The introduction of a PEG linker to a molecule provides many benefits for pharmaceutical and biotech R&D due to its water solubility, lower toxicity and non-immunogenicity.

The introduction of different functional groups to the end of a PEG linker allows for more site-specific reactions.  For example, proteins have various amino acid residue that may be involved in chemical reactions with amine, sulfhydryl, carboxyl and carbonyl groups being more likely to be targeted for bioconjugation.  By altering the end group of the PEG linkers, it is easier to target these amino acid residues or specific functional groups. Table 1 lists reactive groups and available PEG linkers that can be used to target these reactive groups.

Table 1: Reactive groups and corresponding activated PEG linkers

Reactivity Class

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PEG Linkers




PEG Acid

PEG Aldehyde

PEG NHS ester

PEG PFP ester


Aminooxy PEG

Carboxyl and Active Ester

Amino PEG

Click Chemistry

Alkyne PEG

PEG azide

Copper Free Click Chemistry




Tetrazine PEG

Thiol Reactive

Bromo PEG


Modified PEG linkers can be used for different applications. In some instances, reaction conditions must be altered so that proteins are able to properly react with the PEG reagent.  Below are some common PEGylation chemistry reactions.

Aldehyde Conjugation
PEG aldehyde can be used in bioconjugation due to reactions between aminooxy or hydrazide moiety.

Figure 1: Reaction scheme of PEG aldehyde chemistry.

Amine Conjugation
PEG Amines can react with acids, succinimidyl-active esters or pentaflurophenyl esters for labelling, chemical modification and surface or particle modification.

Figure 2: Reaction scheme of amino PEG chemistry.

Thiol Conjugation
PEG Thiols are reactive with maleimides, disulfides, haloacteamides and other types of thiols. They can also be involved in metal surface binding.




Click Chemistry
Click chemistry describes a wide variety of reactions that occur between two reactive functional groups that can attach to one another under milder, aqueous conditions.  Click chemistry tools have improved over the years. First generation click chemistry tools involved copper-catalyzed reactions of terminal alkyne and azide groups. Second generation click chemistry tools made use of strain-promoted alkyne azide reactions without being copper-catalyzed. Third generation Click Chemistry involves the reaction between tetrazine and alkenes such as trans-cyclooctene.

Figure 4: First generation Click Chemistry of a Cu (I) catalyzed reaction between an azide and alkyne.
Figure 5: Second generation Click Chemistry involves strain-promoted reactions between azides and alkynes with no Cu(I) catalyst.
Figure 6: Third generation Click Chemistry between tetrazine and an alkene to promote strain-induced reactions. This reaction occurs very quickly and works without a Cu(I) catalyst.


1. Pasut, Gianfranco, Veronese, Francesco M., Drug Discovery 10, 21 (2005).

2.  “Chemistry of Crosslinking” ThermoFischer Scientific.

3. Journal of Pharmaceutical Sciences 105 (2016) 460-475.

4. “Click Chemistry” Sigma-Aldrich, 6 July 2018.

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David Zhang, PhD
BroadPharm® is a leading customer-focused biotech company in San Diego, California. We are dedicated to manufacturing and supplying high purity PEG linkers, Click Chemistry Reagents and advanced Bio-labeling reagents such as Dye Labeling and Biotin Labeling compounds to our clients worldwide. In addition, we also offer IP-protected custom synthesis for our clients in the pharmaceutical and biotech industries. We provide timely technical support to address our client’s need and offer technical advice for the best use of our new products. Founded in 2009, BroadPharm® takes our customer needs as our highest priority. We have over 2,000 discrete, high purity PEG reagents in stock which can be shipped to our clients immediately. PEG is an abbreviation for Polyethylene Glycol which consists of repeating ethylene oxide units. Unlike traditional PEGs, all of BroadPharm®’s PEG products represent a specific, single chemical structure with high purity. Each product is synthesized and purified using BroadPharm®’s proprietary advanced technology and characterized by modern NMR and LC/MS. BroadPharm®’s PEG products offer many advantages over traditional linkers such as increased water solubility, reduced aggregation and low immunogenicity. These PEG reagents have been widely used in bioconjugation, antibody-drug conjugates (ADCs) therapeutic, drug delivery and diagnostics field. With our strong expertise in modern chemistry, innovative & novel PEG technology and state-of-the-art equipment, BroadPharm® can help our customers to accelerate their research through cost-effective and efficient solutions.