Common Classifications of Peptide Drugs

The development of biotechnology has significantly advanced the research and production of peptide and protein drugs. Currently, more than 40 major therapeutic drugs are on the market, and over 700 biotechnological drugs are undergoing Phase I–III clinical trials or being reviewed by the FDA, with more than 200 drugs in the final approval stage (Phase III clinical trials and FDA evaluation).

1. Classification by Secretion Site

- Vasopressin and its derivatives: Brain neurohypophysine, vasopressin, tannic vasopressin, desmopressin, phenylpressin, vasotocin (POR-8), etc.
- Oxytocin and its derivatives: Oxytocin, desamino-oxytocin, oxytocin tartrate, etc.
- Corticotropin and its derivatives: Corticotropin, zinc corticotropin (ACTH-Zn), phosphozinc corticotropin, gelatin corticotropin, carboxymethyl corticotropin, Lys-Pro corticotropin 18-peptide, Glu-Pro corticotropin 18-peptide, zinc corticotropin 24-peptide, corticotropin 24-peptide, 25-peptide, 28-peptide, etc.
- Hypothalamic-pituitary peptides: Gonadotropin-releasing hormone, thyrotropin-releasing hormone, growth hormone-releasing hormone (GHRH), somatostatin (14-peptide), melanocyte-stimulating hormone inhibiting hormone (MRIH), melanocyte-stimulating hormone releasing hormone (MRH), prolactin-releasing hormone (PRH), prolactin-inhibiting hormone (PIH), corticotropin-releasing hormone (CRH), etc.
- Gastrointestinal hormones: Gastrin 34-peptide, 17-peptide, 14-peptide, 5-peptide, 4-peptide; secretin 27-peptide, cholecystokinin 39-peptide, 33-peptide, 8-peptide; gastric inhibitory peptide, motilin, vasoactive intestinal peptide, pancreatic polypeptide, substance P, neurotensin, caerulein, etc.
- Other hormones and active peptides: Thymosin α1 (28-peptide), glucagon (29-peptide), calcitonin (32-peptide), angiotensin I (10-peptide), II (8-peptide), III (7-peptide), enkephalin, endorphin, sleep peptide, memory peptide, melatonin peptide, trypsin inhibitor, bradykinin (8-peptide), caerulein (8-peptide), etc.

2. Classification by Function

2.1 Peptide Vaccines
Infectious diseases like hepatitis, influenza, malaria, and schistosomiasis are widespread and harmful. Although chemical drugs can treat these diseases effectively, reinfection rates are high, requiring constant treatment in epidemic areas. Therefore, vaccines are necessary for their prevention. Traditional inactivated or attenuated vaccines carry the risk of causing infection, especially for dangerous diseases like AIDS. As a result, synthetic peptide vaccines have become important.

In the early 1980s, Lerner proposed the concept of synthetic peptide vaccines. This approach involves identifying the amino acid sequence of the natural antigen (e.g., a virus or its subunits), finding the epitope peptide segment, synthesizing the antigenic peptide, and testing its ability to induce antibody production. Synthetic peptide vaccines, being a non-infectious part of the virus, offer a safer approach to vaccine development and can be mass-produced.

The first step in developing synthetic peptide vaccines is identifying the antigenic peptide, followed by creating peptides with strong immunogenicity and no side effects. These peptides are then combined with suitable adjuvants to achieve an optimal immune response. Three types of synthetic peptide antigens are typically used in vaccine preparation: (1) peptide-carrier complex antigens; (2) multi-antigen peptide antigens; and (3) multivalent synthetic peptide vaccine antigens.

HIV and hepatitis C virus (HCV) vaccines remain unavailable, but research into DNA and peptide vaccines is promising. In 1999, the NIH announced two HIV-I peptide vaccines that, in Phase I clinical trials, showed the ability to induce specific antibodies and cellular immunity while maintaining safety. Tsinghua University in China also confirmed that a segment of the HIV-I membrane protein peptide has strong immunogenicity. Similar progress has been made in HCV peptide vaccines, where a segment of the HCV outer membrane protein E2 peptide has been shown to stimulate protective antibodies. Research on peptide vaccines for other viruses (such as hepatitis A, measles, and Sindbis virus), cancer, and contraceptive applications has also progressed. For instance, U.S. scientists NaZ et al. screened a 12-amino-acid peptide from a phage library that can specifically bind to human eggs and block sperm-egg fusion, paving the way for contraceptive vaccines.

2.2 Anti-Tumor Peptides
Tumor development involves the regulation of oncogene expression. Various enzymes and regulatory factors are required during tumor formation, and selecting specific peptides that target these factors can block tumor growth. Many tumor-related genes and growth-regulating factors have been discovered, and identifying peptides that bind specifically to these targets has become a hot topic in cancer drug research. For example, researchers have identified a short peptide (six amino acids) that significantly inhibits adenocarcinoma growth, opening a new path for treating these cancers. Other peptides, such as hemagglutinin from the influenza virus, can enter tumor cells and activate p53, inducing apoptosis. Substance P (10-peptide) derivatives also show inhibition of small-cell lung cancer growth.

