Oxime-Assisted Catalysis of Organophosphates and Reactivation of AChE

有机磷酸酯的肟辅助催化和乙酰胆碱酯酶的再活化

• 批准号: 7692105
• 负责人: PALMER William TAYLOR
• 金额: $ 17.96万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7692105
• 关键词: Acetylcholinesterase; Ache; Blood - brain barrier anatomy; Blood Circulation; Catalysis; Chemicals; Chemistry; Cholinergic Agents; Croatia; Data; Development; Drosophila genus; Drug Kinetics; Enzymes; Freezing; Germany; Human; Hydrolysis; In Vitro; Insecta; Institutes; Knowledge; Lead; Medical Research; Mus; Mutation; Nervous system structure; Occupational Health; Organophosphates; Oximes; Phosphorus; Plasma; Prophylactic treatment; Rate; Recombinants; Research Personnel; Resistance development; Screening procedure; Series; Site; Structure; Synthesis Chemistry; Therapeutic; Tissues; Toxic Actions; Toxicology; Treatment Efficacy; Triazoles; base; cholinergic; combinatorial; cyclosarin; design; experience; improved; in vivo; mutant; nerve agent; novel; phosphonate; programs; toxic organophosphate insecticide exposure

DESCRIPTION (provided by applicant): Our proposed project is directed to improving prophylaxis and therapy for organophosphate nerve agent organophosphate exposure through the design of mutant human acetylcholinesterases (AChEs), novel oximes and related reactivating nucleophiles. This strategy of "oxime-assisted catalysis" modifies AChE such that, when placed in the circulation, the oxime and AChE become a catalytic, rather than a stoichiometric, scavenger of organophosphates. Proof of principle has already been established for hydrolysis of a series of organophosphates, and we will refine AChE mutations and oxime structure to enhance catalytic rates for hydrolysis and retention in plasma space. Since oxime therapy, 2-PAM and HI-6, also reactivates inhibited AChE at the target site and the therapeutic benefits of long term oxime therapy have become fully appreciated recently, we propose to design new reactivators based on contemporary knowledge of AChE structure to which we and other groups have contributed to over the past two decades. This approach considers impaction of the active center gorge and angle of access of the oxime as limiting constraints in the design strategy. Moreover, the UCSD and TSRI groups have applied a novel freeze-frame, click chemistry to the development of reactivating agents using AChE-phosphonate conjugates as the template for synthesis of the triazoles. In addition to oxime assisted catalysis in plasma, new oximes and other nucleophiles will be developed as novel reactivating agents at the target site. This chemistry also enjoys the advantage of combinatorial screening for medium to high throughput in the synthesis-screening paradigm. Nucleophiles and nucleophile AChE combinations will be optimized for enhancing therapeutic efficacy to the particular offending organophosphate. Hence, our approach will both augment catalytic scavenging of organophosphates in the circulation and enhance reactivation at the target tissues.

描述（由申请人提供）：我们提出的项目旨在通过设计突变的人类乙酰胆碱酯酶（ACHES），新颖的氧气和相关的反应性核糖指数来改善有机磷酸神经剂有机磷酸盐暴露的预防和治疗。这种“摄氏辅助催化”的策略会改变疼痛，以使摄影和酸痛成为催化剂，而不是有机磷酸盐的化学计量计量学的催化剂。原理证明已经建立了一系列有机磷酸盐的水解，我们将完善ACHE突变和摄影结构，以增强血浆空间中水解和保留率的催化速率。自从Oxime Therapy（2-PAM和HI-6）还可以重新激活目标部位的抑制ACHE，并且最近对长期甲电疗法的治疗益处得到了充分的认识，我们建议设计基于当代对ACHE结构的当代知识的新反抗器，在过去的二十年中，我们和其他群体对此做出了贡献。这种方法将活动中心峡谷的影响和氧电的进入角度视为设计策略中的限制限制。此外，UCSD和TSRI组已经应用了一种新型的冻结框架，单击化学以使用ACHE-膦酸酯偶联物作为合成三唑的模板来开发重新激活的剂。除了血浆中的摄影电机辅助催化剂外，新的氧化和其他亲核试剂还将在目标部位开发为新的重新激活剂。这种化学还具有合成范围范式中中等到高通量的组合筛选的优势。亲核试剂和亲核酸ACHE组合将被优化，以增强对特定有害有机磷酸盐的治疗功效。因此，我们的方法既可以增强循环中有机磷酸盐的催化清除，又可以增强目标组织的重新激活。