TCO-C3-PEG3-C3-amine

TCO-C3-PEG3-C3-amine is a bifunctional PROTAC linker designed to connect targeting ligands through a PEG-based spacer while providing a reactive amine handle for subsequent conjugation. Its flexible, hydrophilic PEG segment can help tune solubility and spatial presentation of the binding motifs, supporting efficient ternary complex formation in targeted protein degradation workflows. The detailed Structure and Reactivity considerations for constructing PROTACs with this linker are provided below.

Structure: The linker comprises a trans-cyclooctene (TCO) moiety linked through short alkyl spacers to a triethylene glycol–type PEG segment, terminating in a primary amine. It contains carbon–carbon and carbon–nitrogen bonds, an ether-rich PEG chain, and a strained olefin suitable for bioorthogonal reactivity, contributing to favorable aqueous compatibility.

Reactivity: The TCO group is commonly used in strain-promoted inverse-electron-demand cycloaddition with tetrazines, enabling rapid, catalyst-free conjugation under mild aqueous conditions. The terminal amine supports amide-bond formation via activated carboxylic acids or NHS/EDC-type coupling strategies, typically in buffered organic/aqueous mixtures. For PROTAC assembly, ligation steps are often sequenced to preserve TCO integrity until the final tetrazine-mediated step.