed to regulate blood glucose levels. The treatment for diabetes involves injecting insulin or stimulating insulin secretion-related targets, such as the GLP-1 receptor, to produce insulin. The initial strategy in peptide drug development was to find natural peptides and hormones or substitute them with animal homologs (such as insulin, GLP-1, somatostatin, GnRH, 8-Arg-vasopressin, and oxytocin). However, the limitations of these natural peptides sparked interest in optimizing their natural sequences, leading to the development of a series of natural hormone-mimicking peptide drugs. 

Hormone-Mimicking Peptides

GLP-1-Derived Peptide Drugs: GLP-1 is a 37-amino acid peptide that regulates insulin production and secretion, with a very short half-life in the body. Considerable efforts have been made to modify its sequence to enhance the stability of this hormone while maintaining its efficacy and pharmacological effects, leading to the development of three best-selling peptide drugs for treating type 2 diabetes: Trulicity, Victoza, and Ozempic.

Table.1 GLP-1-derived peptide at Creative Peptides.

Gonadotropin-Releasing Hormone (GnRH)-Derived Peptide Drugs: GnRH is a 10-amino acid peptide produced by GnRH neurons in the hypothalamus. Modifications to the natural sequence of GnRH have led to the development of several peptide drugs, such as leuprorelin and degarelix. Leuprorelin mimics the biological activity of GnRH by activating GnRH receptors and is used as a GnRH receptor agonist to treat hormone-responsive prostate cancer, endometriosis, uterine fibroids, and precocious puberty. Although degarelix's sequence is optimized from GnRH, it acts as a GnRH antagonist by competitively binding to GnRH receptors and is used to treat advanced prostate cancer.

Several other approved peptide drugs are also derived from natural hormones, including octreotide, a somatostatin analog used to treat growth hormone-secreting tumors and pituitary tumors; Despressin, an 8-arginine antiriuretic analogue, used in the treatment of diabetes insipidus and nocturia. Carergoline, an oxytocin homologue used to treat amenorrhea, and atosiban, an oxytocin antagonist used to prevent preterm labor.

Peptides Identified from Natural Products

Many bioactive peptides derived from bacteria, fungi, plants, and animals possess therapeutic properties. For example, snake venom, considered a vascular endothelial growth factor (VEGF) analog, VEGF-F or svVEGF, typically consists of disulfide-rich cyclic peptides with fewer than 80 residues, which can induce cytotoxicity by targeting ion channels and other membrane-bound receptors. Peptide toxins from snake and scorpion venom have been modified for therapeutic applications. Additionally, exenatide (derived from Gila monster venom) is a GLP-1 agonist, and ziconotide, a peptide toxin from the cone snail, has been used to treat chronic neuropathic pain.

Non-ribosomal peptides (NRPs) are another class of peptides identified from natural products. The presence of non-standard residues in the sequence means that NRPs are not produced through traditional ribosomal biosynthesis pathways but are synthesized by non-ribosomal peptide synthetases via a pathway consisting of initiation, elongation, and termination modules. Compared to ribosomally synthesized peptides, NRPs are more resistant to hydrolytic enzymes and have higher stability in the body. The most studied NRPs are mainly derived from bacteria and fungi, including vancomycin, cyclosporine, and rutamycin, which exhibit antimicrobial activity, as well as antitumor agents such as a-amanitin, nanomycins, and actinomycin. Moreover, cyclic peptides, a specific type of NRP, are commonly identified in plants, such as enniatin B and amodyspsin. These peptide drugs show enhanced plasma stability, enabling oral administration. However, the synthesis and structure-activity relationship of NRPs remains one of the most challenging and exciting areas of research.

Design of Peptides Based on Protein-Protein Interactions

The development of proteomics and structural biology has led to the discovery of many PPIs that are involved in most cellular processes and biological functions. To date, more than 14,000 PPIs have been studied, accounting for about 1% of all human PPIs. PPIs also regulate many important cellular pathways in human diseases, making them potential drug targets. Peptides as PPI inhibitors or agonists have inherent advantages compared to small molecules and antibodies. Therefore, a new peptide drug discovery technique, rational peptide design, based on known PPI crystal structures, has emerged as a promising strategy for discovering novel peptide drug candidates.

