Developing dual and specific inhibitors of dimethylarginine dimethylaminohydrolase-1 and nitric oxide synthase: toward a targeted polypharmacology to control nitric oxide.
Developing dual and specific inhibitors of dimethylarginine dimethylaminohydrolase-1 and nitric oxide synthase: toward a targeted polypharmacology to control nitric oxide.
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DOI：
10.1021/bi9007098
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发表时间：
2009-09-15
期刊：
影响因子：
2.9
通讯作者：
Fast, Walter
中科院分区：
文献类型：
--
作者：
Wang, Yun;Monzingo, Arthur F.;Hu, Shougang;Schaller, Tera H.;Robertus, Jon D.;Fast, Walter
阻断一氧化氮（NO）生物合成的分子具有重要意义。例如，一氧化氮合酶（NOS）抑制剂已被建议作为抗肿瘤治疗剂，二甲基精氨酸二甲基氨基水解酶（DDAH）（一种分解代谢内源性NOS抑制剂的酶）的抑制剂也是如此。双靶向抑制剂有望成为比单靶向化合物更有效的阻断NO生物合成的试剂。在这项研究中，一小组已知的NOS抑制剂作为重组人DDAH-1的抑制剂进行调查。从这些中，选择烷基脒支架用于同源化。一个取代基的逐步延长将NOS选择性抑制剂转化为双靶向NOS/DDAH-1抑制剂，然后转化为DDAH-1选择性抑制剂，如在N5-N的抑制常数中所见。（1-亚氨基乙基）-，N5-（1-亚氨基丙基）-，N5-（1-亚氨基戊基）-和N5-（1-亚氨基己基）-l-鸟氨酸，分别用于神经元NOS（1.7、3、20、> 1，900 μM）和DDAH-1（990、52、7.5、110 μM）。N5-（1-亚氨基丙基）-l-鸟氨酸：DDAH-1复合物的1.9 X射线晶体结构表明抑制剂的脒基碳和活性位点Cys 274之间形成共价键，并且溶液研究显示可逆竞争性抑制，与烷基脒抑制剂的DDAH抑制的可逆共价模式一致。这些代表了一个通用的支架，用于开发一个有针对性的多药理学方法来控制NO生物合成。
Molecules that block nitric oxide's (NO) biosynthesis are of significant interest. For example, nitric oxide synthase (NOS) inhibitors have been suggested as anti-tumor therapeutics, as have inhibitors of dimethylarginine dimethylaminohydrolase (DDAH), an enzyme that catabolizes endogenous NOS inhibitors. Dual-targeted inhibitors hold promise as more effective reagents to block NO biosynthesis than single-targeted compounds. In this study, a small set of known NOS inhibitors are surveyed as inhibitors of recombinant human DDAH-1. From these, an alkylamidine scaffold is selected for homologation. Stepwise lengthening of one substituent converts an NOS-selective inhibitor into a dual-targeted NOS/DDAH-1 inhibitor and then into a DDAH-1 selective inhibitor, as seen in the inhibition constants of N5-(1-iminoethyl)-, N5-(1-iminopropyl)-, N5-(1-iminopentyl)- and N5-(1-iminohexyl)-l-ornithine for neuronal NOS (1.7, 3, 20, >1,900 μM, respectively) and DDAH-1 (990, 52, 7.5, 110 μM, respectively). A 1.9Å X-ray crystal structure of the N5-(1-iminopropyl)-l-ornithine : DDAH-1 complex indicates covalent bond formation between the inhibitor's amidino carbon and the active-site Cys274, and solution studies show reversible competitive inhibition, consistent with a reversible covalent mode of DDAH inhibition by alkylamidine inhibitors. These represent a versatile scaffold for the development of a targeted polypharmacological approach to control NO biosynthesis.
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影响因子：
4.8
作者：
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通讯作者：
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DOI：
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发表时间：
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