Synthesis of methylating ligands that reactivate aged acetylcholinesterase

合成重新激活老化乙酰胆碱酯酶的甲基化配体

• 批准号: 8216466
• 负责人: Daniel M Quinn
• 金额: $ 30.2万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8216466
• 关键词: Acetylcholinesterase; Active Sites; Acute; Address; Antidotes; Binding; Catalysis; Chemical Warfare Agents; Dealkylation; Development; Enzyme Inhibition; Enzymes; Evaluation; Health; Lead; Ligands; Nerve; Neuromuscular Junction; Oximes; Peripheral Nervous System; Pharmaceutical Preparations; Poison; Predisposition; Reaction; Recovery; Risk; Sarin; Security; Serine; Societies; Soman; Toxic effect; Work; adduct; aged; design; enzyme activity; improved; nerve agent; success

DESCRIPTION (provided by applicant): Organophosphorus (OP) chemical warfare agents, such as sarin and soman, are acutely toxic compounds that act by inhibiting the activity of the enzyme acetylcholinesterase (AChE) at nerve-nerve and neuromuscular junctions in the central and peripheral nervous systems, respectively. Inhibition of the enzyme occurs by phosphylation of the active site serine nucleophile that is normally involved in catalysis. Prompt administration of oximes can lead to dephosphylation of the phosphyl-AChE adduct and hence is an antidote strategy. However, and particularly with the chemical warfare agent soman, the initial phosphyl-AChE adduct undergoes a dealkylation reaction that leads to what is called the aged adduct, for which there is no known antidote. This application proposes to address this perplexing problem by synthesis and evaluation of AChE ligands that can bind in the active site of the aged enzyme adduct, and subsequently serve as methyl transfer agents to realkylate the aged enzyme. This in turn will resurrect the susceptibility of the adduct to nucleophilic dephosphylation by oximes and hence lead to recovery of enzyme activity. Success in this endeavor should therefore open the door to the development of efficacious drugs for antidote therapy against currently intractable OP chemical warfare agents. PUBLIC HEALTH RELEVANCE: This application endeavors to synthesize and evaluate ligands of the enzyme acetylcholinesterase that can serve as antidotes against organophosphorus (OP) chemical warfare agents. This work is motivated by the concern that terrorist organizations may aspire to inflict mass casualties by use of these agents. It is anticipated that as OP agent antidote therapy improves, the health and security risks that these agents pose to our society will be ameliorated.

描述（由申请人提供）：有机磷（OP）化学战剂，例如沙林和梭曼，是剧毒化合物，通过抑制中枢和外周神经-神经和神经肌肉接头处乙酰胆碱酯酶（AChE）的活性发挥作用。分别是神经系统。该酶的抑制是通过通常参与催化的活性位点丝氨酸亲核体的磷酸化而发生的。及时给药 肟的合成可导致磷酰基-AChE 加合物脱磷，因此是一种解毒剂策略。然而，特别是对于化学战剂梭曼，最初的磷酰基-乙酰胆碱酯酶加合物会发生脱烷基化反应，形成所谓的老化加合物，对此没有已知的解毒剂。本申请提出通过合成和评估AChE配体来解决这个令人困惑的问题，该配体可以结合在老化酶加合物的活性位点上，并随后充当甲基转移剂以将老化酶重新烷基化。这反过来将恢复加合物对肟亲核脱磷作用的敏感性，从而导致酶活性的恢复。因此，这一努力的成功将为开发针对目前棘手的OP化学战剂的解毒疗法的有效药物打开大门。 公共健康相关性：该应用致力于合成和评估乙酰胆碱酯酶的配体，该配体可作为有机磷（OP）化学战剂的解毒剂。这项工作的动机是担心恐怖组织可能会利用这些制剂造成大规模伤亡。预计随着 OP 剂解毒疗法的改进，这些剂对我们社会造成的健康和安全风险将得到改善。