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<p>Sustained effort has been dedicated to the development of novel cholinesterase reactivators—the only causal antidotes—to counter organophosphorus (OP) intoxication. As more lethal nerve agents—such as A-agents—continue to emerge, the existing arsenal of causal antidotes remains unchanged. Approved oxime reactivators—<b>2-PAM</b>, <b>HI-6</b>, and <b>LüH-6</b>—are restricted by their limited efficacy spectrum, poor blood–brain 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—cholinesterase reactivation and direct OP compound degradation. In vitro and in vivo experiments identified <b>LG-1795</b> as the lead candidate with the broadest OP spectrum. The averaged second-order reactivation constant (<i>k</i><sub><i>r2</i></sub>) across five <i>h</i>AChE–OP and two <i>h</i>BChE-OP complexes was 16.8&#xa0;mM<sup>−1</sup>&#xa0;min<sup>−1</sup>, surpassing clinical standards. Notably, <b>LG-1795</b> reactivated both AChE and BChE, a dual activity not previously reported for reactivators. In vivo, <b>LG-1795</b> 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 <b>LG-1795</b> supports its further preclinical development as a next-generation countermeasure for both clinical and regulatory use in chemical defense.</p>

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Next-generation broad-spectrum reactivators for effective countermeasure against organophosphorus poisoning

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月16日

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  • Jana Zdarova Karasova,
  • Martina Hrabinova,
  • Alzbeta Dlabkova,
  • Vendula Hepnarova,
  • Natalie Zivna,
  • Monika Schmidt,
  • Valeria Sheshko,
  • Carilyn Torruellas,
  • Jakub Opravil,
  • Lukas Prchal,
  • Natalie Vanova,
  • Jakub Fibigar,
  • Zbynek Vecera,
  • Tomas Kucera,
  • Jaroslav Chladek,
  • Gabriele Horn,
  • Franz Worek,
  • Jan Marek,
  • Jaroslav Pejchal,
  • Daniel Jun,
  • Ondrej Soukup,
  • Jan Korabecny,
  • Lukas Gorecki

摘要

Sustained effort has been dedicated to the development of novel cholinesterase reactivators—the only causal antidotes—to counter organophosphorus (OP) intoxication. As more lethal nerve agents—such as A-agents—continue to emerge, the existing arsenal of causal antidotes remains unchanged. Approved oxime reactivators—2-PAM, HI-6, and LüH-6—are restricted by their limited efficacy spectrum, poor blood–brain 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—cholinesterase reactivation and direct OP compound degradation. In vitro and in vivo experiments identified LG-1795 as the lead candidate with the broadest OP spectrum. The averaged second-order reactivation constant (kr2) across five hAChE–OP and two hBChE-OP complexes was 16.8 mM−1 min−1, surpassing clinical standards. Notably, LG-1795 reactivated both AChE and BChE, a dual activity not previously reported for reactivators. In vivo, LG-1795 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 LG-1795 supports its further preclinical development as a next-generation countermeasure for both clinical and regulatory use in chemical defense.