Polypeptides usually refer to compounds with 10-100 amino acids linked by peptide bonds. It has a history of more than 100 years since its discovery, and has been used as a drug for more than 70 years.
Polypeptides are bioactive substances naturally existing in organisms. Up to now, tens of thousands of peptides have been found in organisms.
As hormones, neurotransmitters, cell growth factors and other signal molecules, polypeptides are involved in many physiological functions in the body, and are used as substitutes for insufficient peptides in vivo.
Peptide drugs include peptides or their modifications used for disease prevention, diagnosis and treatment.
According to their functions, they can be divided into peptide vaccine, anti-tumor polypeptide, antiviral peptide, peptide targeting drug, cytokine mimic peptide, antibacterial active peptide, diagnostic polypeptide, etc. it is mainly used in the treatment of asthma, allergy, hepatitis, AIDS, tumor, diabetes and other diseases.
1、 Market situation of peptide drugs
In recent years, polypeptide drugs as a key field of biomedical innovation and research at home and abroad, has maintained a good development prospect. Polypeptide drugs account for a small proportion in the global biomedical market, but they are developing rapidly.
In 2019, the global peptide drug market will exceed US $30 billion, with an average annual compound growth rate of about 10%. According to the statistics of cortellis, as of May 2019, there are about 1153 kinds of peptide synthetic drugs in the world.
Due to the high difficulty and high price of peptide drugs, the market is mainly concentrated in developed countries such as North America and Europe.
Large pharmaceutical companies in the world have also increased the distribution of peptide drugs, such as Roche, Pfizer, Sanofi, etc. they have increased the research and development of peptide drugs, and have gained a lot of listed drugs through acquisition and merger.
However, with a large number of polypeptide patent drugs expiring in 2015-2019 and a large number of generic drugs are on the market, emerging economies such as China and India will compete with European and American countries for part of the market, and peptide API manufacturers will benefit from the growth of generic drug market.
China’s peptide drugs started late, and the market is small, but the growth rate is far greater than that of the world.
In 2019, the market scale will exceed 80 billion yuan, and the annual compound growth rate will exceed 15%.
There are about 40 kinds of polypeptide drugs on the market in China, and more than half of them have been localized, but the imported products still occupy the main market.
There are many domestic enterprises engaged in peptide drug R & D and production, but the scale is small, the market concentration is low, and the competition is fierce.
With the increase of domestic investment in research and development of peptide drugs, foreign-funded enterprises such as Novartis pharmaceutical, American saisheng, Swiss Huiling and Merck syrano still occupy certain advantages, but the local Chengdu suno enterprises are also rising.
Although China has begun to take shape in peptide raw materials, most of them are primary products with less than 10 amino acids, and high-end peptide raw materials still rely on imports.
2、 Characteristics of polypeptide drugs
Compared with chemical drugs and protein drugs, peptide drugs have some characteristics of both because their molecular weight is between the two.
They have the characteristics of good stability, high purity and controllable quality of small molecular chemical drugs, as well as strong specificity and high biological activity of protein drugs.
However, due to the complexity and difficulty of the process, the cost is high.
The route of administration of polypeptide drugs is single and cannot be taken orally.
On the one hand, due to the influence of polypeptide enzymes, peptide drugs are easy to degrade, with short half-life and low stability;
on the other hand, because polypeptide drugs are difficult to pass through the intestinal mucosa, the main route of administration is intravenous injection or drip.
3、 Preparation of polypeptide drugs
Peptide drugs are mainly prepared by extraction from animals and plants, chemical synthesis and gene recombination, among which chemical synthesis is the main method. At present, more than 90% of the peptide drugs on the market in the world are prepared by chemical synthesis.
- Extraction from animals and plants is to use physical and chemical technology to conduct preliminary treatment of animal and plant tissues, and then to degrade protein precursors through enzymatic hydrolysis or other digestion technologies, and finally extract peptides by solvent. However, due to the low content of bioactive peptides in animals and plants, the extraction purity is low, and there are potential biosafety risks, which limit the clinical application, and the technology is gradually phased out.
- There are mainly two kinds of chemical synthesis methods: solid-phase synthesis and liquid-phase synthesis. The production process is complex and has many steps. The production of a polypeptide molecule sometimes exceeds 100 steps, which greatly increases the production difficulty and production cost.
Liquid phase synthesis is to prepare amino acids or polypeptides into a homogeneous solution, with N-protected amino acids as the starting amino acids, protect the non reactive groups, activate the reaction groups, carry out the synthesis reaction, link the amino acid residues gradually, purify the peptide after synthesis, and remove the unreacted substances. This method can also be carried out by segmented synthesis, each step of purification and final synthesis of target peptide drugs.
