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Signaling Modulation Mediated by Ligand Water Interactions with the Sodium Site at μOR 配体水与μOR 钠位点相互作用所介导的信号调节
IF 18.2 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2024-07-17 DOI: 10.1021/acscentsci.4c00525
Rohini S. Ople, Nokomis Ramos-Gonzalez, Qiongyu Li, Briana L. Sobecks, Deniz Aydin, Alexander S. Powers, Abdelfattah Faouzi, Benjamin J. Polacco, Sarah M. Bernhard, Kevin Appourchaux, Sashrik Sribhashyam, Shainnel O. Eans, Bowen A. Tsai, Ron O. Dror, Balazs R. Varga, Haoqing Wang, Ruth Hüttenhain, Jay P. McLaughlin, Susruta Majumdar
The mu opioid receptor (μOR) is a target for clinically used analgesics. However, adverse effects, such as respiratory depression and physical dependence, necessitate the development of alternative treatments. Recently we reported a novel strategy to design functionally selective opioids by targeting the sodium binding allosteric site in μOR with a supraspinally active analgesic named C6guano. Presently, to improve systemic activity of this ligand, we used structure-based design, identifying a new ligand named RO76 where the flexible alkyl linker and polar guanidine guano group is swapped with a benzyl alcohol, and the sodium site is targeted indirectly through waters. A cryoEM structure of RO76 bound to the μOR-Gi complex confirmed that RO76 interacts with the sodium site residues through a water molecule, unlike C6guano which engages the sodium site directly. Signaling assays coupled with APEX based proximity labeling show binding in the sodium pocket modulates receptor efficacy and trafficking. In mice, RO76 was systemically active in tail withdrawal assays and showed reduced liabilities compared to those of morphine. In summary, we show that targeting water molecules in the sodium binding pocket may be an avenue to modulate signaling properties of opioids, and which may potentially be extended to other G-protein coupled receptors where this site is conserved.
μ阿片受体(μOR)是临床常用镇痛药的靶点。然而,由于呼吸抑制和身体依赖性等不良反应,有必要开发替代疗法。最近,我们报道了一种设计功能选择性阿片类药物的新策略,即以μOR中的钠结合异构位点为靶点,设计出一种具有骶上活性的镇痛药C6guano。目前,为了提高这种配体的系统活性,我们采用了基于结构的设计方法,确定了一种名为 RO76 的新配体,其中柔性烷基连接体和极性胍基与苯甲醇互换,通过水间接靶向钠位点。RO76 与 μOR-Gi 复合物结合的冷冻电镜结构证实,RO76 通过水分子与钠位点残基相互作用,而不像 C6guano 直接与钠位点结合。信号测定与基于 APEX 的接近标记相结合,表明钠口袋中的结合会调节受体的功效和贩运。在小鼠尾部戒断实验中,RO76 具有全身活性,与吗啡相比,其毒性有所降低。总之,我们的研究表明,以钠结合口袋中的水分子为靶点可能是调节阿片类药物信号传导特性的一个途径,而且有可能扩展到该位点保守的其他 G 蛋白偶联受体。
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引用次数: 0
Chemoproteomic Covalent Ligand Discovery as the PROTAC-gonist: The Future of Targeted Degradation Medicines 化学蛋白质组共价配体发现作为 PROTAC-配体:靶向降解药物的未来
IF 12.7 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2024-07-16 DOI: 10.1021/acscentsci.4c01093
Kyosuke Shishikura, Megan L. Matthews
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引用次数: 0
Pentaphosphorylation via the Anhydride of Dihydrogen Pentametaphosphate: Access to Nucleoside Hexa- and Heptaphosphates and Study of Their Interaction with Ribonuclease A 通过五偏磷酸二氢酐进行五磷酸化:获得核苷六磷酸盐和七磷酸盐并研究它们与核糖核酸酶 A 的相互作用
IF 12.7 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2024-07-15 DOI: 10.1021/acscentsci.4c00835
Gyeongjin Park, Evans C. Wralstad, N. Faginas-Lago, Kevin Qian, Ronald T. Raines, G. Bistoni, Christopher C. Cummins
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引用次数: 0
Cathepsin B Nuclear Flux in a DNA-Guided “Antinuclear Missile” Cancer Therapy DNA 引导的 "抗核导弹 "癌症疗法中的螯合蛋白 B 核通量
IF 12.7 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2024-07-15 DOI: 10.1021/acscentsci.4c00559
Fei Cao, Caroline Tang, Xiaoyong Chen, Zewei Tu, Ying Jin, Olivia M. Turk, Robert N. Nishimura, Allen Ebens, Valentina Dubljevic, James A. Campbell, Jiangbing Zhou, James E. Hansen
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引用次数: 0
Probing the Origin of Affinity in the GM1-Cholera Toxin Complex through Site-Selective Editing with Fluorine 通过氟的位点选择性编辑探究 GM1-Cholera Toxin 复合物亲和力的起源
IF 12.7 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2024-07-12 DOI: 10.1021/acscentsci.4c00622
Christina Jordan, Taiki Hayashi, Arnelle Löbbert, Jingran Fan, Charlotte S. Teschers, Kathrin Siebold, Marialuisa Aufiero, Felix Pape, Emma Campbell, Alexander Axer, Kathrin Bussmann, Klaus Bergander, Jesko Köhnke, A. Gossert, R. Gilmour
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引用次数: 0
Rolling on the Chip: SARS-CoV-2 Detection by DNA Motors 芯片上的滚动:通过 DNA 电机检测 SARS-CoV-2
IF 18.2 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2024-07-12 DOI: 10.1021/acscentsci.4c00940
Longjiang Ding, Na Liu
Rolosense uses DNA motors for SARS-CoV-2 detection, enabling rapid, smartphone-based testing with high specificity and sensitivity, useful for early diagnosis and outbreak control.