Rational peptide design involves computer-assisted bioinformatics techniques based on target PPI crystal structures. Bioinformatics and computational analyses of PPI binding interfaces can identify essential amino acids on the surfaces of two interacting proteins. These essential amino acids contribute to the main Gibbs energy of the PPI and are often referred to as "hotspots." Hotspots may be continuous peptide segments or scattered residues on different secondary structures of the proteins. The design of PPI peptide modulators is based on these hotspots, either directly using continuous segments or using strategies that connect scattered residues as the initial sequence. However, to improve their activity and physicochemical properties, further peptide development and structural optimization are required, including peptide cyclization and backbone modifications. For example, by studying the structure-activity relationship, essential peptide residues are identified, and non-essential residues are substituted, while chemical modifications are made to stabilize peptide secondary structures such as turns, helices, hairpins, and extended conformations, enhancing biological activity and improving physicochemical properties.

Discovery of Peptide Drug Candidates through Phage Display

Phage display is an efficient and reliable technology used to identify ligands for biological targets, first reported by Smith in 1985. Phage display uses recombinant techniques to display target ligands on the surface of phages. Peptides containing protein amino acids are produced in the phage, not NRPs. This high-throughput sequencing method can be used to identify drug leads, including antibodies and peptides. Phage display has been widely used for discovering new peptide ligands. Lerner and others reported the discovery of potent peptide mimics of GLP-1 and other membrane receptor ligands through phage display, including proteins, peptides, and venoms, primarily as agonists. Additionally, peptides targeting transforming growth factor (TGF)-β1 or epidermal growth factor receptor (EGFR), as well as peptide antagonists that disrupt fibroblast growth factor (FGF)-1-FGFR1 interactions, are good examples of peptide drugs discovered via phage display. Recent developments in phage display technology focus on finding more effective screening methods to simplify ligand selection from large datasets, such as by reducing the phage selection cycle. Heinis and others obtained chemically modified peptides, including disulfide-cyclic peptides, from traditional phage display using "on-phage" modifications. Another strategy involves developing novel display methods. For example, Schumacher and others developed mirror-image phage display to explore D-enantiomer peptides, while Szostak and others used mRNA display to discover and select macrocyclic peptides containing non-natural amino acids. Suga and others used ribosome display to develop lead peptides containing D-amino acids and non-natural amino acids, including bioactive macrocyclic peptides. These advancements have enabled the construction of large display libraries to discover new peptide candidates.

Synthesis and Modification of Therapeutic Peptides

The discovery of peptides with therapeutic potential is the first step in the development of peptide drugs. Subsequently, peptides are synthesized through chemical or biological methods and modified in sequence to improve their pharmacological properties. Here, we summarize the basic techniques used in peptide production and modification.

Chemical Synthesis of Peptides

Peptide chemical synthesis, particularly solid-phase peptide synthesis (SPPS), has advanced significantly since its development in 1963. SPPS simplifies peptide production by combining amino acid coupling and deprotection in one reactor, which led to automatic peptide synthesizers. Compared to recombinant methods, SPPS peptides are purer, free from biological impurities like enzymes and DNA, and easier to purify since impurities mostly come from incomplete reactions.

SPPS involves attaching amino acids to solid resins and sequentially adding protected amino acids. Various resins and protective groups help prevent aggregation and ensure peptide purity. Two main SPPS methods—Fmoc-SPPS and Boc-SPPS—are used to remove protecting groups. Fmoc-SPPS is preferred due to milder conditions, while Boc-SPPS is better for long peptides due to its effectiveness in reducing aggregation.

Recent research focuses on solving issues like aggregation in long peptides and the formation of aspartimide, which lowers peptide purity. Solutions include using low-substitution resins, microwave heating, and additives like 1-hydroxybenzotriazole (HOBt).

