What are Peptide Drugs? What are the Various Types?
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Currently, the main methods for treating tumors include surgical resection, radiotherapy, and chemotherapy. Chemotherapeutic drugs not only damage tumor cells but also affect a wide range of normal cells, leading to various toxic side effects. The development of resistance to chemotherapy drugs is also a reason why they cannot effectively treat tumors.
Therefore, it is crucial to develop efficient and low-toxicity anti-tumor drugs. Compared to traditional chemotherapy drugs, peptide drugs have characteristics such as small molecular weight, sensitivity to tumors, low likelihood of developing resistance, and low cost. This has led to active research and development of peptide drugs both domestically and internationally. Additionally, peptides play a significant role in tumor antigens, and the development of peptide vaccines offers hope for cancer patients.
Anti-tumor mechanisms of peptide drugs
Peptides are molecules composed of amino acids as basic units, with a molecular weight generally below 10 kDa, lying between small chemical molecules and biopharmaceuticals. Their main features include high selectivity and low effective concentrations.
1. Regulating immune function
Tumor immunotherapy aims to elicit a response from the body's own immune system against tumors, making it the fourth important method for cancer treatment, alongside surgery, radiotherapy, and chemotherapy.
The immune response can be divided into specific and non-specific responses. Non-specific immunity, also known as innate immunity, involves cells such as macrophages, dendritic cells, and NK cells, which recognize and act against pathogens through pattern recognition receptors or limited diversity antigen recognition receptors.
Research by Sun et al. demonstrates that different concentrations of Pleurotus eryngii mycelium peptide (PEMP) can stimulate macrophages to release NO, H2O2, TNF-α, inhibiting cancer cell proliferation and enhancing the phagocytic ability of macrophages to exert anti-tumor effects.
Specific immunity can be further divided into T lymphocyte-mediated adaptive immunity, including cellular immunity, and B lymphocyte-mediated humoral immunity. T cells consist of CD4+ T cells and CD8+ T cells, with cytotoxic T lymphocytes (CTL) being the main effector cells in specific antigen sites. CTL plays a crucial role in cell-mediated immunity by selectively killing intracellular pathogens and tumor cells.
Research by Sun et al. developed immunogenic peptides derived from human phosphatidylethanolamine-binding protein 4 (hPEBP4) to induce antigen-specific CTL against breast cancer. A novel immunogenic peptide, P40-48 (TLFCQGLEV), was identified, capable of eliciting specific CTL responses in HLA-A2.1/Kb transgenic mice and peripheral blood lymphocytes from breast cancer patients. The induced CTLs from P40-48 demonstrated hereditary transfer more effectively than natural peptides, suppressing tumor growth.
Xie et al. used HLA binding prediction algorithms to search for new human leukocyte antigen (HLA)-A2402-restricted epitopes from Eps8 protein. The novel HLA-A2402-restricted peptides, 327 (EFLDCFQKF), 534 (KYAKSKYDF), and 755 (LFSLNKDEL), induced peptide-specific CTL with higher levels of IFN-γ secretion, exhibiting enhanced cytotoxic activity against malignant cancer cells. Peptides 327 and TAT327, acting as new peptide inhibitors, were shown to inhibit tumor growth more effectively by suppressing Eps8/EGFR interaction, offering innovative approaches for treating various cancers.
B cells, as the major cells in humoral immunity, have a dual role in tumor development, promoting anti-tumor responses and inducing immune tolerance. According to their function, B cells can be divided into effector B cells and regulatory B cells.
Regulatory B cells (Bregs) are closely related to tumors, and their mechanisms in tumor immunity include: reducing the differentiation of Th1 cells and Th17 cells by secreting IL-10, thereby decreasing the expression of tumor-suppressive cytokines and promoting tumor growth; inducing the production of Tregs by secreting TGF-β, co-stimulatory molecules, and IL-10, which, in turn, inhibits the function of immune effector cells through Tregs to protect tumor cells.
Effector B cells are divided into type 1 (Be1) and type 2 (Be2). Be1 cells mainly produce pro-inflammatory cytokines such as TNF-α, IFN-γ, and IL-12, exerting anti-tumor effects. On the other hand, Be2 cells mainly produce IL-4, IL-13, and are associated with Th2 cell responses."
