The linker is the variable that a degrader program adjusts most often, because its length and composition set the distance and relative orientation between the recruited E3 ligase and the target protein, and therefore the geometry of the ternary complex on which degradation depends. The same chain also carries much of the molecule's polarity and flexibility, which places it at the center of solubility and permeability optimization. Linker series are consequently built early and revisited throughout a program. Amerigo Scientific offers PEG and alkyl linkers across a range of chain lengths and terminal chemistries, covering direct conjugation, click chemistry assembly, activated leaving groups and protected intermediates for stepwise synthesis.
Bifunctional PEG Linkers
A linker bearing a different reactive group at each end allows the two halves of a degrader to be attached in sequence rather than simultaneously, which keeps each coupling step selective. Amine and carboxylic acid termini cover amide bond formation at both ends, hydroxyl termini allow etherification or further activation, and tert-butyl esters mask a carboxylic acid until acid treatment releases it, so that the free amine can be coupled first.
Our product portfolio features amino-PEG linkers ranging from PEG1 to PEG6 with acid, alcohol, and tert-butyl ester termini, alongside a symmetrical bis-acid PEG8 linker for longer spacing and a general purpose PROTAC linker.
| Type | Product |
|---|---|
| Flexible PEG linker (amine-terminated) | Amino-PEG1-t-butyl ester |
| Amino-PEG2-acid | |
| Amino-PEG2-t-butyl ester | |
| Amino-PEG3-acid | |
| Amino-PEG3-alcohol | |
| Amino-PEG3-t-butyl ester | |
| Amino-PEG4-acid | |
| Amino-PEG4-alcohol | |
| Amino-PEG4-t-butyl ester | |
| Amino-PEG5-alcohol | |
| Amino-PEG6-alcohol | |
| Dual-reactive linker (homobifunctional) | Bis-PEG8-acid |
| Universal linker | PROTAC Linker 4 |
Applications
- Stepwise assembly of PROTAC molecules
- Linker length series construction
- Amide coupling at both termini
- Solubility and flexibility adjustment
Click Chemistry Linkers
Azide and alkyne partners react with each other and leave the other functional groups in a molecule untouched, which makes click chemistry the practical route to parallel synthesis of a linker series. Copper-catalyzed reactions pair an azide with a terminal alkyne, while strained cyclooctynes such as DBCO and BCN react with azides in the absence of copper, which suits sensitive substrates and biological samples.
Amerigo Scientific provides azido-PEG linkers from PEG2 to PEG6 carrying amine, acid, alcohol and bromide groups at the opposite terminus, together with cyclooctyne linkers activated as NHS esters for coupling to amines.
| Type | Product | Description |
|---|---|---|
| Click chemistry linkers (azide, amine terminus) | Azido-PEG2-amine | Azide-PEG linkers with a primary amine at the opposite terminus. The amine end is coupled to a ligand by amidation and the azide end is assembled by CuAAC or SPAAC click chemistry |
| Azido-PEG4-amine | ||
| Amino-PEG4-Azide | ||
| Click chemistry linkers (azide, hydroxyl terminus) | Azido-PEG2-alcohol | Azide-PEG linkers with a free hydroxyl for etherification or further activation, available from PEG2 to PEG6 for linker length series |
| Azido-PEG3-alcohol | ||
| Azido-PEG4-alcohol | ||
| Azido-PEG5-alcohol | ||
| Azido-PEG6-alcohol | ||
| Click chemistry linkers (azide, carboxylic acid terminus) | Azido-PEG2-CH2CO2H | Azide-PEG linkers with a carboxylic acid terminus for amide coupling to an amine-bearing ligand, combined with click assembly at the azide end |
| Azido-PEG3-acid | ||
| Azido-PEG3-CH2CO2H | ||
| Azido-PEG4-acid | ||
| Click chemistry linkers (azide, electrophilic terminus) | Bromo-PEG2-azide | Bifunctional PEG carrying a bromide and an azide, allowing alkylation first and click assembly second |
| Strained cyclooctyne linkers | endo-BCN-PEG4-NHS ester | Cyclooctyne and NHS ester termini for copper-free click chemistry (SPAAC) with azides combined with amine coupling, suited to live cell and protein systems |
| DBCO-PEG4-NHS Ester |
Applications
- Modular assembly of degrader libraries
- Parallel synthesis of linker length series
- Copper-free conjugation for sensitive substrates
- Amine coupling combined with click assembly
Activated and Thiol-Reactive Linkers
Some couplings are better served by a leaving group than by an activated carbonyl. Sulfonate esters convert a hydroxyl terminus into an electrophilic site for substitution by amines, thiols and other nucleophiles, which is the standard route for attaching a linker to a phenol or a secondary amine on a ligand. Maleimides address free cysteine residues and other thiols, and react selectively at near-neutral pH.