While Fmoc-SPPS is effective for peptides under 50 residues, large-scale synthesis of longer peptides remains challenging due to uneven heating and side reactions. However, automated synthesizers aid in rapid peptide production for research, and advances in SPPS continue to drive the development of therapeutic peptides.  

Table.2 Peptide synthesis services at Creative Peptides.

Chemical Modifications of Peptides and Peptoids

Peptides, as a class of specialized therapeutic drugs, have biological activity closely related to their chemical structure. After peptide synthesis, drug chemistry techniques are needed to modify, simulate, stabilize, or construct ideal secondary structures to enhance their biological activity, ensuring the selectivity, stability, and solubility of peptide drugs.

Before modifying lead peptide candidates, the minimal active sequence with the required biological characteristics must be determined. The classic sequence scanning, known as alanine scanning, is commonly used to replace each residue with alanine to generate a series of peptide analogs to determine which key residues impart biological activity to the lead peptide: a decrease in activity indicates the replaced residue is important, while no significant decrease in activity suggests the replaced residue is redundant. Further modifications are then made to the replaceable residues of the lead peptide and its C- and N-termini to produce the final peptide drug.

Table.3 Peptide modification service at Creative Peptides.

Peptide Backbone Modifications

One of the main reasons for backbone modifications is to improve the proteolytic stability of the peptide. Proteolytic cleavage sites in peptides can be identified through stability studies and metabolite assays. Backbone modifications include replacing L-amino acids with D-amino acids, inserting methylamino acids, and incorporating β-amino acids and peptoid-like structures. Introducing these non-natural amino acids into peptide sequences, especially at proteolytic cleavage sites, is an effective strategy for prolonging the plasma half-life of peptide drugs. A successful example is desmopressin, which is derived from vasopressin, has similar target selectivity, but a longer plasma half-life.

Side Chain Modifications of Peptides

Side chain modifications of peptides involve replacing natural amino acids with analogs during peptide synthesis to enhance their binding affinity and target selectivity. Variants of natural amino acid analogs, such as homo-arginine, benzoxytolyl tyrosine, and β-phenylalanine, are typically commercially available and can be conveniently used for chemical modifications of peptide side chains. Several GLP-1 analog drugs, such as liraglutide and somaglutide, have modified side chains.

Stabilizing Secondary Structures with Backbone and Side Chain Modifications 

Solid-phase peptide synthesis (SPPS), developed in 1963, has greatly advanced peptide production by combining amino acid coupling and deprotection in one reactor, leading to automatic synthesizers. SPPS produces purer peptides than recombinant methods, free from biological impurities like enzymes and DNA, with easier purification.

In SPPS, amino acids are attached to solid resins, and protected amino acids are added step by step. Various resins and protective groups prevent aggregation and ensure purity. The two main SPPS methods are Fmoc-SPPS, which uses milder conditions, and Boc-SPPS, preferred for long peptides due to its effectiveness in reducing aggregation.

Research addresses challenges like aggregation in long peptides and aspartimide formation, which reduces purity. Solutions include using low-substitution resins, microwave heating, and additives like 1-hydroxybenzotriazole (HOBt).

While Fmoc-SPPS works well for peptides under 50 residues, large-scale synthesis of longer peptides is still difficult due to uneven heating and side reactions. However, automated synthesizers help with fast peptide production for research, and SPPS advancements continue to support the development of therapeutic peptides.  

Recombinant Technology for Peptide Production

Chemical synthesis is the preferred method for industrial peptide production, enabling the introduction of non-natural amino acids and probes for further modifications. It is automated and scalable, making it ideal for producing short and medium-length peptides, though long peptides remain challenging to synthesize.

Therapeutic peptides can also be produced biologically through methods like extraction from natural sources, enzyme synthesis, fermentation, recombinant DNA technology, and semi-synthesis. These methods can be combined depending on the peptide's complexity.

Peptide drugs have been isolated from natural sources since the 1920s, with insulin being the first widely used peptide drug. This success led to other animal-derived peptides like adrenocorticotropic hormone and calcitonin entering clinical use. Non-ribosomal peptides, such as vancomycin and cyclosporine, are produced by non-ribosomal peptide synthetases and offer diverse structures and functions beyond traditional peptide drugs. Natural sources, like venoms and toxins, are also valuable for discovering bioactive peptides.

