کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10537783 | 962830 | 2010 | 9 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
(d)-Amino acid analogues of DT-2 as highly selective and superior inhibitors of cGMP-dependent protein kinase Iα
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کلمات کلیدی
MPPcGMPi.p.VmaxpKai.v.PKGMichaelis–Menten constant - دائمی Michaelis-Mentenintraperitoneal - داخل صفاقیIntravenous - داخل وریدیsmooth muscle - عضله صاف mean arterial blood pressure - فشار خون شریانیinhibition constant - مهار ثابتProtein kinase inhibitors - مهار کننده های پروتئین کینازmap - نقشهcAMP-dependent protein kinase - پروتئین کیناز وابسته به cAMPcGMP-dependent protein kinase - پروتئین کیناز وابسته به cGMP
موضوعات مرتبط
مهندسی و علوم پایه
شیمی
شیمی آنالیزی یا شیمی تجزیه
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چکیده انگلیسی
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.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics - Volume 1804, Issue 3, March 2010, Pages 524-532
Journal: Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics - Volume 1804, Issue 3, March 2010, Pages 524-532
نویسندگان
Christian K. Nickl, Shiv Kumar Raidas, Hong Zhao, Matthias Sausbier, Peter Ruth, Werner Tegge, Joseph E. Brayden, Wolfgang R. Dostmann,