Abstract:

In this work, we use self-immolative polymers as an antenna to communicate chemical signals to achieve protein-protein communication. Specifically, we focus on the polydisulfide based on an endogenous compound, lipoic acid (PDS LA). This polymer is water soluble and to our knowledge, the only self-immolative polymer based on a natural metabolite. We demonstrate a further unique property of PDS LA, since it degrades via two distinctly different mechanisms, namely main chain degradation or self-immolation, depending on the stoichiometry of the reducing agent used to trigger polymer decomposition. Most impressively, full polymer decomposition was rapid and came to completion within minutes. LA PDS was reacted to a cysteinyl protease to afford protein-polymer conjugates via a “chain transfer” conjugation, previously only observed in nature but not on synthetic polymers. Resulting conjugates were devoid of enzymatic activity but could reveal it upon polymer degradation, thus comprising a zymogen. LA PDS effectively reacted with thiol-containing proteins in solution and through self-immolation, communicated this chemical information to the protein active site, registered through renewed enzymatic activity of the protein. Design of a chemical zymogen which can be activated by protein-activators as well as the transfer of chemical information using self-immolative polymers are novel tools with utility in biotechnology and bioengineering