Enzyme synthesis is used for short peptides, while fermentation is an environmentally friendly method for producing bioactive peptides. Recombinant DNA technology helps produce peptides with specific sequences and is particularly useful for complex peptides. Combining recombinant DNA with genetic code expansion allows for functional group incorporation, and semi-synthesis connects synthetic and recombinant peptides for large bioactive peptides.

Peptide Modification through Genetic Code Expansion

Natural proteins are synthesized from 20 standard amino acids, and this limited and conserved amino acid pool significantly restricts the diversity and complexity of protein structures and functions. Genetic code expansion is a technology developed two decades ago to overcome this limitation. Genetic code expansion allows the incorporation of non-canonical amino acids (ncAA) with new chemical and physical properties at specific sites in the growing peptide during protein translation. Achieving this requires four components: 1) ncAA with the desired chemical and physical properties; 2) unique codons for specifying ncAA, such as the amber stop codon (UAG) or a tetranucleotide codon; 3) orthogonal tRNA that suppresses the unique codon and does not interfere with its endogenous counterpart; 4) orthogonal aminoacyl-tRNA synthetase that can specifically charge ncAA to orthogonal tRNA without interfering with the endogenous aminoacyl-tRNA synthetase/tRNA pair.

So far, more than 200 different ncAAs with various functions have been genetically encoded into different organisms, such as Escherichia coli, yeast, mammalian cells, viruses, and even animals, providing valuable tools for protein research and engineering. This expanded set of building blocks includes bioorthogonal chemical conjugation partners, metal chelators, photoreactive crosslinkers, proximity-based crosslinkers, photochemical masking amino acids, post-translationally modified amino acids (e.g., phosphorylation, sulfation, acetylation), redox-active amino acids, and infrared, NMR, and fluorescence probes. These have been widely applied in the research, manipulation, and evolution of proteins. The ability to genetically encode multiple ncAAs allows for the rational optimization and production of chemically modified recombinant proteins with defined structure, function, and stoichiometry. Here, we focus on the application of genetic code expansion in the evolution of therapeutic peptides and proteins. 

PEGylation of Peptides and Proteins

Short protein and peptide therapeutics often suffer from poor pharmacokinetics, including rapid serum degradation and elimination. To extend their half-life, PEGylation, the conjugation of polyethylene glycol (PEG) to proteins, is commonly used. PEG increases molecular weight, reducing renal clearance and protecting proteins from degradation. This method, used since the 1970s, has led to over ten PEGylated protein therapeutics available on the market.

Traditional PEGylation occurs at lysine or cysteine residues, but lack of selectivity can result in heterogeneous conjugates. Site-specific PEGylation has been developed using expanded genetic codes and non-canonical amino acids (ncAAs) with bioorthogonal chemical handles. In 2004, the first site-specific PEGylation method was reported using pAzF (p-azido-phenylalanine) and CuAAC click reactions to attach PEG to superoxide dismutase (SOD), preserving its activity. This technique was later applied to interferon (IFN)-α2b, improving pharmacokinetics and biological activity.

In 2011, recombinant proteins using genetic code expansion entered clinical trials. Human growth hormone (hGH) variants were created by introducing para-acetylphenylalanine (pAcF) and PEGylating specific residues, resulting in enhanced pharmacodynamics, reduced injection frequency, and improved stability. Multi-PEGylated hGH variants showed lower immunogenicity and better pharmacokinetics.

Moreover, PEG-containing ncAAs have been directly incorporated into target proteins and peptides using in vitro translation systems, showing promising results. For example, GLP-1 with eN-heptanoyl-L-lysine (HepoK) exhibited prolonged hypoglycemic effects, demonstrating the potential of genetic code expansion in optimizing therapeutic proteins. 

