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首页> 外文期刊>Biochemical Pharmacology >BAY 60-2770 activates two isoforms of nitric oxide sensitive guanylyl cyclase: Evidence for stable insertion of activator drugs
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BAY 60-2770 activates two isoforms of nitric oxide sensitive guanylyl cyclase: Evidence for stable insertion of activator drugs

机译：托架60-2770激活两种一氧化氮敏感的冠状动脉环酶：稳定插入活化剂药物的证据

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摘要

Nitric oxide sensitive guanylyl cyclase (NOsGC), a hemoprotein and the major physiological receptor for nitric oxide (NO), is a heterodimer with the alpha(1)/beta(1) and alpha(2)/beta(1) isoforms known to be important for NO-signaling and conversion of GTP to cGMP in humans. Two innovative classes of compounds modulating the NO/cGMP signaling pathway have been discovered: the heme-dependent sGC stimulators, that stimulate NOsGC directly and also increase the affinity towards NO, and the heme-independent sGC activators, that are thought to bind to oxidized and heme-free NOsGC in tissues exposed to oxidative stress. In the current study, we evaluate the effects of the sGC activators BAY 58-2667 (cinaciguat) and BAY 60-2770 on the isoforms alpha(1)/beta(1) and alpha(2)/beta(1) expressed in Sf9 cells. Western blot analysis of cytosolic fractions revealed a decrease in overexpressed NOsGC in the presence of sGC activators, which is dependent on an intact catalytic site of the enzyme. For both isoforms, we show a higher efficacy for BAY 60-2770 compared to cinaciguat after purification of NOsGC by affinity and size exclusion chromatography. Using a new experimental strategy of expression of NOsGC with activator and subsequent purification, we demonstrate a stable insertion of activator drugs into the enzyme during protein biosynthesis independent of the heme redox state. We postulate that the balance between stable insertion of activator during de novo synthesis and replacement of NOsGC ferric heme in tissues exposed to oxidative stress can be influenced by the dosage regimen. (C) 2017 Elsevier Inc. All rights reserved.
机译：一氧化氮敏感的紫薇环化酶（NoSGC），血蛋白和一氧化氮（NO）的主要生理受体，是α（1）/β（1）和α（2）/β（1）种类的异二聚体对于在人类中的GTP到CGMP的No-Signing和GTP转换很重要。已经发现了两种创新类别的化合物，调节NO / CGMP信号通路途径：血红素依赖性SGC刺激器，可直接刺激NoSGC，并增加对NO的亲和力和血红素无关的SGC活化剂，认为被认为与氧化结合在暴露于氧化应激的组织中，无血红蛋态鼻咽。在目前的研究中，我们评估SGC活化剂托架58-2667（Cinaciguat）和Bay 60-2770对在SF9中表达的同种型α（1）/β（1）和α（2）/β（1）上的影响细胞。细胞溶质级分的Western印迹分析显示出在SGC活化剂存在下过表达的NoSGC的降低，这取决于酶的完整催化位点。对于两种同种型，我们通过亲和力和尺寸排除色谱法纯化NoSGC后，对Bay 60-2770进行了更高的疗效。使用具有活化剂和随后的纯化的NoSGC表达的新实验策略，我们证明了在蛋白质生物合成中稳定地插入酶，而缺乏血红素氧化还原状态。假设在暴露于氧化应激暴露于氧化应激的组织中，在Novo合成和替代NoSGC氟血红素期间的稳定插入稳定插入之间的平衡可以受剂量方案的影响。 （c）2017年Elsevier Inc.保留所有权利。

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