Polypeptide APIS New development direction of peptide drugs binding peptides

Polypeptides are compounds between small molecules and proteins. Peptides also have a variety of structures, including chain polypeptides, cyclic peptides and so on.

Because the chain polypeptides are too flexible, they can be twisted and overturned at will, which makes them too loose to be well prepared.

Through the introduction of ring structure, R & D personnel restrict the activity of polypeptide, increase the stability of polypeptide, make it show better pharmacological activity and stability, and make it possible to make more peptides into drugs.

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

A large number of studies have shown that peptides with α – helix structure and rich positive charge can pass through the cell membrane, but once the peptide is separated from the parent, it can not maintain the original secondary structure.

Therefore, a method using carbon carbon bond as scaffold to stabilize the α – helix structure of polypeptide has been developed. The peptide obtained by this method is called stapled peptide. Bicyclic peptides have two amino acid sequence rings, which are regulated by a linker in the middle. Bicycle therapeutics, a British company, is in a leading position in the research and development of bicyclic peptides, and a candidate drug has entered clinical trials.

Binding peptide drugs in clinical trials

Although binding peptides have good pharmacological activities, it is not so easy to develop these compounds into marketed drugs. 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 these drugs were not satisfactory, the manufacturing process was also very complex, and the bioavailability was far from the expected results. These problems seriously hindered the development of such drugs.

Of course, there are more than these problems. Some companies focus on the design of binding peptide drugs. For example, ensemble discovery was founded in 2004 and uses the DNA coding library to generate cyclic polypeptides.

However, this method of peptide generation is blind, and the possibility of patent medicine is small and the cost is high. In 2017, the company officially closed down. Subsequently, tranzyme Pharma was acquired by ocera therapeutics in 2013.

Companies that stick to it will eventually have a ray of hope, with polyphor getting an initial public offering of $165 million in May 2018. The company has established pemfinder and macrofinder platforms for the development of binding peptide pipeline drugs. More than 5000 binding peptides have been found for drug screening by using these platforms. Three drugs, murepavadin, balixafortide and pol6014, have entered clinical trials.

Murepavadin is a novel antibiotic targeting outer membrane protein of Gram-negative bacteria, targeting lipopolysaccharide transporter D (lptd). For the treatment of nosocomial pneumonia, has been in clinical trial phase III. Because of the deep outer membrane of Gram-negative bacteria, it is difficult for ordinary antibiotics to enter the bacteria and kill bacteria.

Murepavadin has strong affinity to lipopolysaccharide and outer membrane protein of bacteria outer wall, which brings a new breakthrough in the treatment of refractory infections caused by gram-negative bacteria.

Preclinical studies have shown that murepavadin has a specific and efficient inhibitory effect on Pseudomonas aeruginosa, even for multi drug resistant bacteria. Clinical trials showed that in 12 patients, the clinical cure rate of TOC was more than 80%, and the 28 day all-cause mortality rate was 8%.

Balixafortide is a chemokine receptor-4 CXCR4 is a member of G protein coupled receptor superfamily, which has the biological functions of chemotactic immune cells and maintaining the dynamic balance of immune cells. CXCR4 is overexpressed in most human tumor cells, including breast cancer, prostate cancer, lung cancer, colon cancer and multiple myeloma.

CXCR4 plays an important role in tumor growth and metastasis, and inhibits CXCR4 It can inhibit the growth of tumor cells. Balixafotide is a natural peptide from tachypleus amebocyte lysate, which 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 balixafotide combined with irebrin can improve the tumor response rate in patients with advanced and severe metastatic breast cancer.

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

Clinical studies have shown that pol6014 has a high inhibitory effect on human neutrophil elastase from activated sputum, and has good safety and tolerance for patients. At present, pol6014 is in phase I clinical study.

RA pharmaceuticals received $106 million of IPO investment in 2016, and apelis pharmaceuticals also received $150 million of IPO investment in 2017. Both of them share a common goal of developing therapies for the rare disease paroxysmal nocturnal hemoglobinuria (PNH). 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 for the treatment of PNH. At present, only one antibody drug with the same target, eculizumab, has been used to treat PNH. However, breakthrough hemolysis will be observed when patients use eculizumab, especially at the end of the administration cycle.

Compared with eculizumab, ra101495 has better controllability, reduces the risk of breakthrough hemolysis and provides convenience for patients. The drug is currently in phase II of clinical trials.

Interaction sites of ra101495 and eculizumab at C5

APL-2, a C3 protein inhibitor, is currently in phase III clinical trials for the treatment of PNH. APL-2 can prevent the formation of complement membrane attack complex (MAC), thus preventing the activation of mutant platelets and intravascular hemolysis, thus reducing the risk of thrombosis.

Thrombosis is one of the main causes of PNH death. APL-2 can also prevent extravascular hemolysis and further reduce anemia and transfusion dependence in PNH patients. At the same time, the frequency of APL-2 administration is less, usually once a day, which increases the convenience of patients.

Alrn-6924 of aileron therapeutics is a subscription peptide, which is an activator of p53 protein and activates tumor suppressor proteins 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 monoclonal antibody for the treatment of solid tumors and liquid tumors.

At present, the clinical trials of alrn-6924 for acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and peripheral T-cell lymphoma (PTCL) are in progress.

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

Bt-1718 is a dicyclic peptide toxin coupled drug targeting membrane type 1 matrix metalloproteinase (MT1-MMP). MT1-MMP plays an important role in the invasion and metastasis of tumor cells, and is overexpressed in many solid tumors. Preclinical experiments have shown that bt-1718 has a significant targeting effect on MT1-MMP and has therapeutic effect on many solid tumors.

expectation

The binding peptide combines the advantages of small molecules and biological macromolecules. It not only has strong targeting and affinity similar to 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 binding peptides, they are favored by pharmaceutical companies.

Venture capital funds also attach great importance to this field, and start-up companies 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 are also quietly working in this field. There are also many start-up companies and large pharmaceutical companies in joint research and development.

A famous example is the strong alliance between bicycle 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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