Covalent Peptide/Protein Drugs

Small molecule covalent drugs offer advantages such as improved potency, enhanced pharmacokinetics, prolonged action time, and strong inhibitory effects on difficult targets. However, their low selectivity and potential immunogenicity have limited their development. Recent advancements in active protein analysis and other technologies have renewed interest in covalent drugs, leading to several approved small molecule covalent drugs.

Covalent protein drugs could offer similar benefits but have faced challenges due to the difficulty of forming covalent bonds with native proteins. A novel approach, activation reaction therapy (PERx), has overcome this limitation by incorporating non-canonical amino acids (ncAAs) like fluorosulfonyl-L-tyrosine (FSY) into proteins. For example, FSY-modified PD-1 selectively binds to PD-L1, enhancing its bioactivity in immune cells and improving tumor suppression in mouse models compared to wild-type PD-1.

The PERx strategy was also applied to HER2 receptor inhibition, demonstrating its potential for developing a variety of covalent protein drugs. Unlike non-covalent drugs, PERx drugs do not need modifications to extend their half-life, as covalent binding decouples efficacy from pharmacokinetics. This approach minimizes off-target effects and expands the range of proteins for therapeutic use.

Additionally, lipidation and conjugation with plasma proteins, such as serum albumin, are used to improve the pharmacokinetics of covalent peptide drugs, increasing circulation time and reducing degradation, as seen with drugs like liraglutide.

Advantages and Disadvantages of Therapeutic Peptides

Therapeutic peptides are used as hormones, growth factors, neurotransmitters, ion channel ligands, or anti-infectives. They bind to cell surface receptors with high affinity and specificity, similar to biologics like proteins and antibodies. However, peptides have lower immunogenicity and production costs than biologics.

Small molecule drugs, with a long history of use, offer benefits such as low production costs, oral bioavailability, and good membrane permeability. They are more affordable than peptides and biologics, and oral small molecules improve patient compliance. Their small size allows them to target intracellular molecules. However, small molecules struggle to inhibit large surface interactions like protein-protein interactions, which are critical in many diseases. Peptides, due to their larger size and flexible backbone, can better inhibit PPIs. Small molecules also have lower specificity compared to peptides, leading to potential off-target effects and cytotoxicity.

Therapeutic peptides, based on natural amino acids, face two main challenges: poor membrane permeability and poor stability in vivo. Peptides often cannot pass through cell membranes to reach intracellular targets, limiting their use. Over 90% of clinical peptides target extracellular receptors like GPCRs, GnRH receptors, and GLP-1 receptors. Additionally, natural peptides are chemically unstable, as amide bonds can be easily broken by enzymes in the body, resulting in short half-lives and rapid elimination. 

Applications of Therapeutic Peptides 

Therapeutic peptides, short chains of amino acids linked by peptide bonds, have emerged as an important class of biologically active molecules with significant potential in the treatment of various diseases. Peptides are involved in many biological processes, including hormone regulation, immune response, and cellular signaling. Their application in therapeutic fields is vast, as they can interact with specific receptors or enzymes, making them highly selective and effective in targeting specific molecular pathways involved in disease. This article explores the development and current applications of therapeutic peptides in the treatment of diseases, focusing on diabetes, cardiovascular diseases, gastrointestinal disorders, gastric diseases, cancer, and viral infections.

Table.4 Therapeutic peptides at Creative Peptides.

Therapeutic Peptides in Diabetes

Diabetes mellitus, a chronic condition characterized by impaired insulin production or function, has seen a significant benefit from therapeutic peptides. The treatment landscape for diabetes has evolved dramatically with the development of peptide-based therapies that focus on regulating glucose metabolism and insulin sensitivity.

GLP-1 Receptor Agonists: One of the most successful therapeutic peptides in diabetes treatment is glucagon-like peptide-1. GLP-1 is an incretin hormone that enhances insulin secretion in response to meals, reduces glucagon release, and slows gastric emptying. This hormone plays a crucial role in regulating blood glucose levels. GLP-1 receptor agonists, such as liraglutide, semaglutide, and exenatide, mimic the effects of endogenous GLP-1 and have become important components of type 2 diabetes treatment. These agents not only help to lower blood glucose but also aid in weight loss, offering an additional benefit for diabetic patients who often struggle with obesity.

