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Homogenous fluorescent assays for characterizing small-molecule activators of AMP-activated protein kinase (AMPK). 表征amp活化蛋白激酶(AMPK)小分子激活因子的均相荧光分析。
Pub Date : 2008-02-25 DOI: 10.2174/1875397300801010034
Laurie J Reichling, Steven M Riddle, Baigen Mei, Rica Bruinsma, Tony A Goossens, Kristin G Huwiler, Mark Maffitt, Alyssa M G Newport, Xiao-Dong Qian, Carmen Ruttimann-Johnson, Kurt W Vogel

AMP activated protein kinase (AMPK) is a key regulator of cellular metabolism. AMPK activity is modulated in part by binding of AMP to the gamma-subunit of the kinase, which increases the activity of the catalytic alpha-subunit. Because increased AMPK activity in the liver and in skeletal muscle leads to increased fatty acid oxidation and decreased cholesterol and fatty acid biosynthesis, activators of AMPK are being sought for treatment of type-2 diabetes and other metabolic disorders. The unique mechanism of AMPK activation offers an opportunity to develop small molecules that directly upregulate AMPK activity, and there exists a need for simplified methods to identify and characterize small-molecules that show isoform-specific effects on AMPK. We have developed a suite of fluorescence-based assays to identify and characterize such compounds, and have used these to characterize and compare activity of recombinant AMPK alpha(1)beta(1)gamma(1) and alpha(2)beta(1)gamma(1) isoforms in response to small molecule activators and inhibitors.

AMP活化蛋白激酶(AMPK)是细胞代谢的关键调节因子。AMPK的活性部分是通过AMP与激酶的γ亚基结合来调节的,这增加了催化α亚基的活性。由于肝脏和骨骼肌中AMPK活性的增加导致脂肪酸氧化增加,胆固醇和脂肪酸生物合成降低,因此人们正在寻找AMPK的激活剂来治疗2型糖尿病和其他代谢紊乱。AMPK活化的独特机制为开发直接上调AMPK活性的小分子提供了机会,并且需要简化方法来鉴定和表征对AMPK具有同种异构体特异性作用的小分子。我们已经开发了一套基于荧光的检测方法来识别和表征这些化合物,并使用这些方法来表征和比较重组AMPK α (1) β (1) γ(1)和α (2) β (1) γ(1)亚型对小分子激活剂和抑制剂的反应活性。
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引用次数: 2
The use of AlphaScreen technology in HTS: current status. alphasgreen技术在HTS中的应用现状。
Pub Date : 2008-02-25 DOI: 10.2174/1875397300801010002
Richard M Eglen, Terry Reisine, Philippe Roby, Nathalie Rouleau, Chantal Illy, Roger Bossé, Martina Bielefeld

AlphaScreen (Amplified Luminescent Proximity Homogeneous Assay Screen) is versatile assay technology developed to measuring analytes using a homogenous protocol. This technology is an example of a bead-based proximity assay and was developed from a diagnostic assay technology known as LOCI (Luminescent Oxygen Channeling Assay). Here, singlet oxygen molecules, generated by high energy irradiation of Donor beads, travel over a constrained distance (approx. 200 nm) to Acceptor beads. This results in excitation of a cascading series of chemical reactions, ultimately causing generation of a chemiluminescent signal.In the past decade, a wide variety of applications has been reported, ranging from detection of analytes involved in cell signaling, including protein:protein, protein:peptide, protein:small molecule or peptide:peptide interactions. Numerous homogeneous HTS-optimized assays have been reported using the approach, including generation of second messengers (such as accumulation of cyclic AMP, cyclic GMP, inositol [1, 4, 5] trisphosphate or phosphorylated ERK) from liganded GPCRs or tyrosine kinase receptors, post-translational modification of proteins (such as proteolytic cleavage, phosphorylation, ubiquination and sumoylation) as well as protein-protein and protein-nucleic acid interactions.Recently, the basic AlphaScreen technology was extended in that the chemistry of the Acceptor bead was modified such that emitted light is more intense and spectrally defined, thereby markedly reducing interference from biological fluid matrices (such as trace hemolysis in serum and plasma). In this format, referred to as AlphaLISA, it provides an alternative technology to classical ELISA assays and is suitable for high throughput automated fluid dispensing and detection systems.Collectively, AlphaScreen and AlphaLISA technologies provide a facile assay platform with which one can quantitate complex cellular processes using simple no-wash microtiter plate based assays. They provide the means by which large compound libraries can be screened in a high throughput fashion at a diverse range of therapeutically important targets, often not readily undertaken using other homogeneous assay technologies. This review assesses the current status of the technology in drug discovery, in general, and high throughput screening (HTS), in particular.

