TCO-PEG4-DBCO

TCO-PEG4-DBCO is a bifunctional, polyethylene glycol–based PROTAC linker designed to connect a trans-cyclooctene (TCO) handle to a cyclooctyne (DBCO) partner for efficient bioorthogonal conjugation. Its PEG spacer improves aqueous solubility and spatial accessibility, supporting robust formation of targeted protein-degrading constructs. The linker’s click-type reactivity enables modular assembly of PROTACs under mild conditions, and the detailed structure and reactivity considerations are provided below.

Structure: The molecule contains a flexible PEG spacer that separates two cyclooctene/cyclooctyne-reactive motifs. It features ether linkages within the PEG chain and strained-ring alkene/alkyne functionalities characteristic of TCO and DBCO chemistries. These elements confer water compatibility and promote fast conjugation kinetics.

Reactivity: Suitable PROTAC assembly typically uses strain-promoted inverse electron-demand cycloaddition between TCO and DBCO, proceeding without copper catalysis. Reactions are commonly performed in aqueous or mixed aqueous buffers compatible with cyclooctyne reactivity, with careful control of pH and temperature to preserve functional group integrity. The mechanism relies on ring strain release upon cycloaddition, yielding a stable triazoline/triazole-linked conjugate.