Linker (peptide synthesis)
Peptide synthesis molecule
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In solid phase peptide synthesis, a linker is a molecule that connects the solid phase (a beaded resin support) to the growing peptide chain. The linker is often permanently attached to the solid phase, but carries a transient covalent bond to the peptide (typically its C-terminus) that can be cleaved after completion of the synthesis to release the peptide. Cleavage can take place under various conditions depending on the linker type and result in different C-terminal functionalities of the released peptide, e.g. amides,[1] carboxylic acids,[2] esters,[3] lactams,[4] etc. Linkers that do not attach via the C-terminus do also exist.
Examples
| Linker | First reported use | C-Terminal outcome | Protecting group chemistry | Stability to deprotection conditions | Typical cleavage conditions |
|---|---|---|---|---|---|
| Merrifield | 1963 | Carboxylic acid | Boc | Unstable in neat TFA | Anhydrous HF |
| Rink Amide | 1987 | Amide | Fmoc | Stable to 20% piperidine | 95% TFA in dichloromethane |
| Wang | 1973 | Carboxylic acid | Fmoc | Stable to 20% piperidine | 50-95% TFA in dichloromethane |
| Sieber | 1987 | Amide | Fmoc | Stable to 20% piperidine | 1-5% TFA in dichloromethane |
| 4-(Hydroxymethyl)benzoic acid | 1981 | Carboxylic acid, amide, ester, lactam, etc. (depends on cleavage conditions)[5][3][4] | Fmoc | Stable to 20% piperidine (diketopiperazine formation risk after deprotection of 2nd amino acid) | Nucleophilic base |
| o-Nitrobenzyl | 1975 | Amide | Fmoc | Stable to TFA and 20% piperidine | UV light[6] |
