Polypeptides are compounds between small molecules and proteins. They also have many structures, including chain polypeptides, cyclopeptides and so on. Because the chain polypeptides are too flexible, they can be twisted and flipped at will, which makes them too loose to make medicine. By introducing ring structure, the researchers can restrict the activity of polypeptide, increase the stability of polypeptide, make it show better pharmacological activity and stability, and make more polypeptide become medicine possible.

Structural diagram of small molecule, restriction peptide and biomacromolecule (from left to right)

There are many kinds of binding peptides, including monocyclic peptide, stapled peptide and bicyclic peptide. Monocyclic peptide is easy to understand, that is, the peptide head and tail amino acids connect to form a ring, which is the simplest binding peptide. At present, RA pharmaceutical and polyphor are good at developing this peptide.

A large number of studies have shown that peptides with a helix structure and rich in positive charge can pass through the cell membrane, but once the peptide is separated from the mother, it can not maintain the original secondary structure. Therefore, people have developed a method using carbon carbon bond as a scaffold to stabilize the α helix structure of the peptide. The peptide obtained by this method is called stapling peptide.

Bicyclic peptide has two amino acid sequence rings, the middle of which is regulated by a linker. The British company cycle therapeutics is in the leading position in the research and development of bicyclic peptide, and a candidate drug has been put into clinical trials.

Single cyclic peptide, stapling peptide and double cyclic peptide model (from left to right)

Binding peptide drugs entering clinical trials
Although binding peptides have good pharmacological activities, it is not so easy to develop these compounds into drugs on the market. As early as the beginning of this century, a number of binding peptides have been synthesized, and cell experiments have proved that they have good activity and targeting, and are expected to be developed into drugs.

However, in the actual development, it was found that the pharmacokinetic results of this kind of drugs are not satisfactory, the manufacturing process is very complex, and the bioavailability is far from the expected results. These problems seriously hinder the development of this kind of drugs.

Of course, there are more problems. Some companies focus on the design of binding peptide drugs. For example, assembly discovery was founded in 2004 and uses DNA coding library to generate cyclic peptides. However, this method is blind and less likely to be used for the production of peptides, with high cost. In 2017, the company officially closed down. Later, tranzyme Pharma, a similar company, was acquired by ocera therapeutics in 2013.

List of binding peptide drugs entering clinical trials

And the firm that can't fail will eventually usher in the dawn of hope, with polyphor receiving an initial public offering of $165 million in May 2018. The company has established restriction peptide development platforms pemfinder ® and macrofinder ® for the research and development of restriction peptide pipeline drugs. More than 5000 restriction peptides have been found for drug screening using these platforms. Three drugs, murepavadin, balixafortide and pol6014, have entered clinical trials.

Murepavadin is a new antibiotic targeting the outer membrane protein of Gram-negative bacteria, targeting lipopolysaccharide transporter D (lptd). At present, it is in phase III of clinical trial. Due to the deep outer membrane of Gram-negative bacteria, it is difficult for ordinary antibiotics to enter the bacteria and kill bacteria. Murepavadin has a strong affinity for lipopolysaccharide and outer membrane protein of bacterial outer wall, which brings a new breakthrough for the treatment of refractory infection caused by gram-negative bacteria.

The preclinical study showed that murepavadin had a specific and highly effective inhibitory effect on Pseudomonas aeruginosa, even on multidrug resistant bacteria. Clinical trials showed that in 12 patients, the clinical cure rate of TOC was more than 80%, and the all-cause mortality rate at 28 days was 8%.

The interaction between murepavadin and outer membrane protein

Balixafortide is a chemokine receptor-4 (CXCR4) inhibitor. CXCR4 belongs to the G-protein-coupled receptor superfamily. It has the biological functions of chemotaxis and maintaining the dynamic balance of immune cells. CXCR4 is overexpressed in most human tumor cells, including breast cancer, anterior adenocarcinoma, lung cancer, colon cancer and multiple myeloma. CXCR4 is in the process of tumor growth and metastasis It plays an important role in inhibiting the growth of tumor cells by inhibiting CXCR4.

Balixafortide is a kind of natural polypeptide ■ - polyphemusin analog obtained from Limulus amebocyte lysate. It can inhibit the metastasis of tumor cells, increase the sensitivity of tumor cells to chemotherapy, and activate immune cells to kill tumor cells. Clinical studies have shown that when balixafortide is used in combination with aribrin, it can improve the tumor response rate in patients with advanced and severe metastatic breast cancer.

