Internal molecular structure modification: through cyclization, D-substituted amino acids, N/C terminal closure, introduction of non-natural amino acids and other means, the active site of the polypeptide easy to degrade is eliminated from the molecular level, the active conformation of the polypeptide is fixed, the probability of deamidation, oxidation and enzymatic hydrolysis of the polypeptide is fundamentally reduced, and the intrinsic stability of the polypeptide is greatly improved. It is the core basic strategy to improve stability.
Chemical modification protection: site-specific chemical modification techniques such as PEGylation, fatty acid side chain decoration, and glycosylation are used to form a spatial barrier outside the polypeptide molecule to prevent protease from contacting the active site of the polypeptide and improve the physical and chemical stability of the polypeptide. Among them, the decoration of long-chain fatty acids can further extend the residual time of polypeptides in vivo by binding to serum albumin, which is the mainstream conversion means of long-term polypeptide drugs.
Preparation process optimization: freeze-drying, spray drying and other dehydration processes are used to greatly reduce the water activity in the polypeptide preparation and inhibit the occurrence of hydrolysis, oxidation and other degradation reactions from the physical level; at the same time, the pH value and ionic strength of the preparation are accurately adjusted to avoid the extreme acid-base environment in which the polypeptide is easy to degrade, and significantly improve the long-term stability of the polypeptide during storage. Synergistic effect of stabilizers and excipients: adding mannitol, trehalose and other freeze-drying protective agents, as well as functional excipients such as amino acids and surfactants, to stabilize the natural image of the polypeptide through hydrogen bonding and hydrophobic interactions, and inhibit the aggregation and denaturation of the polypeptide. The physical stability of the polypeptide is greatly improved without changing the molecular structure of the polypeptide.
Physical encapsulation of delivery system: PLGA microspheres, pH sensitive nanoparticles, liposomes and other polymer carriers are used to completely encapsulate the polypeptide, forming a physical barrier between the polypeptide and the external environment and the protease in the body, which can not only protect the polypeptide in the acidic environment of the gastrointestinal tract from degradation, but also realize the slow release of the polypeptide in the body, and further improve the stability of the polypeptide in the body.
Frontier collaborative modification strategy: using new combination technologies such as "double fatty acid conjugation" and "double modification of glycolipid" to optimize multiple attributes such as enzymatic hydrolysis resistance, fat solubility and water solubility of polypeptides, which can extend the half-life of polypeptides to more than 200 hours and achieve ultra-long effect, which is the frontier research and development direction in the field of polypeptide stability improvement.
Post time: 2026-10-16