PAS protein modification technology refers to the combination of functional polypeptides and polypeptide sequences composed of proline, alanine and serine by gene fusion and fusion expression by gene engineering to realize the modification of polypeptides. At present, for small-molecular polypeptide drugs, their small volume leads to a shorter half-life in plasma. In clinical practice, PEG is used to modify small-molecular polypeptide drugs to make them have a larger hydrodynamic volume and increase their pharmacological activity. However, in recent years, with more and more PEG modified drugs entering the clinical application market, the safety drawbacks of PEG fmoc-osu chemical polymers have been continuously discovered. Therefore, it is necessary to find more safe and effective methods other than PEG, and PAS shows great advantages in the modification of small molecular peptides

With the development of molecular biology, the development and application of polypeptide drugs, including growth factors, cytokines, monoclonal antibodies and enzymes, has become a hot spot in the development of biomedical industry due to the advantages of specific and efficient action of polypeptide drugs. However, there are many problems when polypeptides are injected into organisms as drugs, such as strong immunogenicity, short half-life, strong enzymolysis and low solubility. The problem of short half-life seriously restricts the development of small peptide drugs. This is mainly because the molecular weight is lower than the glomerular filtration threshold (about 60-70 kD), which makes the drugs in the blood be cleared quickly when passing through the kidney, thus greatly reducing the half-life of peptide drugs in the plasma. 

Therefore, it is necessary to increase the dosage and frequency of medication to maintain the effective concentration of drugs in the body, which adds a lot of distress to patients. PEGylation is a popular protein modification technology developed in the late 1970s. PEG is a kind of polymer, which is widely used in the modification of a variety of protein drugs or non-protein drugs. It can effectively increase the hydrodynamic volume of small peptide drugs and prolong the half-life in vivo. However, recent studies have found that PGE-modified drugs can cause a series of problems during long-term treatment of patients, such as kidney vacuolation and polymer accumulation in vivo, and even reports that PEG biological product antibodies have been found in vivo, which have caused widespread concern about the safety of PEG drugs

PAS protein modification is a fusion protein modification technology developed in recent years. The N-terminal or C-terminal of protein drugs are connected by proline (Pro), alanine (Ala) and serine

(Ser). PAS sequence is a hydrophilic, uncharged biopolymer, which has very similar biophysical properties to polyethylene glycol (PEG), can form a natural non-structural polypeptide chain, and has large hydrodynamic volume and high solubility. Compared with PEG chemical modification, PAS fusion protein will be rapidly absorbed by intracellular lysosomal protease after being absorbed by the receptor on the cell surface

Degradation, effectively avoiding deposition in cells. In addition, the PAS sequence is composed of three natural amino acids, and the advanced structure formed is relatively simple, so it is suitable for the current common biological expression system. The production method of genetic engineering technology can greatly reduce the cost. At present, PAS modified protein technology has been used to prolong the plasma half-life of various biological products in vivo, such as antibody Fad fragment, growth hormone, enzyme and interferon.

PAS sequence design

Selection of amino acids

PEG polymer has the characteristics of high hydrophilicity, large hydromechanical volume and uncharged property. In order to make the amino acid sequence composed have similar physical properties, the charged and hydrophobic amino acids with hydrophobic side chain and strong hydrophobicity are first excluded. Among the remaining amino acids with strong electrical and hydrophilicity, aspartic acid Glutamine and threonine are excluded because of their strong tendency to form a regular structure; Histidine is excluded because of its strong tendency to interact with metal ions, so the three selected amino acids are proline, alanine and serine

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From custom peptide synthesis company China-Omizzur