Yoder Ryan J, Zhuang Qinggeng, Beck Jeremy M, Franjesevic Andrew, Blanton Travis G, Sillart Sydney, Secor Tyler, Guerra Leah, Brown Jason D, Reid Carolyn, McElroy Craig A, Doğan Ekici Özlem, Callam Christopher S, Hadad Christopher M
Department of Chemistry and Biochemistry, The Ohio State University, Marion Campus, 1465 Mt. Vernon Avenue, Marion, Ohio 43302, United States.
Department of Chemistry and Biochemistry, The Ohio State University, 100 West 18th Avenue, Columbus, Ohio 43210, United States.
ACS Med Chem Lett. 2017 May 8;8(6):622-627. doi: 10.1021/acsmedchemlett.7b00037. eCollection 2017 Jun 8.
Acetylcholinesterase (AChE) is an essential enzyme that can be targeted by organophosphorus (OP) compounds, including nerve agents. Following exposure to OPs, AChE becomes phosphylated (inhibited) and undergoes a subsequent aging process where the OP-AChE adduct is dealkylated. The aged AChE is unable to hydrolyze acetylcholine, resulting in accumulation of the neurotransmitter in the central nervous system (CNS) and elsewhere. Current therapeutics are only capable of reactivating inhibited AChE. There are no known therapeutic agents to reverse the aging process or treat aged AChE. Quinone methides (QMs) have been shown to alkylate phosphates under physiological conditions. In this study, a small library of novel quinone methide precursors (QMPs) has been synthesized and examined as potential alkylating agents against model nucleophiles, including a model phosphonate. Computational studies have been performed to evaluate the affinity of QMPs for the aged AChE active site, and preliminary testing with electric eel AChE has been performed.
乙酰胆碱酯酶（AChE）是一种重要的酶，可被包括神经毒剂在内的有机磷（OP）化合物作用。接触OP后，AChE会发生磷酸化（被抑制），随后经历老化过程，在此过程中OP-AChE加合物会发生脱烷基化。老化的AChE无法水解乙酰胆碱，导致神经递质在中枢神经系统（CNS）及其他部位蓄积。目前的治疗方法仅能使被抑制的AChE重新活化。尚无已知的治疗药物可逆转老化过程或治疗老化的AChE。醌甲基化物（QMs）已被证明在生理条件下可使磷酸盐烷基化。在本研究中，已合成了一个新型醌甲基化物前体（QMPs）的小型文库，并将其作为针对模型亲核试剂（包括模型膦酸酯）的潜在烷基化剂进行了研究。已进行了计算研究以评估QMPs对老化AChE活性位点的亲和力，并用电鳗AChE进行了初步测试。
