The synthetic modification of proteins is a powerful method for enhancing their cellular uptake, reducing immunogenicity, and targeting their delivery to diseased tissues.  However, covalent modification of proteins frequently leads to protein inactivation and there is great interest in the development self-immolative degradable linkages that can be used for protein conjugation. Herein, we report the design and synthesis of a self-immolative linker utilizing a disulfide bond, which is chemically inert during synthetic transformations, and undergoes intracellular sulfhydryl-assisted cleavage to release unmodified proteins.  To demonstrate the feasibility of this method, we first reacted the lysine residues of Cy-5 labeled catalase with a disulfide containing self-immolative linker through a <i>p</i>-nitrophenyl activated terminus, and surprisingly found that cellular uptake was dramatically enhanced.  Kinetic studies were also conducted to understand the rate of free protein release caused by the presence of thiols.  A PEG chain with a self-immolative disulfide bond was also synthesized and conjugated to proteins and peptides, with the goal of extending their circulation half-life, serum stability, and <i>in vivo</i> delivery.  This work demonstrates that thiol cleavable self-immolative linkers can be conjugated to proteins and provides a robust strategy for cargo installation across a diverse range of proteins.

Design and synthesis of thiol cleavable self-immolative linkers and their conjugation to proteins

253rd National Meeting (2017)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.