AlphaScreen(放大发光接近均质分析屏幕)是一种通用的分析技术,用于使用均质协议测量分析物。该技术是基于珠的接近分析的一个例子,是从被称为LOCI(发光氧通道分析)的诊断分析技术发展而来的。在这里,由供体珠的高能辐照产生的单线态氧分子,在一个受限的距离(大约。200 nm)到受体珠。这导致激发一系列级联的化学反应,最终导致化学发光信号的产生。在过去的十年中,广泛的应用已经被报道,从检测涉及细胞信号的分析物,包括蛋白质:蛋白质,蛋白质:肽,蛋白质:小分子或肽:肽相互作用。使用该方法已经报道了许多同质的hts优化分析,包括从配体gpcr或酪氨酸激酶受体产生第二信使(如环AMP、环GMP、肌醇[1,4,5]三磷酸或磷酸化ERK的积累)、蛋白质的翻译后修饰(如蛋白水解裂解、磷酸化、泛素化和聚合化)以及蛋白质-蛋白质和蛋白质-核酸相互作用。最近,基本的AlphaScreen技术得到了扩展,因为受体头的化学性质得到了改进,这样发射的光更强,光谱更清晰,从而显著减少了生物流体基质(如血清和血浆中的微量溶血)的干扰。在这种格式中,称为AlphaLISA,它提供了经典ELISA测定的替代技术,适用于高通量自动化流体分配和检测系统。总的来说,alphasgreen和AlphaLISA技术提供了一个简便的分析平台,可以使用简单的免洗微滴板定量分析复杂的细胞过程。它们提供了一种方法,通过这种方法可以在各种治疗重要靶点上以高通量的方式筛选大型化合物文库,而使用其他均质分析技术通常不容易进行。本文综述了该技术在药物发现中的现状,特别是高通量筛选(HTS)。
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引用次数: 209
Multiplexing bioluminescent and fluorescent reporters to monitor live cells. 多路生物发光和荧光报告监测活细胞。
Pub Date : 2008-02-25 DOI: 10.2174/1875397300801010011
Michael Haugwitz, Omar Nourzaie, Tatiana Garachtchenko, Lanrong Hu, Suvarna Gandlur, Cathy Olsen, Andrew Farmer, Grigoriy Chaga, Hiroaki Sagawa

Reporter proteins are valuable tools to monitor promoter activities and characterize signal transduction pathways. Many of the currently available promoter reporters have drawbacks that compromise their performance. Enzyme-based reporter systems using cytosolic luciferases are highly sensitive, but require a cell lysis step that prevents their use in long-term monitoring. By contrast, secreted bioluminescent reporters like Metridia luciferase and Secreted Alkaline Phosphatase can be assayed repeatedly, using supernatant from the same live cell population to produce many sets of data over time. This is crucial for studies with limited amounts of cells, as in the case of stem cells. The use of secreted bioluminescent reporters also enables broader applications to provide more detailed information using live cells; for example, multiplexing with fluorescent proteins. Here, data is presented describing the characteristics of secreted Metridia luciferase and its use in multiplexing applications with either Secreted Alkaline Phosphatase or a fluorescent protein.

