Department of Chemistry and Biochemistry, The Ohio State University, 100 West 18th Ave, Columbus, OH, 43210, USA.
Current Address: Department of Chemistry, Colorado School of Mines, 1500 Illinois St., Golden, CO, 80401, USA.
Chemistry. 2019 Apr 11;25(21):5337-5371. doi: 10.1002/chem.201805075. Epub 2019 Feb 13.
Organophosphorus (OP) nerve agents and pesticides present significant threats to civilian and military populations. OP compounds include the nefarious G and V chemical nerve agents, but more commonly, civilians are exposed to less toxic OP pesticides, resulting in the same negative toxicological effects and thousands of deaths on an annual basis. After decades of research, no new therapeutics have been realized since the mid-1900s. Upon phosphylation of the catalytic serine residue, a process known as inhibition, there is an accumulation of acetylcholine (ACh) in the brain synapses and neuromuscular junctions, leading to a cholinergic crisis and eventually death. Oxime nucleophiles can reactivate select OP-inhibited acetylcholinesterase (AChE). Yet, the fields of reactivation of AChE and butyrylcholinesterase encounter additional challenges as broad-spectrum reactivation of either enzyme is difficult. Additional problems include the ability to cross the blood brain barrier (BBB) and to provide therapy in the central nervous system. Yet another complication arises in a competitive reaction, known as aging, whereby OP-inhibited AChE is converted to an inactive form, which until very recently, had been impossible to reverse to an active, functional form. Evaluations of uncharged oximes and other neutral nucleophiles have been made. Non-oxime reactivators, such as aromatic general bases and Mannich bases, have been developed. The issue of aging, which generates an anionic phosphylated serine residue, has been historically recalcitrant to recovery by any therapeutic approach-that is, until earlier this year. Mannich bases not only serve as reactivators of OP-inhibited AChE, but this class of compounds can also recover activity from the aged form of AChE, a process referred to as resurrection. This review covers the modern efforts to address all of these issues and notes the complexities of therapeutic development along these different lines of research.
有机磷（OP）神经毒剂和农药对平民和军人构成重大威胁。OP 化合物包括臭名昭著的 G 和 V 化学神经毒剂，但更常见的是，平民接触到毒性较低的 OP 农药，导致同样的负面毒理学效应和每年数千人死亡。经过几十年的研究，自 20 世纪中期以来，尚未实现新的治疗方法。在催化丝氨酸残基发生磷酸化（称为抑制）后，大脑突触和神经肌肉接头中会积累乙酰胆碱（ACh），导致胆碱能危机，最终导致死亡。肟类亲核试剂可以使特定的 OP 抑制的乙酰胆碱酯酶（AChE）重新活化。然而，AChE 和丁酰胆碱酯酶的再激活领域还面临其他挑战，因为很难广谱地再激活这两种酶。其他问题包括穿过血脑屏障（BBB）的能力以及在中枢神经系统中提供治疗的能力。另一个并发症出现在竞争性反应中，称为老化，其中 OP 抑制的 AChE 转化为无活性形式，直到最近，这种形式一直无法逆转为具有活性的功能性形式。已经对未带电的肟类和其他中性亲核试剂进行了评估。已经开发了非肟类再激活剂，如芳香族通用碱和曼尼希碱。老化问题产生带负电荷的磷酸化丝氨酸残基，一直以来，任何治疗方法都难以恢复-也就是说，直到今年年初。曼尼希碱不仅是 OP 抑制的 AChE 的再激活剂，而且这类化合物还可以从 AChE 的老化形式中恢复活性，这一过程称为复活。本综述涵盖了现代解决所有这些问题的努力，并指出了沿着这些不同研究方向进行治疗开发的复杂性。