Solid phase synthesis is to fix the C-terminal of the first protective amino acid on a solid-phase carrier such as resin, and then react with the subsequent amino acids to extend the peptide chain to the target length.
Finally, the peptide is dissociated from the carrier with acid, and the protective group is removed. After purification by liquid chromatography, the target peptide is obtained.
Solid phase synthesis is the most widely used synthesis method at present. Due to its simple purification engineering, easy automatic and semi-automatic production, the development of peptide drugs has been greatly promoted.
With the continuous progress of chemical synthesis technology, the length of polypeptide in the world has reached 40 amino acids at most. Most enterprises in China can only synthesize peptides with less than 10 amino acids, and few enterprises can reach 20 or 30 amino acids.
- Gene recombination is to construct the target gene vector by using DNA recombination technology, and then transfect the vector into eukaryotic cells or prokaryotic cells to express the target polypeptide, and then extract and purify it. This method is mainly used to prepare long peptides with large amount of amino acids and complex peptides with certain spatial conformation. Because the amino acids are natural amino acids synthesized in vivo, further chemical reactions are needed to obtain the modified peptides.
4、 Key enterprises and heavy products of polypeptide drugs
Compared with foreign countries, domestic peptide drugs started late, but with the good market performance of peptide drugs, in addition to foreign enterprises entering the domestic layout, sannuo biological and other characteristic enterprises mainly engaged in peptide drug research and production.
Some polypeptide drug enterprises have expanded the industrial chain through merger and acquisition.
For example, Hanyu pharmaceutical obtained injection medicine medical devices, especially its injection pen, injection rack and “two in one” products through acquisition of Chengji pharmaceutical industry, which combined with polypeptide drugs to form an integrated industrial system of API, preparation and drug delivery equipment, which greatly improved the market competitiveness of the enterprise.
There are about 100 kinds of polypeptide drugs on the market in the world, mainly focusing on the treatment of chronic diseases such as anti-tumor, diabetes, immune regulation, cardiovascular disease, etc., accounting for more than 80% of the total. The major products with sales of more than 1 billion US dollars include gratirel, liraglutide, dulaglycopeptide, octreotide, leuprorelin, tripatide, exenatide and goserelin.
Different from the global market, more than 40 kinds of peptide drugs listed in China are mainly concentrated in immune regulation, digestive system and anti-tumor, accounting for nearly 90%, of which immunomodulatory drugs account for more than half of the total market. Thymopentin, glutathione, thymosin, octreotide, somatostatin and leuprorelin are the best products in China.
5、 Development trend of polypeptide drugs
The stability of peptide drugs can be enhanced in various ways. The stability of peptide drugs is an important factor restricting its development. In order to enhance the stability of peptide structure, researchers are committed to optimize the stability of peptide structure by modifying the peptide structure and increasing the barrier.
The modification of polypeptide is to transform the polypeptide into a ring, modify the amino acid skeleton, insert unnatural amino acid, replace individual amino acid, couple polyethylene glycol, lipid and protein structure, prolong the half-life of protein, so as to increase the stability of polypeptide and reduce the injection frequency of peptide drugs.
Optimization of peptide drug delivery system. Oral drug delivery system: the combination of polypeptide drugs and penetration enhancers can increase the permeability of intestinal mucosa, so that polypeptide drugs can quickly pass through the intestinal mucosa and be absorbed into the blood, so as to realize the application of oral polypeptide drugs.
But on the whole, the oral effect is lower than the injection effect. Novo Nordisk oral somaluptide was approved for the market in 2019. As the only oral drug of GLP-1, it has an impact on the market.
However, according to clinical data, the bioavailability is only about 1%, and it will be subject to various restrictions when taking it. However, with the continuous breakthrough of research, oral peptide drugs are still an important research and development direction.
Injectable drug delivery system: it mainly uses high molecular substances to wrap polypeptides, block the contact between polypeptides and proteases, and play a protective role on polypeptides. In addition to the microspheres for injection which have been applied now, there are also studies on embedding polypeptides in liposomes to achieve sustained-release effect through intravenous injection.
Summary
With the accelerated aging of the population, the rising prevalence and other factors, China’s polypeptide drugs market space is huge, although there is a big gap between domestic peptide drugs and international level, but affected by the national policy support, domestic peptide drugs research and development progress rapidly, will accelerate the domestic substitution of imported peptide drugs.