PEGylation
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
Methodology
PEGylation is the process of attaching the strands of the polymer PEG to molecules, most typically
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
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
- A PEGylated lipid is used as an excipient in both the RNA vaccines consist of Messenger RNA, or mRNA, encased in a bubble of oily molecules called lipids. Proprietary lipid technology is used for each. In both vaccines, the bubbles are coated with a stabilizing molecule of polyethylene glycol. As of December 2020, there is some concern that PEG could trigger an allergic reaction,[19][20] as appears to have occurred by 19 December, in at least three "Alaska health care worker" people who were administered the Pfizer–BioNTech COVID-19 vaccine.[21] The particular PEGylated molecule in the Moderna vaccine is known as DMG-PEG 2000.
- Pegvaliase (Biomarin) – PEGylated recombinant phenylalanine ammonia-lyase for the treatment of Phenylketonuria, approved by the FDA for the US in May 2018.[22][23]
- irinotecan hydrochloride trihydrate for the treatment of metastatic pancreatic cancer in adults proceeding treatment with gemcitabine-based therapy. (Ipsen, 2015)
- Plegridy – PEGylated Interferon Beta-1a for the treatment of patients with relapsing forms of multiple sclerosis. (Biogen, 2014)
- gastrointestinal reactions). (AstraZeneca, 2014)
- Takeda Pharmaceuticals, 2012)
- , 2010)
- Certolizumab pegol (Cimzia) – monoclonal antibody for treatment of moderate to severe rheumatoid arthritis and Crohn's disease, an inflammatory gastrointestinal disorder (Nektar/UCB Pharma, 2008)
- Roche, 2007)
- Pegaptanib (Macugen) – used to treat neovascular age-related macular degeneration (Pfizer, 2004)
- methionyl human granulocyte colony-stimulating factor for severe cancer chemotherapy-induced neutropenia (Amgen, 2002)
- , 2002)
- Hoffmann-La Roche, 2002)
- Peginterferon alfa-2b (PegIntron) – PEGylated interferon alpha for use in the treatment of chronic hepatitis C and hepatitis B (Schering-Plough/Enzon, 2000)
- Doxorubicin HCl liposome (Doxil/Caelyx) – PEGylated liposome containing doxorubicin for the treatment of cancer(Alza, 1995)
- L-asparaginase (Enzon, 1994). This drug was recently approved for front line use.
- severe combined immunodeficiency disease(SCID) (Enzon, 1990)
Patent litigation
The PEGylated
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
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
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
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
- Cytochrome c
- Interferon
- Matrix-assisted laser desorption/ionization
- Proteomics
- Solid lipid nanoparticles
References
- PMID 21718180.
- PMID 20648499.
- S2CID 23901382.
- PMID 16243265.
- PMID 2223816.
- S2CID 11437990.
- ^ 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) - PMID 17826865.
- PMID 12052707.
- S2CID 226664780.
- PMID 21892917.
- PMID 12052708.
- PMID 405385.
- PMID 16907.
- ^ "Dr. Abraham Abuchowski, Ph.D. – Home". prolongpharma.com. Retrieved 2020-01-15.
- ^ 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
- ^ "Amgen 2011 Annual Report and Financial Summary," [1] 2011 AnnualReport.pdf, Feb 23 2012, p. 71
- S2CID 209731201.
- S2CID 229284320.
- ^ 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.
- ^ Firger, Jessica; Caldwell, Travis (19 December 2020). "Third Alaskan health care worker has allergic reaction to Covid-19 vaccine". Cable News Network.
- ^ Powers, Marie (May 29, 2018). "Biomarin aces final exam: Palynziq gains FDA approval to treat PKU in adults". BioWorld.
- S2CID 49411168.
- ^ "FDA approves modified antihemophilic factor for hemophilia A". www.fda.gov. Archived from the original on 2015-11-16.
- ^ 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.
- ^ Vardi N (29 June 2020). "Moderna's Mysterious Coronavirus Vaccine Delivery System". Forbes. Retrieved 1 December 2020.
- S2CID 221504018.
- OCLC 1127111107.[page needed]
- PMID 21490748.
- PMID 22094104.
- .
- ISBN 978-3-7643-8679-5.
- PMID 12584761.
- ISBN 9783527653096.
- ^ "Polypeptide therapeutics and uses thereof". Wipo (PCT). WO (138413A1). 2016.
- ^ "Methods and pharmaceutical compositions for treating candida auris in blood". Wipo (PCT). WO (126695A2). 2019.
- ^ "Arginase formulations and methods". Wipo (PCT). WO (8495A2). 2011.
- S2CID 97373496.
- PMID 29680235.
- PMID 23432141.
- S2CID 7600787.
- PMID 11214751.
- S2CID 22642574.
- PMID 18845567.
- S2CID 51888683.
- S2CID 239999294.