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Hefei KS-V Peptide Biological Technology Co., Ltd. Hefei KS-V Peptide Biological Technology Co., Ltd.
Hefei KS-V Peptide Biological Technology Co., Ltd.
How to Rationally Design Peptide Drugs?

How to Rationally Design Peptide Drugs?

Some people say that the 21st century is the century of peptide drugs, and the fate of this substance between large-molecule proteins and small-molecule compounds is bound to be important for us.

Ⅰ. What are peptide drugs

Polypeptides are a class of compounds composed of amino acids connected by peptide bonds, and are chemically active substances commonly found in organisms. According to the classification method commonly used in the international pharmacy circle, drugs with more than 100 amino acid molecules are protein drugs, and drugs with less than 100 amino acid molecules are polypeptide drugs. At present, tens of thousands of polypeptides have been found in organisms, and most of them have physiological activities, involving hormones, nerves, cell growth and reproduction and other fields. Compared with chemical drugs, peptide drugs are more efficient, safer, and more tolerable. At the same time, they also have the advantages of higher selectivity and not easy to accumulate in the body.

Ⅱ. How to rationally design peptide drugs

First, obtain the crystal of the peptide to determine its secondary and tertiary structure. Then, through analysis methods such as alanine substitution and structure-activity relationship (SAR), the essential amino acids and possible substitution sites are identified. In this process, especially when preparing liquid preparations, it is extremely important to identify unstable amino acids, and isomerization, glycosylation or oxidation reactions should be avoided.

Another important aspect of rational peptide drug design is to improve the physical and chemical properties of natural peptides, because natural peptides tend to agglomerate and have low water solubility. In chemical design, the appearance of perishable hydrophobic groups should be avoided. This can be achieved by substitution or N-methylation on specific amino acids. If there are solubility problems with peptide drugs, attention should be paid to the charge distribution, isoelectric point, and pH of the formulation. Other methods can also improve the stability of the polypeptide, such as the introduction of a stable alpha helix, the formation of a salt bridge, or other chemical modifications, such as a lactam bridge.

Generally speaking, the circulating plasma half-life of natural peptides is relatively short. Therefore, several techniques to extend the half-life have been developed. One technique is to restrict enzyme degradation, replacing the sites in the polypeptide that are easily cleaved by enzymes with other amino acids. The protective enzyme cleavage site can also be obtained by enhancing the secondary structure of the polypeptide, such as inserting probes or forming cyclic peptides.

The second method is to combine peptides with albumin, which can prolong the half-life of peptide drugs and reduce the frequency of drug use. Liraglutide using this method is a successful example. The third method is to modify polypeptides. The technology of polyethylene glycol (PEG) modified polypeptides has been very mature. There have been many protein polypeptide drugs that have been successfully marketed after modification, such as PEG-modified interferon. However, due to safety and tolerability considerations, polyethylene glycol is not the primary choice for injections.