PEGylation

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Polyethylene glycol

PEGylation (or pegylation) is the process of both covalent and non-covalent attachment or amalgamation of polyethylene glycol (PEG, in pharmacy called macrogol) polymer chains to molecules and macrostructures, such as a drug, therapeutic protein or vesicle, which is then described as PEGylated.[1][2][3][4] PEGylation affects the resulting derivatives or aggregates interactions, which typically slows down their coalescence and degradation as well as elimination in vivo.[5][6]

PEGylation is routinely achieved by the incubation of a reactive derivative of PEG with the target molecule. The covalent attachment of PEG to a drug or therapeutic protein can "mask" the agent from the host's immune system (reducing

pharmacological advantages and acceptability, PEGylation technology is the foundation of a growing multibillion-dollar industry.[7]

Methodology

PEG-uricase; PEG-uricase includes 40 polymers of 10kDa PEG. PEGylation improves its solubility at physiological pH, increases serum half-life and reduces immunogenicity without compromising activity. Upper images show the whole tetramer, lower images show one of the lysines that is PEGylated. (uricase from PDB: 1uox​ and PEG-uricase model from reference;[8]
only 36 PEG polymers included)

PEGylation is the process of attaching the strands of the polymer PEG to molecules, most typically

hydrophobicity
etc. These physical and chemical changes increase systemic retention of the therapeutic agent. Also, it can influence the binding affinity of the therapeutic moiety to the cell receptors and can alter the absorption and distribution patterns.

PEGylation, by increasing the molecular weight of a molecule, can impart several significant pharmacological advantages over the unmodified form, such as improved drug solubility, reduced dosage frequency with potentially reduced toxicity and without diminished efficacy, extended circulating life, increased drug stability, and enhanced protection from proteolytic degradation; PEGylated forms may also be eligible for patent protection.[11]

PEGylated drugs

The attachment of an inert and

proteins.[12] Polyethylene glycol was chosen as the polymer.[13][14] In 1981 Davis and Abuchowski founded Enzon, Inc., which brought three PEGylated drugs to market. Abuchowski later founded and is CEO of Prolong Pharmaceuticals.[15]

The clinical value of PEGylation is now well established. ADAGEN (pegademase bovine) manufactured by Enzon Pharmaceuticals, Inc., US was the first PEGylated protein approved by the

pharmaceuticals have followed and many others are under clinical trial or under development stages. Sales of the two most successful products, Pegasys and Neulasta, exceeded $5 billion in 2011.[16][17] All commercially available PEGylated pharmaceuticals contain methoxypoly(ethylene glycol) or mPEG. PEGylated pharmaceuticals on the market (in reverse chronology by FDA approval year) have included:[18]

Patent litigation

The PEGylated

mRNA-1273 has been the subject of ongoing patent litigation with Arbutus Biopharma, from whom Moderna had previously licensed LNP technology.[25][26] On 4 September 2020, Nature Biotechnology reported that Moderna had lost a key challenge in the ongoing case.[27]

Use in research

PEGylation has practical uses in biotechnology for protein delivery,[28] cell transfection, and gene editing in non-human cells.[29]

Process

The first step of the PEGylation is the suitable functionalization of the PEG polymer at one or both ends. PEGs that are activated at each end with the same reactive moiety are known as "homobifunctional", whereas if the functional groups present are different, then the PEG derivative is referred as "heterobifunctional" or "heterofunctional". The chemically active or activated derivatives of the PEG polymer are prepared to attach the PEG to the desired molecule.[30]

The overall PEGylation processes used to date for

ATPS).[32][33]

The choice of the suitable functional group for the PEG derivative is based on the type of available reactive group on the molecule that will be coupled to the PEG. For proteins, typical reactive amino acids include

The techniques used to form first generation PEG derivatives are generally reacting the PEG polymer with a group that is reactive with

amides
etc. are made available for conjugation.

As applications of PEGylation have become more and more advanced and sophisticated, there has been an increase in need for heterobifunctional PEGs for conjugation. These heterobifunctional PEGs are very useful in linking two entities, where a

Third-generation pegylation agents, where the polymer has been branched, Y-shaped or comb-shaped are available and show reduced viscosity and lack of

Esperoct
.

Limitations

Unpredictability in clearance times for PEGylated compounds may lead to the accumulation of large-molecular-weight compounds in the liver leading to inclusion bodies with no known toxicologic consequences.[41] Furthermore, alteration in the chain length may lead to unexpected clearance times in vivo.[42] Moreover, the experimental conditions of PEGylation reaction (i.e. pH, temperature, reaction time, overall cost of the process and molar ratio between PEG derivative and peptide) also have an impact on the stability of the final PEGylated products.[43] To overcome the above-mentioned limitations different strategies such as changing the size (Mw), the number, the location and the type of linkage of PEG molecule were offered by several researchers.[44][45] Conjugation to biodegradable polysaccharides, which is a promising alternative to PEGylation, is another way to solve the biodegradability issue of PEG.[46]

See also

References

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  7. ^ Damodaran V. B. ; Fee C. J. (2010). "Protein PEGylation: An overview of chemistry and process considerations". European Pharmaceutical Review. 15 (1): 18–26.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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  15. ^ "Dr. Abraham Abuchowski, Ph.D. – Home". prolongpharma.com. Retrieved 2020-01-15.
  16. ^ Klauser, Alexander (Head), Roche Group Media Relations, "Roche in 2011: Strong results and positive outlook," www.roche.com/med-cor-2012-02-01-e.pdf, Feb 1, 2012, p.7
  17. ^ "Amgen 2011 Annual Report and Financial Summary," [1] 2011 AnnualReport.pdf, Feb 23 2012, p. 71
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  20. ^ Weiland, Noah; LaFraniere, Sharon; Baker, Mike; Thomas, Katie (17 December 2020). "2 Alaska Health Workers Got Emergency Treatment After Receiving Pfizer's Vaccine". New York Times.
  21. ^ Firger, Jessica; Caldwell, Travis (19 December 2020). "Third Alaskan health care worker has allergic reaction to Covid-19 vaccine". Cable News Network.
  22. ^ Powers, Marie (May 29, 2018). "Biomarin aces final exam: Palynziq gains FDA approval to treat PKU in adults". BioWorld.
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  24. ^ "FDA approves modified antihemophilic factor for hemophilia A". www.fda.gov. Archived from the original on 2015-11-16.
  25. ^ Auth DR, Powell MB (14 September 2020). "Patent Issues Highlight Risks of Moderna's COVID-19 Vaccine". New York Law Journal. Retrieved 1 December 2020.
  26. ^ Vardi N (29 June 2020). "Moderna's Mysterious Coronavirus Vaccine Delivery System". Forbes. Retrieved 1 December 2020.
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  36. ^ "Methods and pharmaceutical compositions for treating candida auris in blood". Wipo (PCT). WO (126695A2). 2019.
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External links