Peptide Knowledge Center

Liquid phase method of cyclic peptides (1)

Cyclic peptides have various physiological functions and more medicinal value than linear peptides. Natural cyclic peptides often contain uncommon amino acids, such as D-amino acid, B-amino acid, etc., which are mainly divided into two categories. : Homodetic cyclo peptides and Heterodeticcyclo peptides. Homocyclic peptides that are all composed of amino acids and are strictly cyclic by peptide bonds; the main chain is composed of peptide bonds, and other functional groups such as disulfide bonds, ester bonds, ether bonds, thioether bonds, etc. The composed pseudopeptides (Depsipeptides or peptolides) are called heterocyclic peptides.


Synthesis of homocyclic peptides

The synthesis of homocyclic peptides is essentially the process of forming an intramolecular peptide bond. The concentration of the reactants has a direct impact on the yield, and high concentrations can easily cause the polymerization of molecules, so the reaction generally must be carried out under highly diluted conditions. The choice of the location of the loop is also an important issue. The researcher (Cavelier-Frontin) used the synthesis of the cyclic tetrapeptide Chlamydocin as a model and used the GenMDl program to calculate, and showed that the main factors that affect the peptide cyclization are: (1) steric hindrance factors, (2) the kinetic competition of the dimerization reaction , (3) the energy level of the transition state. He pointed out that the optimal substrate concentration is the one that causes the least ring strain due to the formation of a cyclic transition state complex, so that peptides with rigid backbones are generally difficult to form a ring.


liquid phase custom peptide synthesis method:

The liquid-phase method is a classic synthesis method, which is generally carried out in a highly diluted solution. The deprotected linear peptide precursor is directly cyclized under the condensation of a condensation reagent, and one end (usually the C-end) can also be activated. Then form a loop. The disadvantage of this method is that intermolecular oligomerization of peptides can easily lead to a serious decrease in the yield and purity of cyclic peptides, and the reaction often involves cumbersome side chain protection strategies.


(1) Active ester method The active ester method is a common method for the initial synthesis of cyclic peptides. The carboxyl group is made into an active ester, the N-terminal protecting group is removed, and then the ring is formed. The active ester intermediate has a certain stability and a certain reactivity, but the active ester has a large steric effect and a low reactivity, which slows down the cyclization speed, so that the carboxyl-activated polypeptide chain long-term existence in solution system increases the possibility of racemization.


(2) The azide method The azide method is to make the carboxyl terminal into an acyl azide host intermediate, and form a ring in a diluted alkaline solution. This method has less racemization and higher efficiency than the active ester method, but the acyl azide intermediate is unstable and the preparation steps are cumbersome.


(4) Thioester method Thioester method is a new type of cyclic peptide synthesis method developed after the 1890s. This method uses the entropy activation effect to promote the cyclization reaction without adding condensation reagents, and the reaction can be It can be completed under mild conditions and in a short time, and can obtain higher yields. The main feature of this type of method is to use the nucleophilicity of the sulfhydryl group to attack the carbonyl group on the C-terminal thioester bond from the N-terminal cysteine sulfhydryl group to form an intramolecular cyclic thioester, and then form an amide through the bond type conversion from S to N. bond to form a cyclic peptide.

Liquid phase method of cyclic peptides (1)