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This post was last edited by goldliyang on 2020-10-11 08:29. With the advances in modern biotechnology, particularly the introduction of genetic engineering techniques, it has become possible to synthesize more peptide drugs in a short period of time, and large-scale production of such drugs has become feasible. There are mainly two approaches to peptide synthesis: chemical synthesis and biosynthesis. Since most peptide drugs are characterized by being ineffective when taken orally directly, having a short biological half-life, and requiring long treatment periods, it is very meaningful to improve existing peptide drugs. Peptide drugs have a wide range of indications, high safety, and significant efficacy; they are currently widely used in the treatment of various human diseases. Peptide drugs mainly fall into seven categories: peptide vaccines, antitumor peptides, peptide-targeted drugs, cytokine mimic peptides, antibacterial active peptides, diagnostic peptides, and other medicinal peptides. Research reports indicate that new formulations and long-acting versions of peptide drugs represent the future direction of development. Improving peptide drugs can address drawbacks such as the high frequency of administration required for injectable forms and poor patient compliance; meanwhile, the development of new dosage forms and long-acting formulations is highly beneficial for the promotion of peptide drugs. In the development of peptide drugs, current international approaches to improving such drugs include making injection-based formulations more long-acting, for example by creating peptide liposomes, peptide microspheres, using polyethylene glycol for modification, forming fusion proteins, or employing subcutaneous implantation; another approach is to avoid injections altogether and use oral administration, transdermal administration, or inhalation administration. 1. Improvement strategy 1: Preparation of peptide liposomes – For example, the DepoFoam technique can be used to load peptides, proteins, and small-molecule drugs, enabling slow drug release over a period of 1–30 days. Although no peptide drugs utilizing DepoFoam technology have yet been launched on the market, the success of bupivacaine liposomes demonstrates that DepoFoam technology is a highly promising sustained-release injection technique. Once this technology is successfully replicated or introduced, it can be used not only for peptides but also in the research and development of various anticancer drugs and painkillers. 2. Improvement Strategy 2: Preparation of PLGA microspheres. PLGA microspheres are the most ideal carriers for sustained-release injectables, enabling continuous release over periods ranging from several days to several months. They are also one of the best approaches for the repurposing of peptide drugs; several such products are already on the market, and their market impact is comparable to that of new molecular entities. Medisorb is a technique for preparing microspheres via emulsification, and the emulsification process can be modified depending on the drug to be encapsulated. The Medisorb technology is also a technology that is well worth introducing and replicating. After all, China has a large market for peptide-based drugs; successful replication or the acquisition of this technology would not only enable technical upgrades to various peptide products but also help to upgrade certain medications used in the treatment of mental illnesses. 3. Improvement strategy 3: PEG modification. PEG modification involves attaching PEG to the surface of proteins or peptides; this not only increases the hydrophilicity of the drug, but also reduces renal filtration of the drug. It can also cover enzyme sites and decrease the rate of biodegradation, thereby achieving a long circulation time. PEG modification technology has been used in the field of polymers for many years; the most typical examples include PEG-modified interferon, PEG-modified filgrastim, and PEG-modified erythropoietin. However, PEG modification also has its own drawbacks, as PEG can accumulate in the body, posing a potential risk of adverse reactions. 4. Improvement strategy 4: Fusion proteins – Combining protein molecules with high stability and high activity with peptide-based drugs can effectively enhance the stability and activity of these peptide drugs. For example, the yeast-expressed serum albumin-interferon-α fusion protein (HSA-IFN-α) has a half-life in marmosets that is about 18 times longer than that of IFN-α alone; furthermore, this fusion protein can be used in combination with PEG modification. 5. Improvement strategy 5: Fatty acid acylation. Fatty acid acylation is one of the key approaches pursued by various pharmaceutical companies. In the case of GLP-1, both liraglutide and semaglutide incorporate fatty chains; the purpose of adding these fatty chains is to increase the drug’s hydrophobicity, mask the DPP-4 enzyme binding sites, reduce renal excretion, and thereby prolong the biological half-life. Some pharmaceutical companies have applied this approach not only to GLP-1 analogs; their long-acting insulin products, detemir and degludec, also achieve sustained release by introducing fatty chains via acylation to increase hydrophobicity. 6. Improvement strategy 6: Polymer-based injectables. In 2002, the U.S. FDA approved Eligard, a long-acting formulation of leuprorelin developed by Atrix Lab. This product is a sustained-release suspension prepared using ATRIGEL technology; its main sustained-release component is PLGH. After injection, it forms a solid in the body, which then releases the drug slowly over a period of up to 6 months. 7. Improvement strategy 7: Development of implants. In terms of implants, the most representative drugs include Goserelin from AstraZeneca, Leuprolide from Endo, Triptorelin from ALZA, and Buserelin from Sanofi. Goserelin is a PLGA-based implant rod that can provide effect for up to 12 weeks after insertion, whereas Endo’s leuprolide implant uses a biocompatible polymer-based delivery system that allows for an effect lasting up to one year. Compared to PLGA microspheres, implants can achieve sustained release over a longer period of time; however, they also have their own disadvantages, as some of these implants need to be removed at regular intervals. Implants are not only an important direction for the secondary development of peptide drugs, but also a highly promising long-acting drug delivery system that can be used to improve the formulation of drugs with low doses, short half-lives, and long treatment periods. 8. Improvement strategy 8: Respiratory administration. In May 2015, the FDA approved glucagon inhalers, paving the way for the inhalational administration of peptide drugs. In fact, success with inhalable peptides was achieved quite early on, with salmon calcitonin being the most typical example. Respiratory administration includes not only inhalation but also nasal administration. The advantage of respiratory administration systems is that they are protected from destruction by digestive enzymes and gastric acid, and there is no first-pass effect in the liver. Compared to injection administration, nasal and inhalation delivery can improve patient compliance; moreover, they act more rapidly and exhibit higher bioavailability than oral administration. Therefore, respiratory delivery of peptide drugs is also a promising approach worth considering. 9. Improvement strategy 9: Transdermal delivery. Studies have shown that the combined use of transdermal enhancers and iontophoresis can effectively improve the transdermal absorption of certain drugs, particularly large molecular peptides. There are few reports on transdermal delivery systems for peptide drugs. 10. Improvement strategy 0: Oral administration. Achieving oral administration of peptide drugs is the ultimate goal for the secondary development of such drugs. However, there are still many challenges to achieving the oral administration of peptide drugs. Peptide drugs are easily destroyed by stomach acid and digestive enzymes; therefore, preventing the degradation of these drugs in the gastrointestinal tract is just the first challenge ； The second challenge is how to promote absorption; generally, molecules with a molecular weight greater than 500 are more difficult to absorb, and peptide drugs usually have molecular weights in the thousands ； The third challenge is how to address the issue of the first-pass effect. It is precisely due to these various issues that existing oral peptide drugs generally have low bioavailability, exhibit significant individual differences, and pose safety risks. Of course, these obstacles are not insurmountable; products with a molecular weight of 2000 or less are already available on the market. Peptide drugs form a vast family and represent one of the most promising areas for development. Medisido’s peptide synthesis research team focuses closely on the research of peptide drugs, striving to address the key issues that hinder their development and application. To date, they have established a comprehensive system that covers everything from the synthesis of upstream non-natural amino acid building blocks, the modification of peptide drugs, and their large-scale production, to downstream research on the signal transduction pathways and mechanisms of action of peptide drugs. Medici’s peptide synthesis has achieved remarkable results in both fundamental and applied research through the collaboration and integration of multiple disciplines such as chemistry, biology, medicine, and pharmacy.