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Reversal of Tabun Toxicity Enabled by a Triazole-Annulated Oxime Library—Reactivators of Acetylcholinesterase |
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| Authors: | Dr Zrinka Kovarik Dr Jaros?aw Kalisiak Dr Nikolina Ma?ek Hrvat Dr Maja Katalini? Dr Tamara Zorbaz Dr Suzana ?unec Dr Carol Green Dr Zoran Radi? Dr Valery V Fokin Prof K Barry Sharpless Prof Palmer Taylor |
| Institution: | 1. Institute for Medical Research and Occupational Health, HR-10000 Zagreb, Croatia;2. Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, 92037 USA
These authors contributed equally to this work.;3. SRI International, Menlo Park, CA, 94025-3493 USA;4. Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, CA, 92093-0650 USA;5. Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, 92037 USA The Bridge@USC, University of Southern California, Los Angeles, CA, 90089 USA;6. Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, 92037 USA |
| Abstract: | Acetylcholinesterase (AChE), an enzyme that degrades the neurotransmitter acetylcholine, when covalently inhibited by organophosphorus compounds (OPs), such as nerve agents and pesticides, can be reactivated by oximes. However, tabun remains among the most dangerous nerve agents due to the low reactivation efficacy of standard pyridinium aldoxime antidotes. Therefore, finding an optimal reactivator for prophylaxis against tabun toxicity and for post-exposure treatment is a continued challenge. In this study, we analyzed the reactivation potency of 111 novel nucleophilic oximes mostly synthesized using the CuAAC triazole ligation between alkyne and azide building blocks. We identified several oximes with significantly improved in vitro reactivating potential for tabun-inhibited human AChE, and in vivo antidotal efficacies in tabun-exposed mice. Our findings offer a significantly improved platform for further development of antidotes and scavengers directed against tabun and related phosphoramidate exposures, such as the Novichok compounds. |
| Keywords: | acetylcholinesterase biochemistry heterocycles nerve agents organophosphate antidotes |