What are PEG Linkers?

What are PEG Linkers?

Published by BroadPharm on December 11, 2020

What are Peg Linkers?

PEG linkers, also known as PEG Reagents, are chemically functionalized polyethylene glycol (PEG) linkers. PEG linkers are particularly attractive as a cross-linker for conjugation and biolabeling, due to their water solubility, lack of toxicity, low immunogenicity.

There are two classes of PEG linkers, monodispersed and polydispersed. Monodispersed PEG has an exact number of PEG units with a specific single chemical structure with precise molecular weight. PEG can be attached with a variety of functional groups such as Azide, Amine, NHS active ester, Alkyne, DBCO, Maleimide, Biotin, DSPE, as exemplified by Azido-PEG12-NHS ester (Figure 1).

Example of Monodispersed PEG Linkers

structure of azido-peg-nhs ester 12
Figure 1. Azido-PEG12-NHS ester is a bifunctional, monodisperse PEG linker.

Whereas polydispersed PEG is a polymer mixture that has an average molecular weight, Monodispersed and Polydispersed PEG.

Peg linkers have become widely used in pharmacological and biotechnological R&D such as antibody drug conjugates, nanoparticle drug delivery, biotinylation, PEGylated protein drugs and small molecule drugs.

PEG Linker in Antibody Drug Conjugate

In antibody drug conjugates (ADCs), a key development has been the ADC Linker Technology. The design of the linker can significantly affect the potency, selectivity, and the pharmacokinetics of an antibody-drug conjugate. For example, the ADC Zynlonta has incorporated several interesting linker components (Figure 2). The linker includer's the monodispersed PEG, the enzymatically cleavable linkers (Val-Ala), and the maleimide group that connect the linker to the antibody.

diagram of antibody drug conjugate linker as well as a description
Figure 2. Zynlonta, shown above, has several unique features including a maleimide group for attachment to the mAbs, a PEG8 linker for solubility, and a cleavable Val-Ala section bound to the drug SG3199.

PEG Lipid in Nanoparticle Drug Delivery

Stable nucleic acid lipid particles (SNALPs) were first developed in 2001. They have now become famous with the development of Moderna and Pfizer COVID-19 vaccines (Figure 3). Typically, SNALPS are composed of a high transition temperature phospholipid, a PEG lipid, and an ionizable cationic phospholipid. One specific example is DSPE-mPEG 2000, which is essential to producing the Pfizer COVID-19 vaccine. Another well-known PEGylated lipid is DMG-PEG 2000, which is found within the Moderna COVID-19 vaccine.

diagram of antibody drug conjugate linker as well as a description
Figure 3. PEG Lipids used in COVID-19 vaccines, Pfizer's DSPE-PEG 2000 shown on top and Moderna's DMG-PEG 2000 shown on bottom.

PEG in Protein PEGylation

Adagen is one example of a PEGylated protein drug (Figure 4). It is comprised of the protein Adenosine Deaminase that has 11-17 PEG 5K chains attached to the lysine groups of the protein. The PEG chains increase the drug's size, which prevents it from renal clearance and extends the lifetime of the drug. Increasing the length of the PEG linker allows for enhanced solubility and decreases the accessibility for proteolytic enzymes and antibodies.

diagram of antibody drug conjugate linker as well as a description
Figure 4. Adagen, shown above, has 11-17 PEG 5K chains attached to the protein's lysine groups that prevents it from renal clearance and extends the lifetime of the drug

PEG in Small Molecule Drug

Introduction of PEG linkers to small molecule drugs increases the drug's solubility and molecular weight. This may allow for an extended drug half-life in the body. Naloxegol (Movantik) is one example of a small molecule drug that incorporates PEG to improve the drug's efficiency by reducing its transport across the blood-brain barrier (Figure 5).

diagram of antibody drug conjugate linker as well as a description
Figure 5. Movantik, shown above, is a pegylated derivative of α-naloxol.

BroadPharm is a Leading PEG Supplier

As a worldwide leader of PEG linkers, BroadPharm offers a wide array of PEG Linkers and Click Chemistry Reagents to empower our customer's advanced research. These compounds feature great aqueous solubility, smart choice of PEG length, and a broad selection of functional groups to choose from.