Peptide Conjugation for Drug Development

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Peptide conjugation has been widely used in drug development because of its ability to endow drug molecules with unique structural and functional properties, making it an important strategy for drug development. Peptides are composed of several amino acid residues with specific bioactivity and biocompatibility, and can specifically bind to biomolecules (such as receptors, enzymes, cell surface molecules) to achieve precise targeting effects. In addition, through rational design and chemical conjugation, peptides can improve the bioavailability of drugs, reduce toxicity, enhance targeting and specificity, and improve the pharmacokinetic properties of drugs. The continuous development and optimization of peptide conjugation technology, provides new possibilities and solutions for modern drug development. In this paper, we introduce the applications of peptide conjugation to antitumor, antiviral and weight loss drugs.

Application of Peptide Conjugation in Antitumor Therapy

Radionuclide-Drug Conjugates(RDCs)

Peptide conjugation has a very important application in the direction of antitumor. Radionuclide-drug Conjugates (RDCs) are formed by chelating radionuclides as payloads and chelating agents, and then conjugated to peptides through linkers. Because peptides can guide the precise targeting of radionuclides, and have the advantages of tissue penetration ability and exhibit low immunogenicity, RDCs can achieve ideal drug delivery in vivo, reducing toxicity and increase efficacy. For example, in 2018, the FDA approved Lutathera for the treatment of gastroenteropancreatic neuroendocrine tumors, which was the first radiopharmaceutical approved by the FDA and EMA for peptide receptor nuclide therapy. In 2022, Pluvicto was developed by Advanced Accelerator Applications (a subsidiary of Novartis) as an RDC for the treatment of prostate-specific membrane antigen (PSMA) expressionmetastatic prostate cancer.

Fig.1 The structural formula of Lutathera.

Peptide-Drug Conjugates (PDCs)

By component, Lutathera and Pluvicto also fall under the category of peptide-drug conjugates (PDCs), which are peptide chains of about 10 amino acids at one end that act as domains targeting cells. At the other end of the spectrum are drug molecules with biological functions, which can achieve efficient targeted delivery of drug molecules and achieve efficient and precise therapeutic effects. PDCs are mainly used in antitumor, but they are also involved in the treatment of multiple disease fields such as antibacterial, antiviral, and neurological diseases. TH1902 is a drug-drug conjugate that binds TH-302 and peptides for targeting breast cancer and other solid tumors. TH-302 is a prodrug that is converted into a cytotoxic substance in a hypoxic environment (common in tumor tissues). The bound peptide moiety is able to specifically recognize receptors on the surface of tumor cells, thereby increasing the concentration of the drug in tumor tissue.

Peptibody

Peptibody is formed by conjugation of peptides and antibodies, which is a fusion protein that combines the specificity of peptides with the long half-life of antibodies and effector functions. Peptibody is usually smaller than traditional antibodies, which facilitates drug absorption. It can be used to treat cancer, autoimmune diseases, infectious diseases, etc. In 2012, the Reidy-Lagunes team reported the results of a phase II clinical trial of AMG 386 in combination with paclitaxel for patients with advanced ovarian cancer. The combination was shown to significantly prolong progression-free survival (PFS).

Peptide-photosensitizer conjugates (PPCs)

Peptide-photosensitizer conjugates (PPCs) are compounds that combine peptides and photosensitizers that utilize the principle of Photodynamic Therapy (PDT) to activate photosensitizers at specific wavelengths of light, resulting in the production of reactive oxygen species, leading to the death of cancer cells or diseased tissues. By combining with cell-penetrating peptides (CPPs) or cell-targeting peptides (CTPs), photosensitizers can promote the transmembrane transport of PPCs or specifically recognize and bind to diseased tissue cells, which greatly improves the targeting and therapeutic efficiency of photosensitizers. In 2023, Wenbing Dai's team reported PPCs consisting of a PD-L1 antagonistic peptide, an MMP-2-specific cleavable sequence, a self-assembling motif, and a photosensitizer Purpurin 18. Studies have shown that PPC nanospheres irradiated with laser promote the infiltration of cytotoxic T lymphocytes and the maturation of DCs, thereby making 4T1 tumor cells sensitive to immune checkpoint blockade therapy. This project provides a simple and effective comprehensive strategy for photoimmunotherapy of breast cancer, and has a certain enlightening effect on the development of PPCs drugs.

