Broad-Spectrum Antidote Discovery by Untangling the Reactivation Mechanism of Nerve-Agent-Inhibited Acetylcholinesterase

Overview

Journal Chemistry

Specialty Chemistry

Date 2022 Apr 14

PMID 35420233

Authors

Cecilia Lindgren

Nina Forsgren

Norman Hoster

Christine Akfur

Elisabet Artursson

Lotta Edvinsson

Richard Svensson

Franz Worek

Fredrik Ekstrom

Anna Linusson

Affiliations

Soon will be listed here.

Abstract

Reactivators are vital for the treatment of organophosphorus nerve agent (OPNA) intoxication but new alternatives are needed due to their limited clinical applicability. The toxicity of OPNAs stems from covalent inhibition of the essential enzyme acetylcholinesterase (AChE), which reactivators relieve via a chemical reaction with the inactivated enzyme. Here, we present new strategies and tools for developing reactivators. We discover suitable inhibitor scaffolds by using an activity-independent competition assay to study non-covalent interactions with OPNA-AChEs and transform these inhibitors into broad-spectrum reactivators. Moreover, we identify determinants of reactivation efficiency by analysing reactivation and pre-reactivation kinetics together with structural data. Our results show that new OPNA reactivators can be discovered rationally by exploiting detailed knowledge of the reactivation mechanism of OPNA-inhibited AChE.

Citing Articles

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Broad-Spectrum Antidote Discovery by Untangling the Reactivation Mechanism of Nerve-Agent-Inhibited Acetylcholinesterase.

Lindgren C, Forsgren N, Hoster N, Akfur C, Artursson E, Edvinsson L Chemistry. 2022; 28(40):e202200678.

PMID: 35420233 PMC: 9400889. DOI: 10.1002/chem.202200678.

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