Characterization of C-alkyl amidines as bioavailable covalent reversible inhibitors of human DDAH-1.
Characterization of C-alkyl amidines as bioavailable covalent reversible inhibitors of human DDAH-1.
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DOI：
10.1002/cmdc.201000392
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发表时间：
2011-01-03
期刊：
影响因子：
3.4
通讯作者：
Robertus, Jon D.
中科院分区：
文献类型：
--
作者：
Lluis, Matthew;Wang, Yun;Monzingo, Arthur F.;Fast, Walter;Robertus, Jon D.
不对称Nω，Nω -二甲基-L-精氨酸的C-烷基脒类似物是人DDAH-1和一氧化氮（NO）合酶的双靶向抑制剂，为开发控制包括感染性休克和某些癌症在内的多种病理学中NO过量产生的治疗药物提供了有前景的支架。使用两部分点击化学介导的活性探针，同源的一系列C-烷基脒在培养的HEK 293 T细胞内抑制DDAH-1的能力进行排名。N5-（1-亚氨基戊基）-L-鸟氨酸被确定为体外和培养细胞中最有效的化合物（Kd = 7 μM），并且通过比较与DDAH-1和无催化活性的C274 S变体的相互作用（通过X射线晶体学和等温滴定量热法测量）来研究结合构象和共价可逆抑制模式。通过中断抑制剂形成共价键的能力，可以估计这种相互作用的贡献。这些结果表明，进一步稳定的共价加合物作为一个有前途的策略，在设计有效的试剂，以阻止NO合成的铅优化。
C-alkyl amidine analogs of asymmetric Nω,Nω -dimethyl-L-arginine are dual-targeted inhibitors of both human DDAH-1 and nitric oxide (NO) synthase, and provide a promising scaffold for developing therapeutics to control NO overproduction in a variety of pathologies including septic shock and some cancers. Using a two-part clickchemistry-mediated activity probe, a homologated series of C-alkyl amidines are ranked for their ability to inhibit DDAH-1 within cultured HEK 293T cells. N5-(1-iminopentyl)-L-ornithine was determined to be the most potent compound in vitro (Kd = 7 μM) as well as in cultured cells, and the binding conformation and covalent reversible mode of inhibition was investigated by comparison of interactions made with DDAH-1 and a catalytically inactive C274S variant as gauged by Xray crystallography and isothermal titration calorimetry. By interrupting the ability of the inhibitor to form a covalent bond, the contribution of this interaction can be estimated. These results suggest further stabilization of the covalent adduct as a promising strategy for lead optimization in the design of effective reagents to block NO synthesis.
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DOI：
10.1006/bbrc.1994.1511
发表时间：
1994-04-29
影响因子：
3.1
作者：
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通讯作者：
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
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影响因子：
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作者：
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影响因子：
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作者：
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