(D)-Amino acid analogues of DT-2 as highly selective and superior inhibitors of cGMP-dependent protein kinase Ialpha.
(D)-Amino acid analogues of DT-2 as highly selective and superior inhibitors of cGMP-dependent protein kinase Ialpha.
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DOI：
10.1016/j.bbapap.2009.12.004
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发表时间：
2010-03
期刊：
影响因子：
--
通讯作者：
Dostmann WR
中科院分区：
文献类型：
--
作者：
Nickl CK;Raidas SK;Zhao H;Sausbier M;Ruth P;Tegge W;Brayden JE;Dostmann WR
cGMP依赖性蛋白激酶I型（PKG I）是全身血管中细胞功能的重要调节因子。DT-2是PKG的肽抑制剂，在确定涉及PKG及其信号传导伙伴的血管控制的分子机制中发挥了核心作用。在此，我们报道了（D）-氨基酸DT-2衍生物，即反转-（D）-DT-2和全（D）-氨基酸类似物（D）-DT-2的开发。两种肽类似物均为强效PKG Iα抑制剂，使用双曲线混合型抑制模型测定Ki值为5.5 nM（ri-（D）-DT-2）和0.8 nM（（D）-DT-2）。此外，这两种类似物在体内蛋白水解稳定，显示出较高的选择性，并显示出增强的膜转位特性。对来自阻力脉管系统的分离动脉的研究表明，管腔内灌注的（D）-DT-2显著抑制由8-Br-cGMP诱导的血管舒张。此外，（D）-DT-2的体内应用在除脑外的阻力脉管系统中建立了均匀的易位模式。因此，（D）-DT-2在不受限制的清醒小鼠中引起平均动脉血压的显著增加。此外，从（D）-DT-2处理的动物分离的肠系膜动脉显示出对8-Br-cGMP的体外扩张反应显著降低。我们的结果清楚地表明，（D）-DT-2是一种上级PKG Iα抑制剂，其体内应用导致血管平滑肌细胞中PKG的持续抑制。（D）-DT-2的发现可能有助于我们了解血管如何收缩和扩张，也可能有助于开发新的策略和治疗药物，以预防和治疗血管疾病，如高血压，中风和冠状动脉疾病。
The cGMP-dependent protein kinase type I (PKG I) is an essential regulator of cellular function in blood vessels throughout the body. DT-2, a peptidic inhibitor of PKG, has played a central role in determining the molecular mechanisms of vascular control involving PKG and its signaling partners. Here, we report the development of (D)-amino acid DT-2 derivatives, namely the retro-inverso ri-(D)-DT-2 and the all (D)-amino acid analog, (D)-DT-2. Both peptide analogs were potent PKG Iα inhibitors with Ki values of 5.5 nM (ri-(D)-DT-2) and 0.8 nM ((D)-DT-2) as determined using a hyperbolic mixed-type inhibition model. Also, both analogs were proteolytically stable in vivo, showed elevated selectivity, and displayed enhanced membrane translocation properties. Studies on isolated arteries from the resistance vasculature demonstrated that intraluminally perfused (D)-DT-2 significantly inhibited vasodilation induced by 8-Br-cGMP. Furthermore, in vivo application of (D)-DT-2 established a uniform translocation pattern in the resistance vasculature, with exception of the brain. Thus, (D)-DT-2 caused significant increases in mean arterial blood pressure in unrestrained, awake mice. Further, mesenteric arteries isolated from (D)-DT-2 treated animals showed a markedly reduced dilator response to 8-Br-cGMP in vitro. Our results clearly demonstrate that (D)-DT-2 is a superior inhibitor of PKG Iα and its application in vivo leads to sustained inhibition of PKG in vascular smooth muscle cells. The discovery of (D)-DT-2 may help our understanding of how blood vessels constrict and dilate and may also aid the development of new strategies and therapeutic agents targeted to the prevention and treatment of vascular disorders such as hypertension, stroke and coronary artery disease.
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DOI：
10.1073/pnas.97.26.14772
发表时间：
2000-12-19
影响因子：
11.1
作者：
Dostmann, WRG;Taylor, MS;Tegge, WJ
通讯作者：
Tegge, WJ
影响因子：
7.3
作者：
Butt, E;Pohler, D;Bucher, B
通讯作者：
Bucher, B
影响因子：
6.6
作者：
Kim, Choel;Vigil, Dommico;Taylor, Susan S.
通讯作者：
Taylor, Susan S.
影响因子：
2.9
作者：
HIDAKA, H;INAGAKI, M;SASAKI, Y
通讯作者：
SASAKI, Y
DOI：
10.1111/j.1432-1033.1991.tb16509.x
发表时间：
1991-12-18
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
RUTH, P;LANDGRAF, W;HOFMANN, F
通讯作者：
HOFMANN, F