According to incomplete statistics, there are more than 400 pharmaceutical enterprises in China currently engaged in the production of biochemical and biotechnological drugs, among which about 80% produce peptide drugs of different types and scales. These enterprises are mainly distributed in some economically developed provinces and cities, such as Beijing, Shanghai, Guangdong, Jilin, Zhejiang, Jiangsu, Shandong, etc. Among these manufacturers, about 80% use modern biotechnology for production, while some also use methods such as extraction and separation, enzymatic hydrolysis, and solid-phase synthesis for production. Shanghai Ketei has introduced the latest international technology, providing thousands of peptide syntheses for domestic customers every year. Some domestic enterprises cooperate with related foreign enterprises to establish scaled peptide drug production bases.
3. Development direction and prospect of peptide drugs in China
3.1 Development of new peptide drug resources
Currently, the acquisition of active peptides in China is still mainly from human and animal sources. However, peptide substances are widely present in various organisms, and their sources need to be further broadened. The search for new peptide drug resources can be considered from the following aspects:
3.1.1 Further comprehensive utilization of animal organs. There are countless different categories of active peptide substances in the organs and tissues of animals, each substance having specific physiological functions or activities. Therefore, raw materials already used for the preparation of certain peptide drugs still have value for further research and development. For example, thymus tissue used for the preparation of thymosin or thymopeptides can also be used to extract lymphocyte inhibitory substances. Organs that were previously less developed can also be newly developed to discover new peptide sources. In addition, using the same type of tissue from different organisms to obtain the same bioactive peptides can also expand the source of raw materials.
3.1.2 Full utilization of plant resources. Active peptides derived from plants have already attracted attention. China has obtained many active peptides through enzymatic hydrolysis, separation, and purification from plants and developed them into new drugs and health products, such as preparing various potential active peptides from certain vegetables, beans, tubers, grains, etc. Preparing active peptides from traditional Chinese medicinal herbs will also be a direction for the research and development of peptide drugs.
3.1.3 Development of insect peptides. Insects are the largest biological group in the world, existing in almost all ecological environments except the ocean. Studies have found that when insects are invaded by external bacteria, they produce large amounts of antimicrobial peptides in their bodies, which can quickly kill bacteria. So far, a large number of antibacterial peptides, antifungal peptides, and peptides that are both antibacterial and antifungal have been discovered in insects. These antimicrobial peptides also act on viruses, protozoa, and cancer cells, and are non-toxic to normal cells of higher animals.
3.1.4 Utilization of marine biological resources. The ocean is a treasure trove containing many bioactive substances. About 80% of the Earth's biological resources exist in the ocean, including about 500,000 species of animals and more than 13,000 species of plants. Therefore, the development of marine peptide drugs has great potential.
3.1.5 Utilization of microbial resources. The number of microorganisms is incalculable, and the metabolism of different types of microorganisms varies greatly. Therefore, microorganisms are the source of bioactive substances, including active peptides. For example, the immunosuppressant cyclosporine widely used in clinical practice is a peptide produced by microorganisms. Microorganisms are an inexhaustible source of peptides, especially peptides whose amino acid residues have been modified.
3.2 Use of modern biotechnology for the production and improvement of peptide drugs
After more than ten years of tracking research and development combining innovation with imitation, the current research on biotechnological drugs in China has begun to enter the stage of independent innovation, especially the use of modern biotechnology for the production of peptide drugs will become the main way for the production and improvement of peptide drugs in China in the future. Specifically, there are several aspects:
3.2.1 Research on novel active peptide mutants. To change some properties of natural active peptides, their structures can be modified through gene site-directed mutagenesis. Mutants already obtained include human calcitonin mutants, recombinant leech factor mutants, etc. Site-directed mutagenesis can enhance the stability and biological activity of drugs and reduce adverse reactions.
3.2.2 Research on fusion proteins. Currently studied and prepared fusion peptides include: leech factor 12 peptide/urokinase fusion protein, which has dual functions of thrombolysis and anti-thrombosis; transmembrane peptide HIV-Tat49-57/CTL epitope fusion peptide vaccine, where transmembrane peptide HIV-Tat49-57 can carry the HLA-A2 restricted CTL epitope peptide of human melanoma differentiation antigen MART-1 into living cells; peptide fusion inhibitors acting on the envelope protein subunit gp41 of HIV, which have the activity of inhibiting the fusion of HIV with target cells, etc.
3.2.3 Cloning of natural active peptide genes and recombinant expression of new peptide drugs. Human insulin, pumpkin trypsin inhibitor I, human knot epitope peptide 12, human atrial natriuretic peptide, etc., have been expressed. Cloning of natural active peptide genes and recombinant expression of new peptide drugs will still be one of the main directions for the industrialization of peptide drugs.
3.2.4 Application of surface display technology in peptide drug research. Surface display technology is a new gene operation technique that displays expressed exogenous peptides as fusion proteins on the surface of bacteriophages or cells, collectively referred to as surface display libraries. In the display library, each bacteriophage particle or cell only displays one sequence of exogenous peptide. Surface display technology links the displayed peptide with its gene, forming a vast conformational library, from which peptides with specific functions can be selected. These peptides may not exist in nature at all, or they may be mutants of wild-type peptides after performance improvements. Effective screening can be carried out in this conformational library according to the characteristics of drug action targets, thereby selecting excellent peptides for research and development.
3.2.5 Use of enzyme engineering to produce peptide drugs. Enzyme engineering is a material conversion technology that uses the catalytic action of enzymes, which is a new technology combining enzyme theory with chemical engineering technology. The production of peptide drugs using enzyme engineering needs to reduce production costs through immobilized animal cells, which is very important for reducing production costs in industries producing active peptides through enzymatic hydrolysis of proteins.
3.2.6 Use of plant cell engineering to develop and study peptide drugs. In recent years, obtaining natural active peptides from plants has become a new important source of peptide drugs. With the development of plant genetic engineering, producing natural peptide drugs based on plant cell culture technology, especially active peptides produced by rare plants, has great potential.
3.2.7 Use of genetically modified animals and plants to produce peptide drugs. Using genetically modified animals and plants to produce peptide drugs has attracted high attention from scholars at home and abroad. Erythropoietin has already been produced using genetically modified tobacco, and interferon has been produced using genetically modified radishes. Producing peptide drugs using genetically modified animals and plants yields high production, low cost, and root secretion expression of active peptides using soilless cultivation of plants deserves attention.
3.2.8 Use of combinatorial chemistry and high-throughput screening technology combined to develop peptide drugs. Combinatorial chemistry technology makes it possible to synthesize tens of thousands of peptides at once, and high-throughput drug screening can quickly screen out compounds with special biological activities from tens of thousands of compounds. Combining combinatorial chemistry technology with high-throughput drug screening technology will still be an important way to develop peptide drugs.