Rolosense 利用 DNA 马达检测 SARS-CoV-2 病毒,实现了基于智能手机的快速检测,具有高特异性和高灵敏度,可用于早期诊断和疫情控制。
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引用次数: 0
A New Facility Will Harness Plasma to Guide Interplanetary Craft 利用等离子体引导星际飞船的新设施
IF 18.2 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2024-07-10 DOI: 10.1021/acscentsci.4c01052
Katherine Bourzac
A plasma wind tunnel being built in Colorado will help test new ideas about navigating hypersonic vehicles in harsh conditions.
正在科罗拉多州建造的等离子风洞将有助于测试在恶劣条件下航行高超音速飞行器的新想法。
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引用次数: 0
A Semisynthetic Oligomannuronic Acid-Based Glycoconjugate Vaccine against Pseudomonas aeruginosa 基于半合成寡甘露糖酸的铜绿假单胞菌糖结合疫苗
IF 18.2 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2024-07-09 DOI: 10.1021/acscentsci.4c00387
Yiyue Zhang, Xiaotong Wang, Youling Liang, Liangliang Zhang, Jiahao Fan, You Yang
Pseudomonas aeruginosa is one of the leading causes of nosocomial infections and has become increasingly resistant to multiple antibiotics. However, development of novel classes of antibacterial agents against multidrug-resistant P. aeruginosa is extremely difficult. Herein we develop a semisynthetic oligomannuronic acid-based glycoconjugate vaccine that confers broad protection against infections of both mucoid and nonmucoid strains of P. aeruginosa. The well-defined glycoconjugate vaccine formulated with Freund’s adjuvant (FA) employing a highly conserved antigen elicited a strong and specific immune response and protected mice against both mucoid and nonmucoid strains of P. aeruginosa. The resulting antibodies recognized different strains of P. aeruginosa and mediated the opsonic killing of the bacteria at varied levels depending on the amount of alginate expressed on the surface of the strains. Vaccination with the glycoconjugate vaccine plus FA significantly promoted the pulmonary and blood clearance of the mucoid PAC1 strain of P. aeruginosa and considerably improved the survival rates of mice against the nonmucoid PAO1 strain of P. aeruginosa. Thus, the semisynthetic glycoconjugate is a promising vaccine that may provide broad protection against both types of P. aeruginosa.
铜绿假单胞菌是造成医院内感染的主要原因之一,而且对多种抗生素的耐药性越来越强。然而,开发针对耐多药铜绿假单胞菌的新型抗菌剂极其困难。在此,我们开发了一种基于低聚甘露糖醛酸的半合成糖结合疫苗,该疫苗能对粘液和非粘液铜绿假单胞菌菌株的感染产生广泛的保护作用。用弗罗因德佐剂(Freund's adjuvant,FA)配制的定义明确的糖结合疫苗采用了高度保守的抗原,能引起强烈的特异性免疫反应,保护小鼠免受铜绿假单胞菌粘液菌株和非粘液菌株的感染。由此产生的抗体能识别不同的铜绿假单胞菌菌株,并根据菌株表面藻酸盐的表达量,以不同的水平介导对细菌的杀灭。接种糖结合疫苗加 FA 能显著促进肺部和血液对铜绿假单胞菌粘液 PAC1 株的清除,并大大提高小鼠对铜绿假单胞菌非粘液 PAO1 株的存活率。因此,半合成糖轭合物是一种很有前景的疫苗,可针对两种类型的铜绿假单胞菌提供广泛的保护。
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引用次数: 0
Spatial Visualization of A-to-I Editing in Cells Using Endonuclease V Immunostaining Assay (EndoVIA) 利用内切酶 V 免疫染色测定 (EndoVIA) 观察细胞中 A 到 I 编辑的空间可视化情况
IF 18.2 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2024-07-07 DOI: 10.1021/acscentsci.4c00444
Alexandria L. Quillin, Benoît Arnould, Steve D. Knutson, Jennifer M. Heemstra
Adenosine-to-inosine (A-to-I) editing is one of the most widespread post-transcriptional RNA modifications and is catalyzed by adenosine deaminases acting on RNA (ADARs). Varying across tissue types, A-to-I editing is essential for numerous biological functions, and dysregulation leads to autoimmune and neurological disorders, as well as cancer. Recent evidence has also revealed a link between RNA localization and A-to-I editing, yet understanding of the mechanisms underlying this relationship and its biological impact remains limited. Current methods rely primarily on in vitro characterization of extracted RNA that ultimately erases subcellular localization and cell-to-cell heterogeneity. To address these challenges, we have repurposed endonuclease V (EndoV), a magnesium-dependent ribonuclease that cleaves inosine bases in edited RNA, to selectively bind and detect A-to-I edited RNA in cells. The work herein introduces an endonuclease V immunostaining assay (EndoVIA), a workflow that provides spatial visualization of edited transcripts, enables rapid quantification of overall inosine abundance, and maps the landscape of A-to-I editing within the transcriptome at the nanoscopic level.
