TCO-PEG6-NHS ester

TCO-PEG6-NHS ester is a bifunctional PROTAC linker designed to combine a strained trans-cyclooctene (TCO) handle for bioorthogonal ligation with an NHS-activated ester for efficient coupling to primary amines. Its PEG-based spacer supports favorable solubility and linker flexibility, which can improve conjugation performance and maintain productive geometry in targeted protein degradation workflows. Detailed structural and reactivity considerations for PROTAC construction are provided below.

Structure: The molecule contains an NHS-activated carboxylate for acylation of amines and a trans-cyclooctene moiety suitable for rapid cycloaddition with tetrazines. A PEG-based chain provides a flexible hydrophilic spacer, with ester and ether linkages contributing to aqueous compatibility and reduced aggregation.

Reactivity: The NHS ester reacts with nucleophilic primary amines via acyl substitution, typically under mildly basic aqueous buffer conditions to form stable amide bonds. The TCO group undergoes strain-promoted inverse-electron-demand Diels–Alder cycloaddition with tetrazines, enabling fast, chemoselective conjugation without catalysts. Common solvents include buffered aqueous media with compatible organic co-solvents when needed to maintain solubility.