Schematic diagram of interaction between balixafortide and CXCR4

Pol6014 is a highly specific human neutrophil elastase inhibitor, which is mainly used to reduce inflammation related to cystic fibrosis. It also has therapeutic effect on other neutrophil lung diseases, such as non cystic fibrosis bronchiectasis, or rare diseases, such as alpha-1 antitrypsin deficiency.

The clinical study showed that pol6014 had a high inhibitory effect on elastase of human neutrophils in active sputum, and had a good safety and tolerance to patients. At present, pol6014 is in phase I clinical study.

RA pharmaceuticals received $106 million in IPO investment in 2016, and apellis pharmaceuticals also received $150 million in IPO investment in 2017.

Both of them have a common goal of developing treatments for paroxysmal nocturnal hemoglobinuria (PNH), a rare disease. PNH is a chronic and life-threatening rare blood system disease caused by the wrong attack and destruction of red blood cells by complement system.

Ra101495 is a C5 protein inhibitor, which is used to treat PNH. At present, only one antibody drug with the same target, eculizumab, is used to treat the disease. However, when using eculizumab, patients will be observed to have breakthrough hemolysis, especially at the end of the administration cycle.

Ra101495, compared with eculizumab, can be administered continuously, has better controllability, reduces the risk of breakthrough hemolysis, and provides convenience for patients. At present, the drug is in phase II of clinical trial.

The action site of ra101495 and eculizumab in C5

APL-2, a C3 protein inhibitor, is currently in phase III of clinical trials for the treatment of PNH. APL-2 can prevent the formation of complement membrane attack complex (MAC), thus prevent the activation of mutant platelets and intravascular hemolysis, thus reducing the risk of thrombosis, which is one of the main causes of PNH death.APL-2 can also prevent extravascular hemolysis and further reduce anemia and blood transfusion dependence of PNH patients. At the same time, APL-2 was given less times, usually once a day, to increase the convenience of patients.

Alrn-6924 of aileron therapeutics is a kind of binding peptide. It is an activator of p53 protein, which can activate tumor suppressor protein mdmx and MDM2.

Alrn-6924 is the only drug that can activate mdmx and MDM2 at the same time. It can be used in combination with mAb for solid tumor and liquid tumor treatment. At present, the clinical trials of alrn-6924 on acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and peripheral T-cell lymphoma (PTCL) are in progress.

Cycle therapeutics is the representative of dicyclic binding peptide pharmaceutical company. In 2017, the company completed the financing of £ 40 million, and its representative drug bt-1718 is in phase I of clinical trial, and there are still two drugs in preclinical stage.

Bt-1718 is a dicyclic peptide and toxin coupled drug targeting membrane-1 matrix metalloproteinase (MT1-MMP). MT1-MMP plays an important role in the invasion and metastasis of tumor cells. It is over expressed in many solid tumors. The preclinical experiment showed that bt-1718 had significant targeting effect on MT1-MMP and had therapeutic effect on many solid tumors.

Model structure of bt-1718

expectation
The binding peptide combines the advantages of small molecules and biomacromolecules. It not only has the strong targeting and affinity of macromolecular antibody drugs, but also has the ability of rapid tissue penetration similar to small molecule drugs.

Due to the unique structure and activity of the binding peptide, it is favored by pharmaceutical companies. Venture capital funds also attach great importance to this field, and start-ups grow rapidly. In addition to the more successful companies mentioned above, there are still many companies scattered in the United States, Europe, Japan and other countries, and they also work in this field silently.

There is also a lot of joint research and development between start-ups and large pharmaceutical companies. A famous example is the joint development of bicyclic therapeutics and AstraZeneca to jointly develop bicyclic peptide drugs. It is believed that binding peptide drugs will be one of the important pipelines in the pharmaceutical field in the future.

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Chengdu Shengnuo Biotechnology Co., Ltd. has "Chengdu polypeptide drug engineering technology research center" in Chengdu, mainly engaged in polypeptide, polypeptide drug and beauty peptide research. Our zero defect has passed the FDA certification, and now it has become the first-class professional peptide drug and product development, technology transfer, technical service and peptide drug industry in the scale production and export of China's parks.