Method for producing cyclized peptide having intramolecular s-s bond

Abstract

The present invention provides a method for producing a cyclized peptide having a structure crosslinked by one or more intramolecular S-S bonds as indicated below. A method for producing a cyclized peptide, the method including: (1-A) a step in which, in a linear peptide ("fully protected peptide") that has two or more SH groups as functional groups on the peptide, the linear peptide being such that all of the SH groups are protected, the N-end amino group may be protected, and the C-end carboxy group and all of the other functional groups on the peptide are protected, all of the functional groups other than the protected SH groups of the peptide are deprotected; (1-B) a step in which, in a linear peptide having two or more SH groups as functional groups on the peptide, all of the SH groups are protected by forming temporary S-S bonds; and (2) a step in which a peptide ("S protected peptide") that has two or more SH groups as functional groups on the peptide, that is such that all of the SH groups are protected by formation of temporary S-S bonds and all of the other functional groups of the peptide are deprotected, and that is obtained in step (1-A) and step (1-B) is subjected to a folding step under redox conditions to reform the S-S bonds within the peptide molecule, whereby a cyclized peptide is obtained.

Description

technical field [0001] The present invention relates to a method for producing a cyclized peptide having a cross-linked structure based on an intramolecular S-S bond (disulfide bond), and is useful in the field of peptide synthesis. Background technique [0002] It has been known for a long time that many peptides containing S-S bonds are peptide drugs, such as somatostatin, octreotide, and atosiban. In recent years, cyclized peptides (for example, linaclotide) that contain more than 4 SH groups in the molecule and form S-S bonds in the molecule through these SH groups have cyclization sites based on multiple S-S crosslinking structures. ), plecanatide, ziconotide, insulin detemir, insulin glulisine, etc.) are being researched and developed. [0003] Conventionally, in the synthesis of peptides cyclized by intramolecular S-S bond formation, after producing a linear peptide (linear peptide) corresponding to the amino acid sequence of the target cyclized peptide, a protecting...

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Problems solved by technology

[0005] In addition to the above, conventional methods also have the following problems: the cyclization reaction based on the formation of intramolecular S-S bonds usually needs to be carried out under low concentration conditions (under the condition of using an excess solvent) to suppress the formation of S-S bonds between molecules. The side reactions are carried out, and the production efficiency is very low

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