Insulin Peptides: Insulin, another peptide hormone, is fundamental in diabetes treatment, particularly for type 1 diabetes. Insulin therapy has been revolutionized with the development of rapid-acting and long-acting insulin analogs, providing better control over blood glucose levels and improving patient quality of life. These synthetic peptides mimic natural insulin but have modified amino acid sequences to alter their pharmacokinetic properties, such as faster absorption or prolonged action.

Therapeutic Peptides in Cardiovascular Disease

Cardiovascular diseases (CVDs), including heart failure, hypertension, and atherosclerosis, continue to be leading causes of morbidity and mortality worldwide. The application of therapeutic peptides in this field has shown promising results in improving cardiac function, reducing blood pressure, and preventing the progression of heart failure.

B-Type Natriuretic Peptide (BNP) and Nesiritide: B-type natriuretic peptide is a naturally occurring hormone involved in the regulation of blood pressure and fluid balance. BNP promotes natriuresis, diuresis, and vasodilation, making it a valuable target in the treatment of heart failure. Nesiritide, a recombinant form of BNP, is used in acute decompensated heart failure to reduce symptoms like shortness of breath and fluid retention. Despite mixed clinical outcomes, nesiritide demonstrates the potential for peptide-based therapies in managing heart failure.

Angiotensin-Converting Enzyme (ACE) Inhibitors and Angiotensin Receptor Blockers (ARBs): Although not peptides themselves, ACE inhibitors and ARBs work by influencing peptide systems in the body. ACE inhibitors, such as enalapril and lisinopril, block the enzyme that converts angiotensin I to angiotensin II, a potent vasoconstrictor. By reducing the levels of angiotensin II, these medications help lower blood pressure and reduce strain on the heart. Similarly, ARBs target the angiotensin II receptor to block its action, which also helps in controlling blood pressure and managing heart failure.

Table.5 CVD related peptides at Creative Peptides.

Therapeutic Peptides in Gastrointestinal Disease

Gastrointestinal diseases, including inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), and celiac disease, can be challenging to manage. Peptide-based therapies are playing an increasingly important role in the treatment of these disorders, particularly by modulating inflammation and improving gastrointestinal motility.

Somatostatin and Octreotide: Somatostatin is a naturally occurring peptide that inhibits the release of various gastrointestinal hormones, including insulin, glucagon, and growth hormone. It also reduces gastric acid secretion and inhibits the motility of the gastrointestinal tract. Octreotide, a synthetic analogue of somatostatin, is used in the treatment of conditions such as acromegaly, gastroenteropancreatic neuroendocrine tumors, and gastrointestinal bleeding.

Ghrelin Agonists: Ghrelin, a peptide hormone that stimulates appetite, is also involved in the regulation of gastric motility. Ghrelin agonists are being explored as potential therapies for patients with gastroparesis or slow gastric emptying, conditions often seen in diabetes and other gastrointestinal disorders. By stimulating ghrelin receptors, these peptides can enhance gastric motility and improve symptoms in patients suffering from delayed gastric emptying.

Therapeutic Peptides in Gastric Disease

The treatment of gastric diseases, such as peptic ulcers and gastritis, has benefited from the development of peptide-based therapies that target the underlying causes of these conditions.

Vasoactive Intestinal Peptide (VIP): Vasoactive intestinal peptide (VIP) is a peptide involved in regulating smooth muscle tone, vasodilation, and gastric acid secretion. It has been investigated for its potential to treat gastritis and peptic ulcers by reducing gastric acid secretion and promoting mucosal healing. VIP's ability to relax smooth muscle in the gastrointestinal tract also makes it a candidate for treating gastric motility disorders.

Proton Pump Inhibitors and Peptide Therapy: While proton pump inhibitors, such as omeprazole, are commonly used to treat gastric acid-related disorders, there is ongoing research into the use of peptides in combination with PPIs to further enhance the healing process and reduce ulcer recurrence. Peptides that promote mucosal protection or enhance the healing of gastric ulcers could offer a more comprehensive approach to treating gastric diseases.