2.3 Antiviral Peptides
Viruses follow several stages when infecting a host: adsorption (to host cells), penetration, uncoating, replication, transcription/translation, and packaging. Blocking any of these processes can prevent viral replication. The most effective antiviral drugs target the adsorption and replication stages. Viruses use specific receptors on host cells to attach and rely on their own proteases for protein processing and nucleic acid replication. Screening peptide libraries for peptides that bind to these viral receptors or proteases is a promising approach for antiviral therapy.

Peptide drugs can work through three antiviral mechanisms: (1) directly binding to viral particles (e.g., α-defensins for herpesvirus, polyphemusin for HIV); (2) inhibiting viral replication (e.g., melittin and cecropin A for HIV); and (3) mimicking the viral infection process (e.g., bee venom peptides). Research into HCV NS3 protein, essential for viral replication, identified a 6-peptide (DDIVPC) that significantly inhibits this enzyme's activity. Similarly, peptides targeting HIV reverse transcriptase and outer membrane proteins have been identified, some of which are undergoing clinical trials.

2.4 Peptide-Targeted Drugs
Many toxins (e.g., Pseudomonas exotoxin) and cytokines (e.g., interleukins) have strong tumor cytotoxicity but can also damage normal cells when used long-term. By fusing tumor-specific peptides with these active agents, they can be concentrated in tumor sites, reducing toxicity and side effects. For example, epidermal growth factor (EGF) receptors are overexpressed on many tumor cells. Fusing toxins or antitumor cytokines with EGF allows these agents to specifically target tumor cells. Peptide library screening has also identified small peptides that bind specifically to tumor antigens, which are more suitable for drug targeting due to their small molecular size.

2.5 Cytokine Mimetic Peptides
Screening peptide libraries using known cytokine receptors to identify cytokine mimetic peptides has become a research hotspot. Researchers have identified mimetic peptides for human erythropoietin, thrombopoietin, growth hormone, nerve growth factor, and interleukin-1, which, while differing in sequence from their respective cytokines, retain biological activity and have smaller molecular weights. These mimetic peptides are currently in preclinical or clinical trials.

This detailed classification and ongoing research into peptide drugs highlight their growing importance in modern medicine.

• Thymosin
  Thymopentin (TP5) is currently the world's leading immunomodulator in terms of prescription volume. TP5 is a synthetic pentapeptide whose amino acid sequence and structure correspond to positions 32-36 of thymopoietin, the active site of TP, and its function is the same as TP. Animal experiments and clinical studies have demonstrated that thymopentin plays an important role in regulating the immune function of patients with immune deficiency and autoimmune diseases. Due to its excellent immunomodulatory function, thymopentin was in high demand in the pharmaceutical market during the SARS epidemic.
• Interferon
  Interferon is a highly active, multifunctional lymphokine produced by mammalian cells under induction, with a molecular weight of 2.0×10^4. It acts on corresponding cells of the same species, granting them antiviral and antitumor "immunity." It inhibits viral replication within cells, enhances macrophage phagocytosis, and increases the killing effect on cancer cells. Interferon has been successfully expressed using both E. coli and yeast systems. There are currently 13 types of interferon preparations on the market: 7 α-IFNs, 2 β-IFNs, and 4 γ-IFNs, all of which have been approved for clinical use in many countries.
• Interleukin
  Interleukin is a class of antitumor immune factors that can promote the growth, proliferation, and differentiation of T cells and B cells, as well as enhance the function of cytotoxic lymphocytes. It is used in cancer treatment. There are 29 types of interleukins, with interleukin-2 being the most abundant. Recombinant interleukin-2 and interleukin-3 are now available on the market.
• Colony-Stimulating Factors (CSFs)
  Colony-stimulating factors are divided into two types: granulocyte colony-stimulating factors (G-CSF) and granulocyte-macrophage colony-stimulating factors (GM-CSF). These cytokines promote the proliferation of white blood cells, enhance granulocyte function, and regulate hematopoiesis. They are used to treat symptoms like leukopenia after cancer chemotherapy. Marketed products generate annual revenues of hundreds of millions of dollars.
• Granulocyte colony-stimulating factors (brand names: Neupogen, Neulasta, etc.) stimulate the formation of granulocyte colonies and promote the proliferation and differentiation of hematopoietic stem cells into neutrophils. They can increase neutrophil function, such as chemotaxis, phagocytosis, enzyme production, and bactericidal action. Additionally, they mobilize mature neutrophils from the bone marrow into peripheral blood and can induce early multipotent hematopoietic stem cells into the cell cycle. G-CSFs are used to elevate neutrophil levels after bone marrow transplantation, to treat neutropenia caused by cancer chemotherapy or myelodysplastic syndromes, and to manage congenital or idiopathic neutropenia.
• Recombinant human GM-CSF (brand name: Leukine) binds to specific receptors on precursor cells of the granulocyte and monocyte/macrophage lineages, promoting their proliferation and differentiation into neutrophils, eosinophils, and monocyte/macrophages. It works synergistically with high-concentration erythropoietin to enhance red blood cell vitality and promotes the release of mature cells into peripheral blood. In vitro studies show that it can also promote macrophage-mediated lysis of tumor cells, improving the body's immune response against tumors and infections.
• Growth Hormone
  Human growth hormone is used to treat dwarfism and promote wound healing, while animal growth hormones accelerate livestock growth and increase milk production. Both human and animal growth hormone genes have been successfully expressed in E. coli, with products already on the market generating annual revenues of $625 million. Growth hormones have shown excellent applications in medicine and animal husbandry.
• Erythropoietin (EPO)
  Erythropoietin is a hematopoietic cytokine produced by the kidneys that acts on the bone marrow. It shortens the maturation period of primitive red blood cells and regulates hematopoietic cells in the bone marrow. EPO is used to treat anemia caused by kidney failure, radiation, chemotherapy, and other rare types of anemia. It is also used in pre-surgery preparation for autologous blood transfusion. As a glycopeptide, glycosylation is critical for its function, so it cannot be expressed in prokaryotic cells like E. coli. Instead, it is expressed in cultured mammalian cells, making production costly and complex. Despite this, EPO generates annual revenues of $1.225 billion, making it one of the highest-grossing recombinant drugs.