报告蛋白是监测启动子活性和表征信号转导途径的重要工具。目前可用的许多启动子报告程序都存在影响其性能的缺陷。使用细胞质荧光素酶的基于酶的报告系统是高度敏感的,但需要一个细胞裂解步骤,这阻碍了它们在长期监测中的使用。相比之下,分泌的生物发光报告基因,如Metridia荧光素酶和分泌的碱性磷酸酶,可以重复检测,使用来自同一活细胞群的上清,随着时间的推移产生多组数据。这对于细胞数量有限的研究至关重要,比如干细胞的研究。分泌的生物发光报告器的使用也使更广泛的应用能够使用活细胞提供更详细的信息;例如,与荧光蛋白进行多路复用。在这里,数据被提出描述分泌的Metridia荧光素酶的特点和它的使用在多路应用与分泌碱性磷酸酶或荧光蛋白。
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引用次数: 16
Cellular assays for high-throughput screening for modulators of Trk receptor tyrosine kinases. 高通量筛选Trk受体酪氨酸激酶调节剂的细胞试验。
Pub Date : 2008-02-25 DOI: 10.2174/1875397300801010027
Jun Wang, Michael K Hancock, Jeanne M Dudek, Kun Bi

Trk receptor tyrosine kinases are required for signal transduction initiated by neurotrophins leading to cell proliferation, differentiation, survival and death. Alterations in Trk kinase activity have been linked to various diseases. To address the need for cell-based assays for screening and studying the selectivity of Trk kinase modulators, we developed high-throughput cell-based assays for Trk receptor kinases using nuclear factor of activated T-cells (NFAT) beta-lactamase reporter lines stably expressing full length human Trk kinases. These assays were functionally validated with cognate neurotrophin(s), inhibitors and TRK RNAi oligos and demonstrated for their utility in identifying potent and selective modulators of Trk receptor kinases.

Trk受体酪氨酸激酶是神经营养因子引发细胞增殖、分化、存活和死亡的信号转导所必需的。Trk激酶活性的改变与多种疾病有关。为了解决基于细胞的检测方法筛选和研究Trk激酶调节剂选择性的需求,我们开发了基于细胞的高通量Trk受体激酶检测方法,使用稳定表达全长人Trk激酶的活化t细胞核因子(NFAT) β -内酰胺酶报告系。这些实验在同源神经营养因子、抑制剂和TRK RNAi低聚物的功能上得到了验证,并证明了它们在识别TRK受体激酶的有效和选择性调节剂方面的实用性。
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引用次数: 18
Fluorescent cascade and direct assays for characterization of RAF signaling pathway inhibitors. 荧光级联和直接测定表征RAF信号通路抑制剂。
Pub Date : 2008-02-25 DOI: 10.2174/1875397300801010043
Kevin R Kupcho, Rica Bruinsma, Tina M Hallis, David A Lasky, Richard L Somberg, Tammy Turek-Etienne, Kurt W Vogel, Kristin G Huwiler

RAF kinases are part of a conserved signaling pathway that impacts cell growth, differentiation, and survival, and RAF pathway dysregulation is an attractive target for therapeutic intervention. We describe two homogeneous fluorescent formats that distinguish RAF pathway inhibitors from direct RAF kinase inhibitors, using B-RAF, B-RAF V599E, and C-RAF. A Förster-resonance energy transfer (FRET) based method was used to develop RAF and MEK cascade assays as well as a direct ERK kinase assay. This method uses a peptide substrate, that is terminally labeled with a FRET-pair of fluorophores, and that is more sensitive to proteolysis relative to the phosphorylated peptide. A second time-resolved FRET-based assay using fluorescently labeled MEK substrate was used to detect direct inhibitors of RAF kinase activity. The cascade assays detect compounds that interact with activated and unactivated kinases within the recapitulated RAF pathway, and the direct assays isolate the point of action for an inhibitor.