Therapeutic Peptides in Cancer 

Cancer therapy has greatly benefited from the development of therapeutic peptides, which can be used to selectively target cancer cells, modulate the immune system, and inhibit the growth of tumors. Peptide-based therapies provide a promising alternative to conventional chemotherapy, which often comes with severe side effects.

Peptide Receptor Radionuclide Therapy (PRRT): Peptide receptor radionuclide therapy (PRRT) involves the use of radiolabeled peptides that specifically bind to receptors overexpressed on cancer cells. This targeted approach allows for the delivery of cytotoxic radiation directly to the tumor, minimizing damage to surrounding healthy tissues. PRRT has shown efficacy in the treatment of neuroendocrine tumors and is currently being investigated for other cancers as well.

Immune Modulatory Peptides: Some therapeutic peptides are designed to enhance the body's immune response against cancer. For example, certain peptides can stimulate the immune system to recognize and destroy tumor cells. These immune-modulatory peptides are being studied in cancer immunotherapy, either as standalone treatments or in combination with other immune checkpoint inhibitors.

Targeted Cancer Therapy: Peptides that bind specifically to cancer cell receptors, such as epidermal growth factor receptor (EGFR) or human epidermal growth factor receptor 2 (HER2), are being used to selectively deliver cytotoxic agents directly to cancer cells. This targeted approach improves the specificity and effectiveness of cancer treatments while reducing off-target toxicity.

Antiviral Peptides

The growing need for effective antiviral agents has led to the exploration of therapeutic peptides with antiviral properties. These peptides act by disrupting the viral lifecycle, blocking viral entry into host cells, or inhibiting viral replication.

Antiviral Peptides for HIV: One of the most notable applications of antiviral peptides is in the treatment of HIV. Peptides such as enfuvirtide (Fuzeon), which is a fusion inhibitor, block the fusion of the HIV virus with host cells. By preventing viral entry, enfuvirtide reduces viral load and helps manage HIV infection.

Antiviral Peptides Against Influenza and Herpes Simplex Virus (HSV): Peptides derived from natural antimicrobial peptides have been found to inhibit viral infections such as influenza and HSV. These peptides can bind to the viral envelope or interfere with viral protein function, thus preventing infection.

Broad-Spectrum Antiviral Peptides: Research into broad-spectrum antiviral peptides is ongoing, aiming to develop peptides that can target a wide range of viruses. These peptides often exploit common features in viral structures, such as the lipid bilayer or viral proteins, making them effective against multiple viral species.  

Summary

Peptides have become a unique class of therapeutic drugs due to their distinct biochemical properties and potential. While they offer advantages over small molecules and large biologics, peptides face challenges like poor membrane permeability and in vivo stability. To overcome these issues, research has focused on discovering, producing, and optimizing peptides. Combining traditional methods with new technologies, such as phage display, has led to effective and selective peptide development. Chemical and recombinant synthesis methods can efficiently produce synthetic peptides on a large scale, with site-specific modifications to enhance stability and biological activity.

Initially focused on natural hormones, therapeutic peptide development has shifted toward designing peptides with ideal biochemical and physiological properties. Advances in molecular biology, peptide chemistry, and delivery technologies have greatly improved peptide drug discovery, production, and therapeutic applications. Over 80 therapeutic peptides have reached the global market, with hundreds more in preclinical or clinical development. These peptides are used to treat various diseases, including diabetes, cardiovascular diseases, gastrointestinal disorders, cancer, infections, and vaccines. Given their therapeutic potential, market opportunities, and economic value, therapeutic peptides are expected to continue attracting investment and research, leading to long-term success.

References

1. Lau, Jolene L., and Michael K. Dunn. Therapeutic peptides: Historical perspectives, current development trends, and future directions. Bioorganic & medicinal chemistry 26.10 (2018): 2700-2707.
2. Wang, Lei, et al., Therapeutic peptides: current applications and future directions. Signal transduction and targeted therapy 7.1 (2022): 48.