"Huang et al. demonstrated that CpG alone is sufficient to inhibit the anti-tumor response induced by BRAF inhibitors, indicating that the compromised anti-tumor activity of BRAF inhibitors observed in mice receiving CpG-based peptide vaccines is mainly dependent on the use of CpG. CpG increases the number of circulating B cells, leading to an increased production of TNF-α, which contributes to the increased resistance of tumors to BRAF inhibitors.
Chang Xu and Ou Hongli conducted research on the anti-tumor effects of American cockroach peptides and their impact on the immune function of tumor-bearing mice. The study indicated that American cockroach peptides achieve their anti-tumor effects by enhancing the immune function of tumor-bearing mice.
Featured peptide inhibitors
2. Inhibition of tumor angiogenesis
Neoangiogenesis is a crucial pathway for tumors to acquire nutrient supply for their development. Tumor angiogenesis is the result of the combined action of various factors induced by tumors, with a balance between promoting and inhibiting factors. Vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis among various promoting factors, and its receptors (VEGFR) include three types: VEGFR-1, VEGFR-2, and VEGFR-3.
The mechanism of anti-tumor peptide drugs in inhibiting angiogenesis is a focus of many researchers. For example, Qi et al. found that the tissue inhibitor of metalloproteinase-3 (TIMP-3) acts as an effective inhibitor of VEGF-mediated angiogenesis and neovascularization by blocking the binding of VEGF to its receptor VEGFR-2.
Bracci et al. studied the branch peptide NT4 binding to heparan sulfate proteoglycan (HSPG) and selectively targeting cancer cells and tissues. NT4 was found to have a significant impact on endothelial cell proliferation, migration, and tube formation, especially when induced by FGF2 and thrombin. Additionally, NT4 plays a crucial role in inhibiting the migration and invasion of invasive tumor cells. Therefore, the anti-angiogenesis mechanism of peptide drugs provides clues for the development of targeted drugs for tumors.
3. Promotion of cell apoptosis
Cell apoptosis, also known as programmed cell death, is a major way for cells to die normally and plays an essential role in the clearance of cells. Abnormalities in apoptosis signaling pathways can lead to various diseases, including cell carcinogenesis, and resistance to apoptosis is closely related to tumor development.
There are two main pathways of cell apoptosis in the body: the extrinsic pathway, mainly activated by apoptosis receptor stimulation on the cell surface, and the intrinsic pathway, which involves disrupting mitochondrial membrane integrity in addition to activating apoptosis signaling. Many signaling pathways are closely related to cell apoptosis, such as the Bcl-2 family and the Fas/FasL pathway. The Bcl-2 family includes two major classes of proteins: anti-apoptotic proteins (Bcl-2) and pro-apoptotic proteins (Bax). Overexpression of the anti-apoptotic protein (Bcl-2) in tumor cells increases their resistance to apoptosis, leading to uncontrolled growth.
Peptide drugs inducing cell apoptosis can affect the Bcl-2 family of proteins. Research by Zhang et al. showed that American cockroach peptides can induce apoptosis in human liver cancer cells (SMMC-7721) by upregulating Bax protein expression and downregulating Bcl-2 protein expression, thereby inhibiting tumor cell proliferation. Therefore, targeting the regulation of the Bcl-2 family becomes an effective approach for treating tumors.
Another signaling pathway related to cell apoptosis is the Fas/FasL pathway, one of the main pathways regulating apoptosis. Activation of the Fas/FasL pathway induces cell apoptosis. Kuo et al. demonstrated that low concentrations of marine antimicrobial peptide (AMP) MSP-4 extracted from Nile tilapia induce apoptosis in osteosarcoma MG63 cells by activating the Fas/FasL signaling pathway, exhibiting anti-tumor effects.
