“Chemical zymogens: specificity and steroidal control of
Abstract: Activation and masking of enzymatic activity on demand is of the highest importance in nature. It is achieved via chemical interconversion of enzymes and the corresponding zymogens through, for example, proteolytic processing or reversible phosphorylation, and affords on-demand activation of enzymes, controlled in space and/or time. In stark contrast, examples of chemical zymogens are very few, and in most cases these are based on the disulfide chemistry, which is largely indiscriminate to the nature of the activating thiol. In this work, we address an outstanding challenge of specificity of reactivation of chemical zymogens. We achieve this through engineering affinity between the chemical zymogen and the activator. Additional, higher level control over zymogen reactivation is installed in a naturemimicking approach using steroidal hormones. Taken together, results of this study take a step towards establishing specificity of reactivation of synthetic, chemical zymogens. We anticipate that results of this study contribute significantly to the development of chemical zymogens as tools for diverse use in chemical biology and biotechnology.