Loading…

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 (Z LA ). The latter was a polydisulfide ba...

Full description

Saved in:
Bibliographic Details
Published in:Nature communications 2022-08, Vol.13 (1), p.4861-4861, Article 4861
Main Authors: Montasell, Mireia Casanovas, Monge, Pere, Carmali, Sheiliza, Dias Loiola, Livia Mesquita, Andersen, Dante Guldbrandsen, Løvschall, Kaja Borup, Søgaard, Ane Bretschneider, Kristensen, Maria Merrild, Pütz, Jean Maurice, Zelikin, Alexander N.
Format: Article
Language:English
Subjects:
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 (Z LA ). 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 Z LA 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. Reversible on/off switches for enzyme activity are foundational in nature but are challenging to design using tools of synthetic chemistry. Here the authors design chemical zymogens amenable for activation via biomolecular interactions.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-022-32609-1