Cyclic peptide synthesis (staple peptide)

The regulation of various life stages in living organisms is realized through the influence of proteins on each other. For example, virus self-assembly, cell growth, division, differentiation and so on. However, the interface of protein-protein interaction is too large, which makes it difficult for small molecule drugs to target it, achieve efficient and specific blocking of this interaction, and show good therapeutic effect.

Because protein drugs are difficult to pass through the cell membrane, they cannot directly target intracellular interactions. Therefore, researchers began to seek a new drug molecule that can overcome the shortcomings of both drugs, which can enter the cell membrane and can specifically target protein-protein interactions.

Studies have shown that polypeptides with alpha-helical structures and rich positive charges can cross cell membranes. However, once separated from the parent, it cannot maintain its original secondary structure, and conformational instability leads to weakened binding to proteins, while ordinary linear peptides cannot cross cell membranes and are easily hydrolyzed.

The basic principle of staple peptide synthesis is the synthesis of an architecture with regulated modules that can be customized to synthesize different skin chains. The advent of this technology allows customized proteins to be combined according to the user's requirements to obtain the desired biological properties.

First, prescriptive peptide synthesis requires a component called a "custom peptide," which is a small peptide with a specific modular property that usually contains the necessary domain or active site in the protein that mediates the construction of the polypeptide. Researchers can select several or dozens of different components as customized peptides according to the requirements, and then identify them using antigen receptors, assemble them, and finally form a protein combination product that meets the needs of customers.

Second, when the product of custom peptide synthesis is detected in the laboratory, its function can be studied. In this process, various biological methods can be used to detect the functional properties of the product, such as molecular enzymatic experiments, determination of antibody activity, etc., so as to further modify and develop the customized protein.

In addition, the synthesis of staple peptides can also be used to prepare other active peptides, as well as to manufacture antibodies and small molecule active substances. Compared with previous protein engineering techniques, the advantage of staple peptide synthesis is that it can achieve transgene, and partially modified proteins show stronger activity and characteristics.

The difference between staple peptide synthesis and conventional peptide synthesis is that two non-natural amino acids containing α-methyl and α-alkenyl groups are introduced in the process of solid phase synthesis of the peptide chain, and then the olefin metathesis reaction between the two non-natural amino acids is generated to form a stable all-carbon scaffold with α-helical structure, and finally the staple peptide is synthesized.

The above figure shows the general structure of two different configurations of unnatural amino acids containing α-methyl and α-alkenyl groups. This type of amino acid synthesis method is generally:

The conventional synthesis route of staple peptides is:

Motif Biotech has always maintained the customer first business perspective, through long-term experimental experience, and constantly improve the synthesis conditions and purification process, has a mature peptide synthesis process, has the strength to provide high quality and high standard of staple peptides to the world, and can fully meet the various research and development needs of customers.

At present, MOTIF has been successfully synthesized as follows: Ac-R****I[S5]L*N[S5]LK***GN-Ahx-LA* Y-NH2 (Figure below)