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Broad-Spectrum Anti...
Broad-Spectrum Antidote Discovery by Untangling the Reactivation Mechanism of Nerve-Agent-Inhibited Acetylcholinesterase
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- Lindgren, Cecilia (author)
- Umeå universitet,Kemiska institutionen,Umeå Univ, Dept Chem, S-90187 Umeå, Sweden
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- Forsgren, Nina (author)
- CBRN Defense and Security, Swedish Defense Research Agency, Umeå, Sweden,Swedish Def Res Agcy, CBRN Def & Secur, S-90621 Umeå, Sweden
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- Hoster, Norman (author)
- Umeå universitet,Kemiska institutionen,Umeå Univ, Dept Chem, S-90187 Umeå, Sweden
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- Akfur, Christine (author)
- CBRN Defense and Security, Swedish Defense Research Agency, Umeå, Sweden,Swedish Def Res Agcy, CBRN Def & Secur, S-90621 Umeå, Sweden
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- Artursson, Elisabet (author)
- CBRN Defense and Security, Swedish Defense Research Agency, Umeå, Sweden,Swedish Def Res Agcy, CBRN Def & Secur, S-90621 Umeå, Sweden
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- Edvinsson, Lotta (author)
- Umeå universitet,Kemiska institutionen,Umeå Univ, Dept Chem, S-90187 Umeå, Sweden
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- Svensson, Richard (author)
- Uppsala universitet,Institutionen för farmaci,Science for Life Laboratory, SciLifeLab
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- Worek, Franz (author)
- Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany,Bundeswehr Inst Pharmacol & Toxicol, D-80937 Munich, Germany
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- Ekström, Fredrik (author)
- CBRN Defense and Security, Swedish Defense Research Agency, Umeå, Sweden,Swedish Def Res Agcy, CBRN Def & Secur, S-90621 Umeå, Sweden
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- Linusson, Anna, 1970- (author)
- Umeå universitet,Kemiska institutionen,Umeå Univ, Dept Chem, S-90187 Umeå, Sweden
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(creator_code:org_t)
- 2022-06-07
- 2022
- English.
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In: Chemistry - A European Journal. - : John Wiley & Sons. - 0947-6539 .- 1521-3765. ; 28:40
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Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
Keyword
- drug design
- kinetics
- nerve agent antidotes
- reaction mechanisms
- structural biology
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Lindgren, Cecili ...
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Forsgren, Nina
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Hoster, Norman
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Akfur, Christine
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Artursson, Elisa ...
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Edvinsson, Lotta
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Svensson, Richar ...
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Worek, Franz
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Ekström, Fredrik
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Linusson, Anna, ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Pharmacology and ...
- Articles in the publication
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Chemistry - A Eu ...
- By the university
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Umeå University
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Uppsala University