2.6 Antimicrobial Peptides
Almost all types of organisms produce small molecule peptides, known as antimicrobial peptides, in response to microbial invasion. More than 100 antimicrobial peptides, composed of 12-45 amino acids, have been identified. These peptides are cationic and often contain arginine, lysine, or histidine, making them positively charged, hydrophobic, or amphipathic. Based on their structure and mechanism, antimicrobial peptides are classified into two types: linear peptides with a helical structure and cyclic peptides containing disulfide bonds or thioethers. Due to their small size, heat stability, good solubility, low immunogenicity, fast action, and broad-spectrum activity, antimicrobial peptides can inhibit bacteria, fungi, viruses, and parasites. They also suppress various cancer cells, transformed cells, and solid tumors without damaging normal cells.

Traditional antibiotics have developed resistant strains, and commonly used anticancer drugs struggle to distinguish between normal and tumor cells. However, antimicrobial peptides are not affected by existing resistant mutations, and the target strains do not easily develop resistance. Their unique selective toxicity and low immunogenicity have generated widespread interest, positioning them as the next generation of antimicrobial and anticancer drugs.

2.7 Peptides for Cardiovascular Diseases
Many traditional Chinese medicines have blood pressure-lowering, lipid-reducing, and thrombolytic effects, making them suitable as drugs or health foods. However, their unclear active ingredients limit their application. It has now been discovered that many active components are small peptides. For example, Chinese scientists isolated a small active peptide from soy (MW<1000), which can be absorbed directly by the small intestine and helps prevent thrombosis, hypertension, hyperlipidemia, delays aging, and enhances antitumor immunity. Other peptides from corn, figs, ginseng, tea leaves, and ginkgo leaves also show potential for treating cardiovascular diseases.

2.8 Other Medicinal Peptides
In addition to the above fields, there has been progress in using small peptides in other areas. For instance, synthetic peptide TP508 promotes wound vascularization and accelerates deep wound healing. A small peptide, RTR4, prevents inflammation in the cornea caused by alkaline damage, while others inhibit bone resorption by osteoclasts.

Endomorphin-1 is another small peptide with potential for development, having strong analgesic activity, even higher than that of morphine. It exists in the brain and is an endogenous μ-opioid receptor agonist. Endomorphin-1 is the peptide with the highest known affinity and selectivity for the μ-opioid receptor, and it can be synthesized rapidly in high purity.

2.9 Peptides for Diagnostics
Peptides are primarily used in diagnostic reagents as antigens for detecting antibodies against viruses, cells, mycoplasma, spirochetes, and parasites. Peptide antigens are more specific than natural microbial or parasite proteins and easier to prepare. Diagnostic systems using peptide antigens show low rates of false negatives and background reactions, making them suitable for clinical applications. Diagnostic kits based on peptide antigens are available for detecting hepatitis A, B, C, and G viruses, HIV, cytomegalovirus, herpes simplex virus, rubella virus, syphilis, cysticercosis, trypanosomiasis, Lyme disease, and rheumatoid arthritis.

2.10 Sensory Peptides for Food
Aspartame is one of the most successful sensory peptides developed for food, acting as a non-sugar sweetener. It is synthesized from phenylalanine and aspartic acid and is 200 times sweeter than sucrose, making it suitable for diabetic patients or those avoiding sugar. It is low in calories and can also be used as a weight-loss product. Other sensory peptides enhance or mask flavors, such as salty peptides as sodium-free seasoning for diabetic and hypertensive patients or flavor-enhancing peptides that act as precursors for flavor and aroma in processed foods.