Chemical zymogens for the protein cysteinome

Mireia Casanovas Montasell, Pere Monge, Sheiliza Carmali, Livia Mesquita Dias Loiola, Dante Guldbrandsen Andersen, Kaja Borup Løvschall, Ane Bretschneider Søgaard, Maria Merrild Kristensen, Jean Maurice Pütz and Alexander N. Zelikin ()
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Mireia Casanovas Montasell: Aarhus University
Pere Monge: Aarhus University
Sheiliza Carmali: Aarhus University
Livia Mesquita Dias Loiola: Aarhus University
Dante Guldbrandsen Andersen: Aarhus University
Kaja Borup Løvschall: Aarhus University
Ane Bretschneider Søgaard: Aarhus University
Maria Merrild Kristensen: Aarhus University
Jean Maurice Pütz: Aarhus University
Alexander N. Zelikin: Aarhus University

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-32609-1

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