RAF激酶是影响细胞生长、分化和存活的保守信号通路的一部分,RAF通路失调是治疗干预的一个有吸引力的靶点。我们用B-RAF、B-RAF V599E和C-RAF描述了区分RAF途径抑制剂和直接RAF激酶抑制剂的两种同质荧光格式。基于Förster-resonance能量转移(FRET)的方法用于开发RAF和MEK级联分析以及直接ERK激酶分析。该方法使用肽底物,末端用fret对荧光团标记,相对于磷酸化肽,对蛋白水解更敏感。使用荧光标记的MEK底物进行第二次时间分辨的基于fret的测定,用于检测RAF激酶活性的直接抑制剂。级联分析检测在重复RAF途径中与活化和未活化激酶相互作用的化合物,直接分析分离抑制剂的作用点。
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引用次数: 8
Editorial. 社论。
Pub Date : 2008-02-25 DOI: 10.2174/1875397300801010001
Wei Zheng
EDITORIAL We are pleased to launch this inaugural issue of Current Chemical Genomics. As an open access online journal, all the papers from this journal can be read free of charge by our readers without any restrictions to access of the full content. This peerreviewed journal publishes research letters/articles, reviews, and technology notes on all aspects of the research and development focusing on integrative approaches at the interface of chemistry and genomics. The journal reports the newly identified small molecule probes and their applications in chemical genomic research. It also reports on the methods and technologies used to identify and optimize chemical probes that interact with proteins of unknown function and with proteins of cellular signaling pathways. Coverage also includes reports on the new chemoinformatics methods for chemical genomics. We hope that these approaches will facilitate the identification of new drug targets and the development of novel therapeutic strategies leading to a new generation of medicines.
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引用次数: 1
Glutamatergic Synaptic Dysfunction and Obsessive-Compulsive Disorder. 谷氨酸能突触功能障碍与强迫症
Pub Date : 2008-01-01 DOI: 10.2174/1875397300802010062
Jonathan T Ting, Guoping Feng

Obsessive-compulsive disorder (OCD) is a debilitating neuropsychiatric condition estimated to afflict 1-3% of the world population. The estimated financial impact in the treatment and management of OCD is in the billions of dollars annually in the US alone. At present there is a marked lack of evidence on the specific causes of OCD. Current hypotheses largely focus on the serotonin (5-HT) system on the basis of the effectiveness of selective serotonin reuptake inhibitors (SSRIs) in alleviating symptoms of patients with OCD, yet a considerable fraction of patients are non-responsive or minimally responsive to these agents. Despite this fact, SSRIs have remained the primary pharmacological treatment avenue for OCD. In recent years, multiple lines of evidence have implicated glutamatergic synaptic dysfunction within the cortico-striatal-thalamo-cortical (CSTC) brain circuit in the etiology of OCD and related disorders, thereby prompting intensified effort in the development and evaluation of agents that modulate glutamatergic neurotransmission for the treatment of OCD. With this in mind, here we review the following topics with respect to synaptic dysfunction and the neural circuitry underlying OCD: (1) evidence supporting the critical involvement of the CSTC circuit, (2) genetic studies supporting the involvement of glutamatergic dysfunction, (3) insights from genetic animal models of OCD, and (4) preliminary findings with glutamatergic neurotransmission-modulating agents in the treatment of OCD. Given the putative mechanistic overlap between OCD and the broader OC-spectrum of disorders, unraveling the synaptic basis of OCD has potential to translate into more effective treatments for an array of poorly understood human disorders.

强迫症(OCD)是一种使人衰弱的神经精神疾病,据估计,全世界有 1%-3% 的人深受其害。据估计,仅在美国,每年用于治疗和管理强迫症的资金就高达数十亿美元。目前,有关强迫症具体病因的证据明显不足。目前的假说主要集中在血清素(5-HT)系统,其依据是选择性血清素再摄取抑制剂(SSRIs)能有效缓解强迫症患者的症状,但相当一部分患者对这些药物无反应或反应很小。尽管如此,SSRIs 仍然是强迫症的主要药物治疗途径。近年来,多种证据表明,皮质-纹状体-丘脑-皮质(CSTC)脑回路中的谷氨酸能突触功能障碍与强迫症及相关疾病的病因有关,从而促使人们加大力度开发和评估用于治疗强迫症的调节谷氨酸能神经递质的药物。有鉴于此,我们在此回顾了有关突触功能障碍和强迫症神经回路的以下主题:(1) 支持 CSTC 回路关键参与的证据,(2) 支持谷氨酸能功能障碍参与的遗传研究,(3) 强迫症遗传动物模型的启示,以及 (4) 谷氨酸能神经递质调节药物治疗强迫症的初步发现。鉴于强迫症与更广泛的 OC 系列疾病之间可能存在机理上的重叠,揭示强迫症的突触基础有可能转化为更有效的治疗方法,用于治疗一系列人们对其了解甚少的人类疾病。
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Current chemical genomics
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