1. Single-target peptides
(a) PD-1/PD-L1 peptides
High-throughput display screening technology plays a crucial role in the screening of immune checkpoint blocking peptides. Tao et al. obtained the PD-1-targeting peptide P-F4 through phage display technology, while Liu et al. obtained the PD-L1-targeting peptide CLP002 using the same method. Li et al. first used bacterial surface display technology to screen the PD-L1-targeting peptide TPP-1, and Kamalinia et al. obtained the PD-L1 peptide SPAM using mRNA display technology.
However, the above peptides are all linear peptides composed of L-configured amino acids, with poor conformation and enzyme-resistant stability. To obtain more stable conformations, cyclic peptides are a better choice.
In 2015, Maute et al. used yeast display technology to obtain a high-affinity PD-L1 mutant of PD-1, with an affinity 74,000 times higher than wild-type PD-1. This high-affinity PD-1 mutant has been applied in the design of PD-L1-targeting peptides.
Jeong et al. truncated peptide fragments from the above PD-1 protein mutant and formed a multivalent PD-L1 peptide conjugate using dendritic macromolecules.
Similarly, Yin et al., based on the high-affinity PD-1 mutant, proposed the concept of 'peptide mimetic design' and designed a cyclic peptide MOPD-1 with high affinity and better anti-tumor effects on PD-L1.
The interaction between PD-1/PD-L1 ligands is one of the key factors mediating tumor immune escape. Inhibiting the negative signaling pathway mediated by it can break the established immune tolerance in the body and improve the functional exhaustion of PD-1 immune cells.
Several research groups and companies both domestically and internationally are developing small-molecule drugs targeting PD-1/PD-L1. Most small-molecule drugs can easily enter the interior of cells. In comparison to traditional radiotherapy and chemotherapy, PD-1/PD-L1 peptide inhibitors typically do not directly affect the proliferation or migration of tumor cells. Instead, they damage tumor cells by mobilizing the immune system.
Furthermore, PD-1 mainly plays a role in maintaining immune tolerance, meaning that PD-1/PD-L1 blockade does not lead to severe adverse reactions. In summary, PD-1/PD-L1 peptide inhibitors are expected to provide highly promising candidate drugs for tumor immunotherapy.
Featured cyclic peptides
(b) Other immune checkpoint peptides
Immunotherapy targeting PD-1/PD-L1, represented by PD-1 antibodies, has achieved significant results in clinical treatment. However, during PD-1 antibody treatment, the upregulation of other immune checkpoint molecules such as TIM-3 and TIGIT can lead to adaptive resistance to PD-1 antibody therapy.
In melanoma patients, even those with high tumor mutation burdens and inflammatory tumor microenvironments, the TIGIT/PVR pathway can still mediate resistance to PD-1 antibody therapy. Considering the dynamic changes in immune responses and the complexity of immune checkpoint expression regulation, it is difficult to achieve optimal therapeutic effects relying on any single target. Research on monoclonal drugs targeting other immune checkpoint pathways is ongoing, and related peptide inhibitors are also gradually gaining attention.
The TIGIT/PVR pathway plays an important role in tumor immune suppression. Blocking TIGIT/PVR can enhance the therapeutic effects of PD-1/PD-L1 blockade and is expected to overcome resistance to PD-1/PD-L1 antibody therapy.
2. Dual-functional peptides
Dual-specific antibodies are currently a hot topic in antibody drug development, with several dual-specific antibodies receiving FDA approval for clinical studies.
Similar to the action of dual-specific antibodies, dual-functional peptides link peptide molecules targeting two functionally related or complementary targets. The resulting peptides not only retain the functional activity of single-target peptides but also increase the stability and half-life of the peptides.
Compared to single-target peptides, dual-functional peptides can simultaneously act on different signal transduction pathways in the body, and a well-designed combination of different target peptides can achieve a synergistic effect of 1+1>2. Designing and synthesizing dual-functional peptides is simpler than dual-specific antibodies.
3. Self-assembling peptides
Through rational design, peptides with specific sequences can self-assemble to construct drug delivery systems. Wang et al. used the self-assembling G7 peptide (GNNQQNY) to link a peptide targeting CD3 with an RGD peptide targeting integrin αvβ3, forming the dual-functional peptide anti-CD3-G7-RGD. This peptide targets T cells' CD3 receptors while using the self-assembly property of the G7 peptide to induce CD3 receptor oligomerization, thereby activating T cells. Moreover, the RGD sequence of the dual-functional peptide can guide T cells to precisely identify and eliminate tumor cells.
