Peptide Knowledge Center

Control strategy of starting materials in solid phase peptide synthesis

Peptide drugs have attracted increasing attention because of their wide range of biological activities, strong specificity and good safety. The development of synthetic peptide drugs has also become an active field in drug research. Solid phase peptide synthesis method has attracted much attention due to its advantages of simple operation and rapid purification. At present, most synthesis routes choose Fmoc protection strategy, but the impurities introduced by starting materials are often difficult to separate, which brings inconvenience to subsequent purification, and quality control must be strengthened from the source.

1.Protected amino acids

Protective amino acid is one of the starting materials for solid-phase peptide synthesis, which has the following characteristics: the protective functional group itself is easy to be introduced, it remains stable in a series of reactions, and it is easy to remove the protective group after the reaction or when the active group needs to be modified. At present, it is mainly divided into three categories according to the protected objects: α- Amino protecting group α- Carboxyl protecting group and side chain amino active group protecting group. Popular protective amino acids such as Fmoc-Pen(Trt)-OH, Fmoc-Pen(Acm)-OH, etc

The guiding principles for pharmaceutical research technology of synthetic peptide drugs mentioned that amino acids and their derivatives are the starting materials for peptide synthesis, and the quality has an important impact on the quality of synthetic peptides. Therefore, we should pay attention to the sources and quality control methods of amino acids and their derivatives. The quality control of starting materials should be sufficient to ensure the consistency of their quality, so as to finally ensure the stability of the quality of synthetic peptides between batches. Generally speaking, the quality control of protected amino acids includes properties, identification, specific rotation, moisture, solubility, free amino acids, enantiomers, residual solvents, related substances and content. If special amino acids or their derivatives are used, such as complex modified unnatural amino acids, amino acids synthesized by new processes, etc., the application materials should also provide relevant information on their synthesis process and structure research

In the research and development of solid-phase synthetic peptides, more attention is paid to the synthesis strategy, the feed ratio of protective amino acids and the choice of cracking agents, while the research on the starting material - Protective amino acids is not comprehensive, which is specifically manifested in the poor specificity of the purity inspection method of protective amino acids (such as only using TLC method for impurity control) or the limit is too broad, which can not effectively control the quality of starting materials and can not effectively guarantee the quality of API. In the process of peptide synthesis, the related impurities produced by the impurities introduced by the starting material may be co eluted with the target peptide in the purification process, so the impurities are difficult to reduce or eliminate. In order to minimize the potential impact on the end products, such impurities should be strictly limited In the control of starting materials, it is necessary to analyze the potential impurities that may be introduced by protective amino acids from the process route and amino acid structure.