Anticocaine catalytic antibodies
Anticocaine catalytic antibodies
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DOI：
10.1016/s0022-1759(02)00237-5
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发表时间：
2002-11-01
影响因子：
2.2
通讯作者：
Landry, DW
中科院分区：
文献类型：
--
作者：
Deng, SX;de Prada, P;Landry, DW
可卡因通过对多个受体的“功能丧失”效应来调节其强化和毒性作用。阻断多效阻滞剂所固有的困难对传统的受体-拮抗剂方法构成了巨大的障碍，并导致（迄今为止）未能设计出针对可卡因过量和成瘾的特定治疗方法。作为替代方案，我们已经开始研究催化抗体，这是一种可编程的人工酶，作为“外周阻断剂”，在可卡因进入中枢神经系统发挥强化或毒性作用之前，结合并降解循环中的可卡因。我们合成了可卡因苯甲酰酯水解的过渡态类似物，免疫小鼠，制备杂交瘤，并开发了第一个抗可卡因催化抗体，该抗体具有将可卡因降解为非强化，无毒产物的能力。我们随后确定了几个抗可卡因催化抗体家族，并发现最有效的抗体具有足够的活性，分别阻断可卡因诱导的成瘾、毒性和过量啮齿动物模型中的强化、器官功能障碍和猝死。人工酶方法具有促进停止使用、延长戒断和提供急性过量治疗的潜力，对可卡因问题作出全面反应。(C) 2002 Elsevier Science B.V.版权所有
Cocaine mediates its reinforcing and toxic actions through a "loss of function" effect at multiple receptors. The difficulties inherent in blocking a pleiotropic blocker pose a great obstacle for the classical receptor-antagonist approach and have contributed to the failure (to date) to devise specific treatments for cocaine overdose and addiction. As an alternative, we have embarked on an investigation of catalytic antibodies, a programmable class of artificial enzyme, as "peripheral blockers" agents designed to bind and degrade cocaine in the circulation before it partitions into the central nervous system to exert reinforcing or toxic effects. We synthesized transition-state analogs of cocaine's hydrolysis at its benzoyl ester, immunized mice, prepared hybridomas and developed the first anticocaine catalytic antibodies with the capacity to degrade cocaine to nonreinforcing, nontoxic products. We subsequently identified several families of anticocaine catalytic antibodies and found that the most potent antibody possessed sufficient activity to block cocaine-induced reinforcement, organ dysfunction and sudden death in rodent models of addiction, toxicity and overdose, respectively. With the potential to promote cessation of use, prolong abstinence and provide a treatment for acute overdose, the artificial enzyme approach comprehensively responds to the problem of cocaine. (C) 2002 Elsevier Science B.V. All rights reserved.