Emergence of catalytic bioscavengers against organophosphorus agents
Emergence of catalytic bioscavengers against organophosphorus agents
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DOI：
10.1016/j.cbi.2016.02.010
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发表时间：
2016-11-25
影响因子：
5.1
通讯作者：
Lushchekina, Sofya V.
中科院分区：
文献类型：
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作者：
Masson, Patrick;Lushchekina, Sofya V.
生物清除剂是神经毒剂（NA）中毒暴露前和暴露后治疗的有效替代方法。生物清除剂是天然或重组酶，反应蛋白和抗体，在NAs到达其生理目标之前中和它们。它们通过注射（蛋白质或基因传递载体）给药，并与血液中的NAs发生反应。其他的给药方式可以使用：吸入用于肺给药，局部面霜用于皮肤保护等。可操作的生物清除剂必须以低成本生产，不易引起免疫反应和不良反应，并且在血液、储存和野外条件下稳定。第一代生物清除剂，胆碱酯酶和羧酸酯酶，是化学计量的生物清除剂。然而，NAs的化学计量中和需要大剂量的昂贵的生物药物。第二代生物清除剂是催化生物清除剂。它们能够再生地解毒有机磷。由于高周转率，毒物的快速中和需要的剂量要低得多。最有希望的催化生物清除剂是磷酸三酯酶（细菌酶，哺乳动物对氧酶）的进化突变体，对有毒的NA异构体表现出对映体的偏好。然而，工程的胆碱酯酶，羧酸酯酶，脯氨酸酶和其他酶，如磷酸三酯酶，从极端微生物内酯酶是感兴趣的。特别是，胆碱酯酶突变体（磷酸化后不受年龄影响）与快速再激活的肟的关联导致了伪催化生物清除剂。因此，催化和伪催化生物清除剂在功效和成本方面是基于生物清除剂的医疗对策的改进。2016爱思唯尔爱尔兰有限公司版权所有。
Bioscavengers are an effective alternative approach for pre-and post-exposure treatments of nerve agent (NA) poisoning. Bioscavengers are natural or recombinant enzymes, reactive proteins, and antibodies that neutralize NAs before they reach their physiological targets. They are administered by injection (protein or gene delivery vector) and react with NAs in the bloodstream. Other ways of delivery can be used: inhalation for pulmonary delivery, topical creams for skin protection, etc. Operational bioscavengers must be producible at low cost, not susceptible to induce immune response and adverse effects, and stable in the bloodstream, upon storage, and under field conditions.First generation bioscavengers, cholinesterases and carboxylesterases, are stoichiometric bioscavengers. However, stoichiometric neutralization of NAs needs administration of huge doses of costly biopharmaceuticals. Second generation bioscavengers are catalytic bioscavengers. These are capable of detoxifying organophosphates regeneratively. By virtue of high turnover, much lower doses are needed for rapid neutralization of toxicants. The most promising catalytic bioscavengers are evolved mutants of phosphotriesterases (bacterial enzymes, mammalian paraoxonases), displaying enantiomeric preference for toxic NA isomers. However, engineering of cholinesterases, carboxylesterases, prolidases and other enzymes, e.g. phosphotriesterases-lactonases from extremophiles is of interest. In particular, association of cholinesterase mutants (not susceptible to age after phosphylation) with fast-reactivating oximes leads to pseudocatalytic bioscavengers. Thus, catalytic and pseudocatalytic bioscavengers are an improvement of bioscavenger-based medical countermeasures in terms of efficacy and cost. (C) 2016 Elsevier Ireland Ltd. All rights reserved.