The tosylate-activated PEG linkers are available from PEG2 to PEG5 with a tert-butyl ester at the opposite terminus, and a maleimide-functionalized alkyl acid for thiol conjugation.
| Type | Product | Description |
|---|---|---|
| Thiol-reactive linkers | 6-Maleimidocaproic acid | Maleimide-alkyl acid for thiol-directed conjugation |
| Sulfonate ester linkers (leaving group) | Tos-PEG2-t-butyl ester | Tosylate-activated PEG acting as an electrophile in etherification and amination couplings |
| Tos-PEG3-t-butyl ester | ||
| Tos-PEG4-t-butyl ester | ||
| Tos-PEG5-t-butyl ester |
Applications
- Alkylation of phenols and amines on ligands
- Attachment where amide coupling is unavailable
- Thiol-directed conjugation
- Orthogonal two-step assembly
Protected and Capped Linkers
Building a degrader in a controlled order requires that one terminus stays unreactive while the other is coupled. Boc and Fmoc groups mask an amine and are removed under acidic and basic conditions respectively, tert-butyl esters mask an acid, and each pairs with the others in an orthogonal deprotection scheme. Capped linkers serve a different purpose, since a methoxy terminus leaves only one reactive end and adjusts chain length and hydrophilicity without extending the conjugation.
Available in our catalog are Boc- and Fmoc-protected amino-PEG linkers, hydroxy-PEG tert-butyl esters, methoxy-capped PEG linkers with amine, acid and alcohol termini, and a biotinylated PEG linker for affinity applications.
| Type | Product | Description |
|---|---|---|
| Protected linkers (synthetic intermediates) | Fmoc-N-amido-PEG3-acid | Fmoc-protected amino-PEG acid, suited to stepwise and solid phase synthesis. The base-labile Fmoc group is orthogonal to acid-labile Boc and tert-butyl protection |
| Hydroxy-PEG2-t-butyl ester | Hydroxyl-PEG tert-butyl esters. Acidolysis removes the ester and releases the carboxylic acid terminus | |
| Hydroxy-PEG3-t-butyl ester | ||
| Hydroxy-PEG4-t-butyl ester | ||
| N-Boc-PEG2-alcohol | Boc-protected amino-PEG alcohols, available from PEG2 to PEG6. The hydroxyl end is coupled first and Boc removal then releases the primary amine for the second coupling | |
| N-Boc-PEG3-alcohol | ||
| N-Boc-PEG4-alcohol | ||
| N-Boc-PEG5-alcohol | ||
| N-Boc-PEG6-alcohol | ||
| NH2-PEG3-C1-Boc | One free primary amine and one Boc-protected amine, allowing the order of the two couplings to be controlled | |
| Capped PEG (chain length and property modulation) | m-PEG3-amine | Methoxy-capped PEG with a single reactive terminus, for adjusting physicochemical properties and for constructing negative control molecules |
| m-PEG4-acid | ||
| m-PEG6-alcohol | ||
| Labeled linkers | Biotin-PEG7-amine | Biotinylated PEG for affinity enrichment, target occupancy and mechanism of action studies |
Applications
- Stepwise synthesis with orthogonal deprotection
- Solid phase and fragment-based assembly
- Chain length and hydrophilicity adjustment
- Affinity enrichment and target engagement studies
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