Walz AJ

References (2)

Title : Synthesis and Molecular Properties of Nerve Agent Reactivator HLo-7 Dimethanesulfonate - Hsu_2019_ACS.Med.Chem.Lett_10_761
Author(s) : Hsu FL , Bae SY , McGuire J , Anderson DR , Bester SM , Height JJ , Pegan SD , Walz AJ
Ref : ACS Med Chem Lett , 10 :761 , 2019
Abstract : The threat of a deliberate release of chemical nerve agents has underscored the need to continually improve field effective treatments for these types of poisonings. The oxime containing HLo-7 is a potential second-generation therapeutic reactivator. A synthetic process for HLo-7 is detailed with improvements to the DIBAL reduction and ion exchange steps. HLo-7 was visualized for the first time within the active site of human acetylcholinesterase and its relative ex vivo potency confirmed against various nerve agents using a phrenic nerve hemidiaphragm assay.
ESTHER : Hsu_2019_ACS.Med.Chem.Lett_10_761
PubMedSearch : Hsu_2019_ACS.Med.Chem.Lett_10_761
PubMedID: 31097996
Gene_locus related to this paper: human-ACHE

Title : Activity Based Protein Profiling Leads to Identification of Novel Protein Targets for Nerve Agent VX - Carmany_2017_Chem.Res.Toxicol_30_1076
Author(s) : Carmany D , Walz AJ , Hsu FL , Benton B , Burnett D , Gibbons J , Noort D , Glaros T , Sekowski JW
Ref : Chemical Research in Toxicology , 30 :1076 , 2017
Abstract : Organophosphorus (OP) nerve agents continue to be a threat at home and abroad during the war against terrorism. Human exposure to nerve agents such as VX results in a cascade of toxic effects relative to the exposure level including ocular miosis, excessive secretions, convulsions, seizures, and death. The primary mechanism behind these overt symptoms is the disruption of cholinergic pathways. While much is known about the primary toxicity mechanisms of nerve agents, there remains a paucity of information regarding impacts on other pathways and systemic effects. These are important for establishing a comprehensive understanding of the toxic mechanisms of OP nerve agents. To identify novel proteins that interact with VX, and that may give insight into these other mechanisms, we used activity-based protein profiling (ABPP) employing a novel VX-probe on lysates from rat heart, liver, kidney, diaphragm, and brain tissue. By making use of a biotin linked VX-probe, proteins covalently bound by the probe were isolated and enriched using streptavidin beads. The proteins were then digested, labeled with isobarically distinct tandem mass tag (TMT) labels, and analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS). Quantitative analysis identified 132 bound proteins, with many proteins found in multiple tissues. As with previously published ABPP OP work, monoacylglycerol lipase associated proteins and fatty acid amide hydrolase (FAAH) were shown to be targets of VX. In addition to these two and other predicted neurotransmitter-related proteins, a number of proteins involved with energy metabolism were identified. Four of these enzymes, mitochondrial isocitrate dehydrogenase 2 (IDH2), isocitrate dehydrogenase 3 (IDH3), malate dehydrogenase (MDH), and succinyl CoA (SCS) ligase, were assayed for VX inhibition. Only IDH2 NADP+ activity was shown to be inhibited directly. This result is consistent with other work reporting animals exposed to OP compounds exhibit reduced IDH activity. Though clearly a secondary mechanism for toxicity, this is the first time VX has been shown to directly interfere with energy metabolism. Taken together, the ABPP work described here suggests the discovery of novel protein-agent interactions, which could be useful for the development of novel diagnostics or potential adjuvant therapeutics.
ESTHER : Carmany_2017_Chem.Res.Toxicol_30_1076
PubMedSearch : Carmany_2017_Chem.Res.Toxicol_30_1076
PubMedID: 28267914