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PEGylation of Small Molecule Drugs .pdf


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PEGylation of Small Molecule Drugs
Polyethylene glycol (PEG) is a polymer of ethylene glycol with a relative
molecular weight of 200 to 8000 or above. It is composed of repeated oxyethyl
groups, which not only has good water solubility, but is also soluble in organic
solvents such as benzene, acetonitrile and ethanol. The characteristics of PEG
molecules are as follows:
① Low dispersion: The dispersion with a relative molecular mass (Mr) of less
than 5000 is 1.01, and the dispersion with a molecular weight (Mr) of more
than 5000 is 1.1, with a wide distribution and greater selectivity;
② Unique amphiphilic: unique structure makes it soluble in both organic
solvents and water;
③ Non-toxic: Studies show that polyethylene glycols greater than 1000 are
non-toxic and have been used in various foods, cosmetics and drugs;
④ Biodegradable: Polyethylene glycol is directly eliminated in the body without
any structural changes. Metabolites with a molecular weight of less than
20,000 can be metabolized by the kidneys, and larger molecules can be
metabolized by the digestive system.

Characteristics of PEGylated Drugs
Most protein drugs, peptide drugs, and chemical drugs are accompanied by
some problems that cannot be overcome by themselves, such as short period
of action, large immunogenicity, and side effects. PEG is neutral, non-toxic,
has unique physical and chemical properties and good biocompatibility, and is
one of the few chemicals approved by the FDA for injectable drugs in vivo.
Therefore, by connecting the activated polyethylene glycol to proteins,
peptides, small molecule drugs and liposomes by chemical methods, that is,
by performing PEGylation of the drug molecule, the biological half-life of the

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drug molecule can be effectively improved and its toxic side effects can be
reduced. Among them, the most studied is the PEG modification of proteins.
Compared with unmodified protein drugs, PEGylated protein drugs have the
following advantages:
(1) Stronger biological activity;
(2) Liposomes have a stronger passive targeting effect on tumors;
(3) longer half-life;
(4) lower maximum blood concentration;
(5) minor fluctuations in plasma concentration;
(6) less enzymatic degradation;
(7) Less immunogenicity and antigenicity;
(8) less toxic;
(9) Better solubility;
(10) reduce the frequency of medication;
(11) Improve patient compliance, improve quality of life, and reduce treatment
costs.

Biochempeg Scientific Inc.

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PEGylation Method
In view of the huge impact of PEGylation on drug properties, PEGylation has
become an important way for drug development and improvement of the
efficacy of already marketed drugs. So, how to carry out PEGylation becomes
the top priority.
First, the appropriate PEG needs to be selected for molecular
modification. The selection of modifiers mainly considers the following 5
aspects:
(1) The selection of the relative molecular weight (Mr) of PEG should consider
both biological activity and pharmacokinetic factors. Applying too large a
PEGylated protein drug will cause the drug to lose most of its biological activity.
When using low-Mr (<20000) PEGylated protein drugs, the modified protein
drugs have no essential changes in biological activity and pharmacokinetic
properties compared to the prototype drugs. Therefore, PEG in the range of
40,000-60000 is generally selected as the modification.
(2) The selection of modification sites should be based on the analysis of the
structure-activity relationship of the protein. The surface residues of the
proteins that do not bind to the receptor are selected as modification sites, so
that the modified protein can retain high biological activity. Common
modification sites are amino modification, carboxy modification and thiol
modification;
(3) The specificity of the reaction between PEG modifier and amino acid
depends on the chemical properties of the modifier and the choice of
modification site.
(4) The hydrolytic stability and reactivity of the PEG modifier depend on the
stability of the activating group and the control of the modification reaction
conditions, especially the pH. In general, PEG modifiers have high reactivity,
so their stability is poor and they are easy to hydrolyze;
(5) The activity, toxicity, and antigenicity of PEGylated protein are related to
the size and type of PEG modification. Generally, as the relative molecular
weight of PEG increases, the loss of protein activity gradually increases. In
addition, different PEG modifiers have different effects on the biological activity
of proteins.
Secondly, activate PEG. PEGylated proteins are mainly achieved by the
reaction of PEG terminal hydroxyl groups with protein amino acid residues.
PEG terminal hydroxyl groups have poor activity and must be activated with an
activator to covalently modify proteins under mild conditions in vivo. Common
PEG activation methods are:

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(1) carbonyl diimidazole method: This method was first used in the synthesis of
polypeptides and has proven to be a good reagent for forming amide bonds.

