What Is a Cyclic Peptide?

The cyclic peptides usually referred to in biology refer to compounds formed by amino acid peptide bonds. In plant chemistry, the concept has been expanded to a class of compounds formed by amide bonds, so the scope has been expanded to include organic amines and macrocycles. Alkaloids are classified into cyclic peptides and straight-chain peptides based on whether they are cyclic or not. Cyclopeptide compounds have been reported to have a variety of biological activities, including antitumor, anti-HIV, antibacterial, antimalarial, sleeping, inhibition of platelet aggregation, blood pressure, tyrosinase, cyclooxygenase, lipid Peroxidase, estrogen-like, immunosuppressive and other biological activities.

Cyclic peptide

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The cyclic peptide usually referred to in biology refers to a compound formed by amino acid peptide bonds.

Jame P. Tam [88-90] et al. Established a method for preparing unprotected cyclic peptides by intramolecular transfer thiolactoneization and Ag + ion-assisted cyclization. For linear peptides with cysteine at the N-terminus and thioester at the C-terminus, in a phosphate buffer at pH = 7, the thiol group and the thioester group form a covalent thiolactone. Atom to N atom acyl migrates to form a cyclic peptide, as shown in the figure:

The authors synthesized a series of Cyclo (Cys-Tyr-Gly-Xaa-Yaa-Leu) with N-terminal cysteine by using the above method. TCEP (tricarboxyethylphosphine), the reaction time is about 4 hours, and the yield is between 78% and 92%. No side reactions and oligomers were detected by HPLC.

For the cyclization of cysteine-free linear polypeptides, thiophilic Ag + ions are used to assist the coordination of the flexible linear polypeptide's N-terminal amino group and C-terminal thioester to form a cyclic intermediate, which promotes intramolecular activation through entropy activation. Ring closure. Similar to the principle of the thiolactone cyclization method, Ag + ions promote intramolecular cyclization through a non-classical ring-chain structure interconversion. The cyclic intermediate is shown below:

A specific example of applying the above method to synthesize a cyclic peptide is the synthesis of Cyclo (Ala-Lys-Try-Gly- Gly-Phe-Leu). 10% DMSO was added to the pH 5.7 acetic acid buffer solution as a co-solvent, and the target product was obtained in 67% yield after 5 hours of reaction.

The cyclic dipeptide (2,5-piperazine dione) is the smallest cyclic peptide. Many natural cyclic dipeptide compounds have clear biological activity, such as antibiotics, bitters, plant growth inhibitors, and hormone release inhibitors. 91-92]. The specificity of the cyclic dipeptide structure makes the synthesis of such compounds self-contained. Usually, the target peptide can be easily obtained by refluxing the linear peptide ester free at the N-terminus in a polar solvent. Although Fischer hydrolyzed linear dipeptide methyl esters in methanol and ammonia to obtain cyclic dipeptides, it was also found that this method was prone to racemization. Nitecki [93] proposed that refluxing the N-terminal free linear dipeptide methyl ester in a mixed solvent of butanol and toluene to synthesize a cyclic dipeptide would not cause racemization. Ueda [94] also used methanol as a solvent to reflux, and also obtained a good yield of cyclic dipeptides; Cook et al. Used 1,2-ethylene glycol as the reaction solvent to obtain two diastereomeric ring dipeptides. Peptides with a total yield of 64.5% [95]. Recently, Wang Youjun reported that a series of cyclic dipeptides were synthesized according to the methods of Ueda and Cook. The yield was between 55% and 99%. Cyclo (Phe-Pro) and Cyclo (Ile-Ile) were found through biological activity experiments. Cyclo (Met-Met) and Cyclo (Met-Met) have a slight calcium antagonistic effect, while Cyclo (Ala-Ala) and Cyclo (Pro-Pro) have shown potent potassium-induced contraction effects [96-97].

The methods for synthesizing end-to-end cyclic peptides so far have been described above. Because the number and types of amino acids contained in the precursors of cyclic peptides-linear peptides vary widely, cyclic peptide synthesis methods are diversified. Reagents and methods that exhibit high efficiency for one type of linear peptide and rapid condensation may become inefficient or ineffective for another type of peptide chain. Therefore, to find the corresponding cyclic peptide synthesis method according to the sequence of the target cyclic peptide must be through careful exploration and hard work

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