Bacterial cocaine esterase: a protein-based therapy for cocaine overdose and addiction.
Bacterial cocaine esterase: a protein-based therapy for cocaine overdose and addiction.
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DOI：
10.4155/fmc.11.194
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发表时间：
2012-02
影响因子：
4.2
通讯作者：
Sunahara RK
中科院分区：
文献类型：
--
作者：
Narasimhan D;Woods JH;Sunahara RK
可卡因具有高度成瘾性，目前尚无药物可用于治疗可卡因急性中毒或慢性滥用。使用小分子拮抗抑制剂如可卡因已被证明是困难的。另一种方法是通过在血清中螯合或水解可卡因并限制其作用部位来改变可卡因的药代动力学特性。我们利用了一种细菌酯酶（CocE），它已经进化到可以水解可卡因，并将其开发为一种治疗药物，可以快速特异地清除受试者体内的可卡因。天然酶在37°C下不稳定，因此限制了CocE的潜力。基于蛋白质结构的创新计算方法有助于阐明其不稳定机制。新的蛋白质工程方法的应用，大大提高其在体外和体内的稳定性。这些改进使CocE成为治疗可卡因中毒的强大而有效的治疗剂，并为开发成瘾治疗方法铺平了道路。
Cocaine is highly addictive and there are no pharmacotherapeutic drugs available to treat acute cocaine toxicity or chronic abuse. Antagonizing an inhibitor such as cocaine using a small molecule has proven difficult. The alternative approach is to modify cocaine’s pharmacokinetic properties by sequestering or hydrolyzing it in serum and limiting access to its sites of action. We took advantage of a bacterial esterase (CocE) that has evolved to hydrolyze cocaine and have developed it as a therapeutic that rapidly and specifically clears cocaine from the subject. Native enzyme was unstable at 37°C, thus limiting CocE’s potential. Innovative computational methods based on the protein’s structure helped elucidate its mechanism of destabilization. Novel protein engineering methodologies were applied to substantially improve its stability in vitro and in vivo. These improvements rendered CocE as a powerful and efficacious therapeutic to treat cocaine intoxication and lead the way towards developing a therapy for addiction.
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影响因子：
3.6
作者：
Cooper, Ziva D.;Narasimhan, Diwahar;Woods, James H.
通讯作者：
Woods, James H.
影响因子：
3.6
作者：
Gao, Daquan;Narasimhan, Diwahar L.;Zhan, Chang-Guo
通讯作者：
Zhan, Chang-Guo
影响因子：
4.8
作者：
Barends, TRM;Polderman-Tijmes, JJ;Dijkstra, BW
通讯作者：
Dijkstra, BW
DOI：
10.1124/jpet.111.186049
发表时间：
2012-01-01
影响因子：
3.5
作者：
Brim, Remy L.;Noon, Kathleen R.;Sunahara, Roger K.
通讯作者：
Sunahara, Roger K.
影响因子：
7.6
作者：
Collins, Gregory T.;Narasimhan, Diwahar;Woods, James H.
通讯作者：
Woods, James H.