Mechanisms of Degradation for Polydisulfides: Main Chain Scission, Self-Immolation, Or Chain Transfer Depolymerization.

Organic polydisulfides hold immense potential for the design of recyclable materials. Of these, polymers based on lipoic acid are attractive, as they are based on a natural, renewable resource. Herein, we demonstrate that reductive degradation of lipoic acid polydisulfides is a rapid process whereby the quantity of added initiator relative to the polymer content defines the mechanism of polymer degradation, through the main chain scission, self-immolation, or "chain transfer" depolymerization. The latter mechanism is defined as the one during which a thiol group released through the decomposition of one polydisulfide chain initiates depolymerization of the neighbor macromolecule. The chain transfer mechanism afforded the highest yields of recovery of the monomer in its pristine form, and just one molecule of the reducing agent to initiate polymer degradation afforded recovery of over 50% of the monomer. These data are important to facilitate the development of polymer recycling and monomer reuse schemes.

Chemical zymogens for the protein cysteinome.

We present three classes of chemical zymogens established around the protein cysteinome. In each case, the cysteine thiol group was converted into a mixed disulfide: with a small molecule, a non-degradable polymer, or with a fast-depolymerizing fuse polymer (ZLA). The latter was a polydisulfide based on naturally occurring molecule, lipoic acid. Zymogen designs were applied to cysteine proteases and a kinase. In each case, enzymatic activity was successfully masked in full and reactivated by small molecule reducing agents. However, only ZLA could be reactivated by protein activators, demonstrating that the macromolecular fuse escapes the steric bulk created by the protein globule, collects activation signal in solution, and relays it to the active site of the enzyme. This afforded first-in-class chemical zymogens that are activated via protein-protein interactions. We also document zymogen exchange reactions whereby the polydisulfide is transferred between the interacting proteins via the "chain transfer" bioconjugation mechanism.