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As more lethal nerve agents\u2014such as A-agents\u2014continue to emerge, the existing arsenal of causal antidotes remains unchanged. Approved oxime reactivators\u2014\n                    <jats:bold>2-PAM<\/jats:bold>\n                    ,\n                    <jats:bold>HI-6<\/jats:bold>\n                    , and\n                    <jats:bold>L\u00fcH-6<\/jats:bold>\n                    \u2014are restricted by their limited efficacy spectrum, poor blood\u2013brain barrier permeability, and suboptimal pharmacokinetics. The objective of this study is to design, synthesize, and characterize a new class of asymmetric monoquaternary bisoxime reactivators with broad-spectrum reactivation potential, favorable pharmacokinetics, and dual mechanisms of action\u2014cholinesterase reactivation and direct OP compound degradation. In vitro and in vivo experiments identified\n                    <jats:bold>LG-1795<\/jats:bold>\n                    as the lead candidate with the broadest OP spectrum. The averaged second-order reactivation constant (\n                    <jats:italic>k<\/jats:italic>\n                    <jats:sub>\n                      <jats:italic>r2<\/jats:italic>\n                    <\/jats:sub>\n                    ) across five\n                    <jats:italic>h<\/jats:italic>\n                    AChE\u2013OP and two\n                    <jats:italic>h<\/jats:italic>\n                    BChE-OP complexes was 16.8\u00a0mM\n                    <jats:sup>\u22121<\/jats:sup>\n                    \u00a0min\n                    <jats:sup>\u22121<\/jats:sup>\n                    , surpassing clinical standards. Notably,\n                    <jats:bold>LG-1795<\/jats:bold>\n                    reactivated both AChE and BChE, a dual activity not previously reported for reactivators. In vivo,\n                    <jats:bold>LG-1795<\/jats:bold>\n                    restored both cholinesterase enzymes and demonstrated prophylactic efficacy against GB, VX, and PXE following intramuscular administration, preventing symptoms in sarin-poisoned animals. These findings represent a significant advance in antidotal therapy, providing the first evidence that asymmetric monoquaternary bisoximes deliver broad-spectrum efficacy against nerve agents and pesticides while simultaneously targeting both OP-inhibited cholinesterases. The translational potential of\n                    <jats:bold>LG-1795<\/jats:bold>\n                    supports its further preclinical development as a next-generation countermeasure for both clinical and regulatory use in chemical defense.\n                  <\/jats:p>","DOI":"10.1007\/s00204-026-04341-y","type":"journal-article","created":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T10:48:44Z","timestamp":1773658124000},"page":"2467-2502","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Next-generation broad-spectrum reactivators for effective countermeasure against organophosphorus poisoning"],"prefix":"10.1007","volume":"100","author":[{"given":"Jana","family":"Zdarova Karasova","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Hrabinova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alzbeta","family":"Dlabkova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vendula","family":"Hepnarova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie","family":"Zivna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monika","family":"Schmidt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Sheshko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carilyn","family":"Torruellas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jakub","family":"Opravil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lukas","family":"Prchal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie","family":"Vanova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jakub","family":"Fibigar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zbynek","family":"Vecera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomas","family":"Kucera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaroslav","family":"Chladek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriele","family":"Horn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franz","family":"Worek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Marek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaroslav","family":"Pejchal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Jun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ondrej","family":"Soukup","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Korabecny","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4791-6556","authenticated-orcid":false,"given":"Lukas","family":"Gorecki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,16]]},"reference":[{"key":"4341_CR1","doi-asserted-by":"publisher","unstructured":"Abraham M, Alekseenko A, Basov V, et al (2024) GROMACS 2024.3 Manual. https:\/\/doi.org\/10.5281\/zenodo.13457083","DOI":"10.5281\/zenodo.13457083"},{"key":"4341_CR2","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1016\/j.cbi.2016.04.036","volume":"259","author":"G Amitai","year":"2016","unstructured":"Amitai G, Gez R, Raveh L et al (2016) Novel bifunctional hybrid small molecule scavengers for mitigating nerve agents toxicity. 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