Carbonyl diimidazole activation of PEG
(2) N-hydroxysuccinimide method: (a) Activate N, N-succinimide carbonate.
This reaction needs to be performed under anhydrous conditions. (B) Activate
succinic anhydride and N-hydroxysuccinimide. The polyethylene glycol
obtained by this method has higher activity. It is best to perform protein
coupling in a non-aqueous environment.

N, N-succinimide carbonate activated PEG

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Succinic anhydride and N-hydroxysuccinimide activated PEG
(3) Cyanuryl chloride method: Cyanuryl chloride, also known as trichlorazine
(TST), is a symmetric heterocyclic compound. David uses TST to react with
the hydroxyl group on polyethylene glycol. Only one chlorine atom is
substituted, and the other chlorine atoms Reacts with protein amino groups.

Cyanuryl chloride activated PEG
(4) Activation method involving phosgene: Kurfuerst mentioned in his patent
some methods to prepare activated polyethylene glycol by reacting
N-hydroxysuccinimide potassium salt, nitrophenol and trichlorophenol with
phosgene. The activation is divided into two steps as shown in the figure
below.

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Phosgene activation of PEG
(5) Chemical modification of cysteine ​ ​ residues of proteins by polyethylene
glycol. The common PEG activation methods for specific modification of sulfo
groups are shown in the figure below.

Specific modification of thiol-activated PEG

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(6) Polyethylene glycol linked to enzyme sites: In addition to traditional
chemical modification methods, modification can also be achieved by other
means such as enzyme catalysis, taking G-TGase as an example.

Enzyme-linked PEG
Finally, select the appropriate protein amino acid residue site or small
molecule drug site for site-specific modification. The site-specific
modification of suitable protein amino acid residues with activated PEG can
improve the efficacy of natural proteins. The biggest problem in PEG
modification technology of protein drugs is the inability to achieve site-specific
modification, the modification products are not uniform, which brings great
difficulty to isolation and purification, and also greatly hinders clinical
application. According to the amino acid properties of proteins and the
characteristics of PEG derivatives, when scientists use PEG to modify, they
choose protein surface residues that do not bind to the receptor as
modification sites. In this way, in addition to the excellent properties brought
about by PEGylation, the modified protein drugs also have high biological
activity. At present, the common modification sites in marketed drugs include
amino, carboxyl, sulfo, disulfide, glycosyl, and some specific positions of
non-polar amino acids.
After decades of research, many PEGylated small molecule drugs have
entered the state of clinical research. PEGylated small molecule drugs are
widely used, the most representative of which are paclitaxel and camptothecin.
More researches also include various types of commonly used anti-tumor
drugs with relatively simple structures and a few non-anti-tumor drugs.

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The Future of PEGylation
At present, PEGylated drugs are mainly irreversible first-generation PEG-drug
complexes and second-generation reversible PEG-drug complexes that are
connected to the drug through a cleavable bond to exert a sustained release
effect. Due to their non-biodegradability and limitation on molecular mass, the
first-generation small molecule drug conjugates are not very satisfactory in
improving their pharmacokinetics. Therefore, in addition to the peptide small
molecule conjugate drugs that have undergone more research, Current
research efforts have focused on the use of new biodegradable and spinal
degradable water-soluble polymers. Degradable high-molecular-weight N(2-hydroxymethyl) methacrylamide (HPMA) polymer small molecule drug
conjugates show improved pharmacokinetics and pharmacodynamics, while
showing ultimate renal clearance . Similarly, new water-soluble, biocompatible,
and biodegradable polymers, such as polycarbonate, are also being
synthesized and evaluated, expanding the range of polymers available for
drug coupling. The future of PEGylation is geared towards the third generation
of PEGylation, which aims to achieve the highest potency and extend the
half-life of drug molecules, site-specificity, and low doses. This can be
achieved by electrostatically linked non-covalent PEG modification. If
successful, with the help of further research, PEGylation has the potential to
become the main method of protein therapy.
Biochempeg can provide a variety of PEG linkers, which is convenient for
pharmacists to carry out the next drug modification.

Related Article:
Things About PEGylation Technology and Biopharmaceuticals You Should
Know
The Applications of PEGylation Reagents
Potential Limitations of PEGylated Therapeutic Proteins


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