Iodoacetyl-PEG4-NHS ester

Iodoacetyl-PEG4-NHS ester is a heterobifunctional PEG-based linker designed to connect an NHS-activated targeting moiety with a thiol-reactive iodoacetamide handle, enabling efficient assembly of PROTACs and related targeted degradation constructs. Its PEG spacer supports favorable solubility and conformational flexibility, which can improve conjugation outcomes and the performance of final degraders. The detailed structural and reactivity features are described below.

Structure: The linker contains a PEG spacer terminating in an NHS ester for acyl transfer to nucleophiles, and an iodoacetyl group that forms a reactive iodoacetamide motif. It features stable ether linkages within the PEG chain, with an activated carboxylate and a carbon–iodine electrophile suitable for selective bioconjugation.

Reactivity: The NHS ester typically reacts with primary amines under mild aqueous buffer conditions to form stable amide bonds, while the iodoacetyl group undergoes thiol–alkylation with cysteine-containing ligands or engineered thiols. Conjugation is commonly performed sequentially or in orthogonal order, using controlled pH to preserve NHS activity and protecting thiols from premature consumption. Reaction mixtures are often prepared in compatible aqueous buffers, with careful exclusion of competing nucleophiles and light-sensitive handling of the iodo functionality.