Lv et al. allowed pep-20 to self-assemble into nanofibers in tumor tissues, breaking the 'don't eat me' signal mediated by the high expression of CD47 in tumor cells, enhancing macrophages' phagocytic effect on tumor cells, effectively inhibiting tumor growth.
Additionally, nanocarriers can be utilized to integrate other drugs with immune checkpoint blockade peptides, exerting a synergistic effect.
Zhu et al. used the DP-PA-1 peptide coupled with the chemotherapy drug doxorubicin (DOX) through a specific substrate sequence of matrix metalloproteinase 2 (MMP2), forming an enzyme-responsive nanoparticle. Through endocytosis, this promotes the accumulation and penetration of drugs in tumors. DP-PA-1 peptide and DOX, through MMP2-responsive release, not only fully exert the killing effect of chemotherapy drugs on tumors but also enhance T cell function.
Cheng et al. designed a dual-amphiphilic peptide composed of 3-diethylamino propyl isothiocyanate (DEAP), MMP2 substrate sequence, and DP-PA-1. This peptide, along with the indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor NLG919, assembles into nanoparticles through hydrophobic interactions.
The nanoparticles have the advantage of dual-stimuli sequential response in the tumor microenvironment: firstly, they accumulate at the tumor site through the enhanced permeability and retention (EPR) effect, and the DEAP sequence undergoes protonation in a weakly acidic environment, causing the nanostructure to expand. Subsequently, the highly expressed MMP2 recognizes the substrate sequence and completely disintegrates the nanoparticles, releasing the DP-PA-1 peptide and NLG919. This design fully combines the properties of peptides and small-molecule drugs with the characteristics of the tumor microenvironment, synergistically enhancing the function of T cells in the tumor tissue and inducing a potent anti-tumor immune response.
4. Nuclear-labeled peptides
The efficacy of tumor immunotherapy targeting immune checkpoints is closely related to the expression of immune checkpoints. Screening patients by detecting the expression levels of immune checkpoints can promote precision treatment. Immunohistochemistry is currently the gold standard for detecting the expression of immune checkpoints. However, this method cannot quantify the expression levels throughout the body in real-time. The expression of checkpoint molecules is highly dynamic during tumor initiation, progression, and treatment. In specific tumor types or metastases, the expression of immune checkpoints also exhibits high heterogeneity. For patient selection and efficacy monitoring, conducting non-invasive whole-body immune checkpoint expression detection with high sensitivity and resolution is crucial.
Positron emission tomography (PET) as a non-invasive imaging technology can be used for real-time, repetitive, and dynamic detection of all lesions, greatly facilitating the clinical screening of potentially benefiting patients, evaluating the efficacy of immunotherapy, and adjusting treatment strategies promptly.
PET imaging has been widely used for tracking various immune checkpoints, including PD-1/PD-L1, TIGIT, LAG-3, and TIM-3 antibodies labeled with radioactive isotopes. Radioactively labeled immune checkpoint antibodies often lack tissue penetration capability, and due to the long half-life of the antibodies, it often takes a long time to achieve strong tissue accumulation.
Low-molecular-weight peptides, due to their appropriate half-life and strong penetration ability into solid tumors, have become ideal candidates for PET imaging probes. High-affinity peptides targeting PD-1 or PD-L1, especially TPP-1 and WL12, have been used in various radioactive-labeled PET imaging.
Currently, the application of radioactively labeled immune checkpoint antibodies or peptides in PET imaging and optical imaging has undergone extensive preclinical and preliminary clinical studies, demonstrating their potential as tools for patient stratification, dynamic monitoring of efficacy, and prognosis. Among them, low-molecular-weight peptides as diagnostic probes have shown strong tumor penetration, minimal adverse reactions, and suitable half-life characteristics, gaining recognition in PET imaging. They are poised to provide a powerful tool for the clinical diagnosis and supportive treatment of cancer patients.
