Mal-PEG2-Val-Cit-amido-PAB-OH

Mal-PEG2-Val-Cit-amido-PAB-OH, is designed to connect a maleimide-bearing handle to a protease- or ubiquitin-ligase recruiting warhead through a PEG spacer and a Val-Cit motif. Its architecture supports efficient conjugation strategies and facilitates formation of degraders that rely on intracellular cleavage to release the active binding element. The linker’s flexible hydrophilic segment and amide-rich connectivity help tune solubility and spatial presentation, and the subsequent sections describe its structure and practical reactivity for PROTAC assembly.

Structure: The linker contains a maleimide functional group for Michael-type conjugation, a PEG spacer that increases hydrophilicity and conformational flexibility, and a Valine–Citrulline cleavage motif embedded within an amide-linked scaffold. An aniline-derived PAB hydroxyl terminus and multiple carbonyl-containing bonds support stable coupling and controlled degradation-triggered release.

Reactivity: The maleimide moiety is suitable for nucleophilic thiol addition under mildly basic aqueous conditions, enabling selective coupling to cysteine-containing ligands or engineered proteins. PEG-associated solubility supports homogeneous reaction mixtures. Subsequent PROTAC construction typically proceeds via amide bond formation using carboxylic acid activation (for example, carbodiimide-mediated coupling) with appropriate amine-bearing partners. Cleavage of the Val-Cit motif follows protease recognition principles, yielding the desired intracellular release behavior.