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FAAH-Catalyzed C-C Bond Cleavage of a New Multitarget Analgesic Drug.
ACS Chemical Neuroscience ( IF 5 ) Pub Date : 2018-10-04 , DOI: 10.1021/acschemneuro.8b00315
Alessia Ligresti 1 , Cristoforo Silvestri 1 , Rosa Maria Vitale 1 , Jose L Martos 2 , Fabiana Piscitelli 1 , Jenny W Wang 3 , Marco Allarà 1 , Robert W Carling 2 , Livio Luongo 4 , Francesca Guida 4 , Anna Illiano 5 , Angela Amoresano 5 , Sabatino Maione 4 , Pietro Amodeo 1 , David F Woodward 3 , Vincenzo Di Marzo 1, 6 , Gennaro Marino 5, 7
Affiliation  

The discovery of extended catalytic versatilities is of great importance in both the chemistry and biotechnology fields. Fatty acid amide hydrolase (FAAH) belongs to the amidase signature superfamily and is a major endocannabinoid inactivating enzyme using an atypical catalytic mechanism involving hydrolysis of amide and occasionally ester bonds. FAAH inhibitors are efficacious in experimental models of neuropathic pain, inflammation, and anxiety, among others. We report a new multitarget drug, AGN220653, containing a carboxyamide-4-oxazole moiety and endowed with efficacious analgesic and anti-inflammatory activities, which are partly due to its capability of achieving inhibition of FAAH, and subsequently increasing the tissue concentrations of the endocannabinoid anandamide. This inhibitor behaves as a noncompetitive, slowly reversible inhibitor. Autoradiography of purified FAAH incubated with AGN220653, opportunely radiolabeled, indicated covalent binding followed by fragmentation of the molecule. Molecular docking suggested a possible nucleophilic attack by FAAH-Ser241 on the carbonyl group of the carboxyamide-4-oxazole moiety, resulting in the cleavage of the C-C bond between the oxazole and the carboxyamide moieties, instead of either of the two available amide bonds. MRM-MS analyses only detected the Ser241-assisted formation of the carbamate intermediate, thus confirming the cleavage of the aforementioned C-C bond. Quantum mechanics calculations were fully consistent with this mechanism. The study exemplifies how FAAH structural features and mechanism of action may override the binding and reactivity propensities of substrates. This unpredicted mechanism could pave the way to the future development of a completely new class of amidase inhibitors, of potential use against pain, inflammation, and mood disorders.

中文翻译:

FAAH催化的新型多靶点镇痛药的CC键裂解。

扩大催化用途的发现在化学和生物技术领域都非常重要。脂肪酸酰胺水解酶(FAAH)属于酰胺酶签名超家族,是一种主要的内源性大麻素失活酶,利用非典型催化机理,涉及酰胺的水解以及偶发的酯键的水解。FAAH抑制剂在神经性疼痛,炎症和焦虑等实验模型中有效。我们报告了一种新的多靶点药物,AGN220653,它包含一个羧酰胺-4-恶唑部分,并具有有效的镇痛和抗炎活性,这部分是由于其具有抑制FAAH的能力,并随后增加了内源性大麻素的组织浓度阿南酰胺。该抑制剂表现为非竞争性,缓慢可逆的抑制剂。与放射性标记的AGN220653孵育的纯化FAAH的放射自显影显示共价结合,然后分子断裂。分子对接表明,FAAH-Ser241可能对羧酰胺-4-恶唑部分的羰基进行亲核攻击,导致恶唑和羧酰胺部分之​​间的CC键裂解,而不是两个可用酰胺键中的任何一个裂解。MRM-MS分析仅检测到Ser241辅助的氨基甲酸酯中间体的形成,因此确认了上述CC键的裂解。量子力学计算与该机理完全一致。这项研究例证了FAAH的结构特征和作用机理如何能超越底物的结合和反应性。
更新日期:2018-09-18
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