腺苷-肌苷(A-to-I)编辑是最广泛的转录后 RNA 修饰之一,由作用于 RNA 的腺苷脱氨酶(ADARs)催化。不同组织类型的 A 到 I 编辑对多种生物功能至关重要,失调会导致自身免疫和神经系统疾病以及癌症。最近的证据还揭示了 RNA 定位与 A 到 I 编辑之间的联系,但人们对这种关系的内在机制及其生物学影响的了解仍然有限。目前的方法主要依赖于对提取的 RNA 进行体外表征,这最终会消除亚细胞定位和细胞间的异质性。为了应对这些挑战,我们重新利用了内切核酸酶 V(EndoV)--一种依赖于镁的核糖核酸酶,它能裂解编辑过的 RNA 中的肌苷酸碱基--来选择性地结合和检测细胞中 A 到 I 编辑过的 RNA。本文的研究工作介绍了一种内切酶 V 免疫染色测定(EndoVIA),该工作流程可提供编辑转录本的空间可视化,实现整体肌苷丰度的快速量化,并在纳米级水平上绘制转录本组中 A 到 I 编辑的全貌。
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引用次数: 0
A Novel Prodrug Strategy Based on Reversibly Degradable Guanidine Imides for High Oral Bioavailability and Prolonged Pharmacokinetics of Broad-Spectrum Anti-influenza Agents 一种基于可逆降解胍酰亚胺的新型原药策略,用于提高广谱抗流感药物的口服生物利用度和延长药代动力学时间
IF 18.2 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2024-07-04 DOI: 10.1021/acscentsci.4c00548
Yujeong Jung, Soo Bin Ahn, Taeyang An, Hyeon-Min Cha, Minjae Kim, Hyunjin Cheon, Yejin Jang, Haemi Lee, Byungil Kim, Meehyein Kim, Yan Lee
We present orally administrable prodrugs (OSC-GCDIs) of guanidino oseltamivir carboxylate (GOC) based on guanidine cyclic diimide (GCDI) to treat influenza viruses. By concealing the guanidine group, which significantly limits the intestinal absorption, its prodrugs OSC-GCDIs demonstrate dramatic improvement of oral bioavailability. The most promising antiviral substance OSC-GCDI(P) readily forms covalent adducts with serum proteins via a degradable linker after the intestinal absorption. Subsequently, the active species, GOC, is released from the conjugate in a sustained manner, which greatly contributes to improving pharmacokinetic properties. Because of the remarkable improvements in both oral bioavailability and longevity of its active metabolite, OSC-GCDI(P) demonstrates outstanding therapeutic efficacy against both wild-type and oseltamivir-resistant (H275Y) influenza virus strains in a mouse infection model, even with a single oral administration.
我们提出了基于胍基环二亚胺(GCDI)的胍基奥司他韦羧酸盐(GOC)口服原药(OSC-GCDIs),用于治疗流感病毒。胍基极大地限制了肠道吸收,通过隐藏胍基,其原药 OSC-GCDIs 显著提高了口服生物利用度。最有前途的抗病毒物质 OSC-GCDI(P)在肠道吸收后很容易通过可降解连接体与血清蛋白形成共价加合物。随后,活性物质 GOC 从共轭物中持续释放,这大大有助于改善药代动力学特性。由于 OSC-GCDI(P) 的口服生物利用度和活性代谢物的持久性都有了显著提高,因此在小鼠感染模型中,即使只口服一次,它对野生型和抗奥司他韦流感病毒(H275Y)株都有出色的疗效。
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