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

Lindgren, CeciliaUmeå universitet,Kemiska institutionen,Umeå Univ, Dept Chem, S-90187 Umeå, Sweden (författare)

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.

Forsgren, NinaCBRN Defense and Security, Swedish Defense Research Agency, Umeå, Sweden,Swedish Def Res Agcy, CBRN Def & Secur, S-90621 Umeå, Sweden (författare)
Hoster, NormanUmeå universitet,Kemiska institutionen,Umeå Univ, Dept Chem, S-90187 Umeå, Sweden(Swepub:umu)noho0008 (författare)
Akfur, ChristineCBRN Defense and Security, Swedish Defense Research Agency, Umeå, Sweden,Swedish Def Res Agcy, CBRN Def & Secur, S-90621 Umeå, Sweden (författare)
Artursson, ElisabetCBRN Defense and Security, Swedish Defense Research Agency, Umeå, Sweden,Swedish Def Res Agcy, CBRN Def & Secur, S-90621 Umeå, Sweden (författare)
Edvinsson, LottaUmeå universitet,Kemiska institutionen,Umeå Univ, Dept Chem, S-90187 Umeå, Sweden (författare)
Svensson, RichardUppsala universitet,Institutionen för farmaci,Science for Life Laboratory, SciLifeLab(Swepub:uu)ricsv977 (författare)
Worek, FranzBundeswehr Institute of Pharmacology and Toxicology, Munich, Germany,Bundeswehr Inst Pharmacol & Toxicol, D-80937 Munich, Germany (författare)
Ekström, FredrikCBRN Defense and Security, Swedish Defense Research Agency, Umeå, Sweden,Swedish Def Res Agcy, CBRN Def & Secur, S-90621 Umeå, Sweden (författare)
Linusson, Anna,1970-Umeå universitet,Kemiska institutionen,Umeå Univ, Dept Chem, S-90187 Umeå, Sweden(Swepub:umu)analin99 (författare)
Umeå universitetKemiska institutionen (creator_code:org_t)

Ingår i:Chemistry - A European Journal: John Wiley & Sons28:400947-65391521-3765

Av författaren/redakt...: Lindgren, Cecili ...; Forsgren, Nina; Hoster, Norman; Akfur, Christine; Artursson, Elisa ...; Edvinsson, Lotta; visa fler...; Svensson, Richar ...; Worek, Franz; Ekström, Fredrik; Linusson, Anna, ...; visa färre...

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MEDICIN OCH HÄLSOVETENSKAP: MEDICIN OCH HÄLS ...; och Medicinska och f ...; och Farmakologi och ...

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