Overview of innovative drug development and drug improvement shortcut PEG modification.

Modern research has proved that polyethyl glycol (PEG) is an inert, non-carcinogenic polymer, which is one of the preferred polymers to modify the surface of bioactive molecules and nanoparticles.
, also known as molecular PEGylation, can enhance the solubility of hydrophobic drugs, proteins, lipids, nucleic acids, improve their stability and extend half-life.
Many chemicals, proteins, peptides and so on in the production of efficacy at the same time, there are its own defects, and PEG modification can make up for these problems, including: increase the water solubility of modifiers, reduce the immunogenicity of modifiers, improve the properties of modifiers drug substitutes and drug efficacy, improve the clinical application of modifiers.
A PEG modifier, Movantik, and its route, Movantik, are representatives of the chemical PEG Derivative, developed by AstraZeneta and approved by the FDA in 2014 for the treatment of constipation in patients with chronic non-cancer pain caused by opioids.
chemical structure, Movantik is a heptanol derivative of naloxone, coupled by biodegradable ether bonds.
naloxone PEG modification is shown in Figure 1 of the Movantik route, which is based on naloxone and 2-methoxyethylene methyl chloride (MEMCl) as the starting material, in alkaline conditions to achieve the protection of phenolic hydroxyl MEM.
Then the asymmetric reduction of the niobium base is achieved under the condition of sodium boron hydrocarbon to obtain intermediate 2; the intermediate 2 and the polyethyl glycol 3 of the Br generation are obtained by the williamson etheration reaction to the prebiotic compound 4; and finally the target product Movantik can be obtained by taking off the MEM protection base under TFA conditions.
Esperoct is represented by the polymer drug PEG Derivatives, developed by Noel nord and approved by the FDA in 2019 for preventive and acute treatment in adult and child haemophiliacs.
Esperoct is a PEG derivative of long-acting recombinant coagulation factor VIII (FVIII), significantly extending Esperoct's half-life and being highly safe and toned.
generally, patients with type A haemophilia require three coagulation factor infusions per week, while Esperoct requires only one infusion every four days to reduce the annual bleeding rate by 96%.
2 FDA approved PEG modification drugs With the continuous deepening of research, PEG modification drug development technology has been improved, many PEG modification drugs have been approved by the FDA and other drug regulatory departments to market. Figure
shows the FDA approved representative PEG modification drugs, from the figure can be seen, including Pfizer, Roche, Merck, Amjin and other pharmaceutical giants, including many pharmaceutical companies have joined the PEG modification drug development team;
summary, PEG decoration has three main advantages: A. Improving pharmacodynamics and pharmacodynamic properties: Studies have shown that after PEG modification, the pharmacodynamic properties of the body will change significantly, including: plasma half-life extension, increased release of drugs in the body, reduced renal clearance rate, etc. Enhance stability: protein, peptide PEGization, on its surface will form a thick hydration film, to prevent the formation of condensation, precipitation phenomenon.
modification of the connection between PEG and lipid derivatives (acetate, ether, desulfur bond, etc.) can also increase the stability of lipids.
addition, PEG's flexible chain produces a spatial bit resistance effect, protecting the modifier from protease attacks and increasing the stability of the modifier.
C. Improve the distribution of the drug body: after the drug is modified by PEG, the molecular weight increases, greatly reducing its filtration through the renal ball during the systemic administration process, thus reducing the excretion of urine.
In addition, PEG modified drugs in the body cycle stability is improved, the retention time is extended, is beneficial to improve the distribution of drugs in the body, especially to help the accumulation of large molecule drugs in tumors and inflammatory areas with residual enhancement effect, thereby prolonging the treatment time in the drug body.
years, with the deepening of research and development, the use of PEG as a connecting body of PEG dual-ernogeneic group heresy modifier drugs and other new PEG modification drugs (X-PEG-Y) have been introduced.
the future with the continuous improvement of modification technology, there will be more and more excellent PEG modification drugs, to provide patients with more and better treatment options.
source: 1. Drug Development Through Modification of Small Molecular Drugs with Monodisperse Polyethylene glycol s, 2020; 2. Advances in the study of polyethyl glycol bi-official hetero-modification, Chinese Pharmaceutical Biotechnology, 2020; 3. Advances in the development of PEG deribatives and pegylated protein drugs, 2018; 4. Research Progress of PEGylation Used in Modifying Drugs, Strait Pharmaceutical Journal, 2016.