Tobacco use disorder is the leading cause of disease and preventable death worldwide, but current medications that are based on pharmacodynamics have low efficacy. Novel pharmacokinetic approaches to prevent nicotine from reaching the brain have been tested using vaccines, but these efforts have failed because antibody affinity and concentration are not sufficient to completely prevent nicotine from reaching the brain. We provide preclinical evidence of the efficacy of an enzymatic approach to reverse nicotine dependence, reduce compulsive-like nicotine intake, and prevent relapse in rats with a history of nicotine dependence. Chronic administration of NicA2-J1, an engineered nicotine-degrading enzyme that was originally isolated from Pseudomonas putida S16, completely prevented nicotine from reaching the brain and reversed somatic signs of withdrawal, hyperalgesia, and irritability-like behavior in nicotine-dependent rats with a history of escalation of nicotine self-administration. NicA2-J1 also decreased compulsive-like nicotine intake, reflected by responding despite the adverse consequences of contingent footshocks, and prevented nicotine- and stress (yohimbine)-induced relapse. These results demonstrate the efficacy of enzymatic therapy in treating nicotine addiction in advanced animal models and provide a strong foundation for the development of biological therapies for smoking cessation in humans.

中文翻译：

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酶促方法可以逆转尼古丁的依赖性，减少强迫性摄入，并防止复发。

烟草使用失调是全球疾病和可预防死亡的主要原因，但是目前基于药效学的药物疗效低下。已经使用疫苗测试了防止尼古丁到达大脑的新药代动力学方法，但是这些努力失败了，因为抗体的亲和力和浓度不足以完全阻止尼古丁到达大脑。我们提供了一种酶学方法逆转尼古丁依赖性，减少强迫性尼古丁摄入量以及预防具有尼古丁依赖性史的大鼠复发的功效的临床前证据。长期施用NicA2-J1，这是一种工程化的尼古丁降解酶，最初是从恶臭假单胞菌中分离出来的S16完全阻止尼古丁到达大脑，并逆转具有尼古丁自我给药史的尼古丁依赖性大鼠的戒断，痛觉过敏和易怒样行为的体征。NicA2-J1还减少了强迫性尼古丁的摄入量，这反映了尽管出现了偶然的足底震荡，但仍做出了反应，并防止了尼古丁和压力（育亨宾）引起的复发。这些结果证明了酶疗法在高级动物模型中治疗尼古丁成瘾的功效，并为开发用于人类戒烟的生物疗法提供了坚实的基础。