Fig.2 Schematic diagram of MMP-2 enzyme response and convertible PD-L1 blocking peptide-photosensitizer conjugate. (Sun Yanan, et al., 2023)

Table 1. Peptide conjugation service at Creative Peptides

Develop hypoglycemic and hypolipidemic drugs

Peptides bind to specific target molecules or metabolic pathways to regulate appetite, promote fat metabolism, or inhibit fat storage to achieve weight loss. For example, some studies may design drugs that precisely regulate the body's metabolic processes by conjugating appetite suppressants or fat oxidants to peptides. Tirzepatide, developed by Eli Lilly and Company, is the first glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist. In May 2022, Tirzepatide was approved by the FDA for improving blood sugar control in adults with type 2 diabetes, and has since been approved in the European Union, Japan, and other countries. In October 2022, the FDA granted Tirzepatide for improving long-term weight management in overweight adults who are obese or have at least one comorbidity. In addition to related products at this stage, Eli Lilly and Company has also laid out new products such as Orforglipron, an oral GLP-1R agonist, and Retatrutide, a GLP-1R/GCGR/GIPR three-target agonist, both of which are in the clinical development stage.

Covalent conjugation with inhibitors to improve antiviral targeting

Antiviral PDC therapies typically involve one or more drug small molecules binding to a cell-penetrating peptide (CPP) carrier, either directly or via linkers. The primary purpose of this integration of two bioactive elements into a single molecular entity is to achieve higher bioavailability in the face of challenges to traditional medicines, but may also generate new and unexpected functions and applications. Inhibitors targeting PLpro have been reported to GRL0617, occupy the binding pocket of the C-terminus of interferon-stimulated gene 15 (ISG15) and show potent antiviral effects intracellularly. In this work, the authors used GRL0617 as a small drug molecule conjugated to a peptide, and designed a group of covalent inhibitors by conjugating to a section of a matte salt-stabilized peptide to improve the targeting specificity and duration of action of the GRL0617. In addition, peptides are also mostly used in the research and development of small molecule inhibitors against HIV virus.

Antigen conjugation with carrier peptide for vaccine development

Peptide vaccine is a vaccine prepared by chemical peptide synthesis technology according to the amino acid sequence of a certain antigen epitope known or predicted in the pathogen antigen gene. Peptide conjugation is used in the synthesis of vaccines and can improve the immunogenicity of antigens. For example, conjugation of an epitope of a pathogen to a carrier peptide can enhance the immune system's recognition and response to the antigen, thereby improving the effectiveness of vaccines. For example, HBsAg (hepatitis B surface antigen) peptide conjugation is used in the hepatitis B vaccine, which improves the immunogenicity of the vaccine. In influenza vaccines, peptide conjugation enhances cross-protection against different subtypes of influenza virus.

Targeted cardiomyopathy with Liposomes

As drug carriers, liposomes have the advantages of protecting drug biological activity, improving stability, prolonging half-life, and improving efficacy, but they lack active targeting. Specific proteins or peptides can be combined with drug-coated liposomes through conjugating or cross-linking to form actively targeted liposomes, which realizes drug-specific localization. Related studies, such as the red blood cell membrane (RCM) and the co-modified liposomes composed of peptides TAT and PCM, reported by Huali Chen's team, have been demonstrated in pharmacokinetic studiesRCM-modified liposomes have a prolonged mean residence time (MRT) and more cardiac accumulation effects.

Summary

Peptide conjugation technology has a wide range of potential in drug development. This article introduces its application in antitumor drugs, antiviral drugs, and hypoglycemic and lipid-lowering drugs. It covers drugs that have been approved by the FDA for marketing, as well as molecules currently under development by companies or scientific research teams. These examples demonstrate that there is still a huge space and potential for peptide drug conjugates in the future.

References

1. Hennrich, Ute, et al., Lutathera®: the first FDA-and EMA-approved radiopharmaceutical for peptide receptor radionuclide therapy. Pharmaceuticals 12.3 (2019): 114.
2. Fallah, Jaleh, et al., FDA approval summary: lutetium Lu 177 vipivotide tetraxetan for patients with metastatic castration-resistant prostate cancer. Clinical Cancer Research 29.9 (2023): 1651-1657.
3. Demeule, Michel, et al., TH1902, a new docetaxel‐peptide conjugate for the treatment of sortilin‐positive triple‐negative breast cancer. Cancer science 112.10 (2021): 4317-4334.
4. Sun, Yanan, et al., An enzyme-responsive and transformable PD-L1 blocking peptide-photosensitizer conjugate enables efficient photothermal immunotherapy for breast cancer. Bioactive Materials 22 (2023): 47-59.
5. Forzano, Imma, et al., Tirzepatide: A systematic update. International Journal of Molecular Sciences 23.23 (2022): 14631.
6. Liu, Na, et al., Design and evaluation of a novel peptide–drug conjugate covalently targeting SARS-CoV-2 papain-like protease. Journal of Medicinal Chemistry 65.1 (2022): 876-884.
7. Liu, Xueyan, et al., In vitro and in vivo evaluation of liposomes modified with peptides and red cell membrane as a novel drug delivery system for myocardium targeting. Drug Delivery 27.1 (2020): 599-606.