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The Basic Principles of the Formation of Peptide Bond

The formation of a peptide bond (which produces a dipeptide) is a simple chemical process on the surface. It refers to two amino acid components that are connected through the peptide bond (amide bond) and remove the water simultaneously.

Under the conditions of mild reaction, the formation of the peptide bond is by activation of an amino acid (A) part of carboxyl; and the second amino acid (B) nucleophilic attack activated carboxyl part and formed A dipeptide (a-b). If the amino group of carboxyl group (A) is not protected, the formation of peptide bonds is uncontrollable and may be mixed with the target compound A- B, with a combination of linear peptide and cyclic peptide. Therefore, in the process of the synthesis of polypeptide, all functional groups that are not involved in peptide bonding must be protected in a temporary reversible manner.

Therefore, polypeptide synthesis - that is, the formation of each peptide bond, including three steps:

The first step is to prepare some of the protective amino acids. The amphoteric ion structure of amino acids no longer exists.

The second step is to form the two-step reaction of the peptide bond, the carboxyl group of the n-protective amino acid must be activated as the active intermediate, then the peptide bond is formed. This coupling reaction can be used as a step reaction or as two consecutive reactions.

The third step is to selectively remove the protection base. Although all of the removal process will not be done until all the peptide chains are assembled, in order to continue peptide synthesis, selective removal of the protective group is also required.

Since the 10 amino acids (Ser, Thr, Tyr, Asp, Glu, Lys, Arg, His, the Sec and Cys) contain the side chain functional groups that require selective protection, the peptide synthesis has become more complex. Because of the different requirements for selectivity, temporary and semi-permanent protection bases must be distinguished.

Ideally, carboxyl components of activation and subsequent peptide bond formation (coupling reaction) should be quick reaction, no despun or by-products formation, moles reactant should be applied in order to obtain high yield rate. Unfortunately, there are few methods of chemical coupling that can meet these requirements, and there are very few methods applicable to actual synthesis.

In the synthesis of peptide, the functional groups involved in multiple reactions are often associated with a chiral center (glycine is the only exception), and there is a potential risk of racemation.

The protection base must be all removed in the last step of the polypeptide synthesis cycle. In addition to the need for total deprotection in the synthesis of dipeptide, selective removal of the protection base is of great significance for the extension of the peptide chain.

The synthesis strategy should be carefully planned, and based on the strategic choice, it can selectively remove the N alpha-amino protection base or carboxyl group protection group. The term "strategy" refers to the sequence of condensation reactions of a single amino acid. In general, there is a difference between progressive synthesis and fragment condensation. In the solution, peptide synthesis (also known as "conventional synthesis") is carried out to the difficult sequence, and in most cases, the progressive extension of the peptide chain can only synthesize shorter segments. To synthesize longer peptides, the target molecule must be segmented into appropriate segments and determined that in the segment condensation process, they can minimize the c-terminal difference to the isomerization degree. After a single fragment is progressively assembled, the connection produces the target compound. Peptide synthesis tactics include selecting the most appropriate protection base combination and the optimal fragment coupling method.

The first solid phase peptide synthesis (SPPS) is only a change in peptide and protein synthesis, and it means that the growth of the peptide chain is connected to an insoluble polymer carrier, reported by Robert Bruce Merrifield in 1963. Today, he was named Merrifield in honor of his 1984 Nobel prize. The fragment condensation reaction can also be carried out on the supporter of polymer.