Current Opinion in Chemical Biology最新文献

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Small molecules as modulators of phage–bacteria interactions 小分子作为噬菌体与细菌相互作用的调节剂。

IF 6.9 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Current Opinion in Chemical Biology

Pub Date : 2025-02-01 DOI: 10.1016/j.cbpa.2024.102566

Joel W.H. Wong , Emily P. Balskus

Bacteriophages (phages) play a critical role in microbial ecology and evolution. Their interactions with bacteria are influenced by a complex network of chemical signals derived from a wide range of sources including both endogenous bacterial metabolites and exogenous environmental compounds. In this review, we highlight two areas where small molecules play a pivotal role in modulating phage behaviors. First, we discuss how temperate phages respond to various chemical cues that influence the lysis-lysogeny decision, describing recent advances in our understanding of noncanonical cues. Second, we examine the diverse array of small molecules that disrupt phage infection, potentially serving as bacterial defense strategies against their long-standing competitors. Collectively, this growing body of research highlights the intricate molecular mechanisms governing phage-bacteria dynamics, offering new perspectives on the chemical language shaping microbial communities.

噬菌体（phages）在微生物生态和进化中起着至关重要的作用。它们与细菌的相互作用受到广泛来源的复杂化学信号网络的影响，包括内源性细菌代谢物和外源性环境化合物。在这篇综述中，我们重点介绍了小分子在调节噬菌体行为中发挥关键作用的两个领域。首先，我们讨论了温带噬菌体如何对影响裂解-溶原性决定的各种化学线索作出反应，描述了我们对非规范线索的理解的最新进展。其次，我们研究了破坏噬菌体感染的各种小分子，这些小分子可能作为细菌对抗长期竞争对手的防御策略。总的来说，这一不断增长的研究强调了控制噬菌体-细菌动力学的复杂分子机制，为塑造微生物群落的化学语言提供了新的视角。

引用次数: 0

Advances in acid-degradable and enzyme-cleavable linkers for drug delivery 酸可降解和酶可切割药物传递连接体的研究进展。

IF 6.9 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Current Opinion in Chemical Biology

Pub Date : 2025-02-01 DOI: 10.1016/j.cbpa.2024.102552

Sheng Zhao , Na Yu , Hesong Han , Shutao Guo , Niren Murthy

Drug delivery vectors have the potential to improve the efficacy of therapeutics, including small molecules and nucleic acid-based drugs. However, challenges remain in developing linkages that enable the precise and efficient release of therapeutic cargo in response to mildly acidic environments or lysosomal enzymes. This review highlights recent advances in acid-degradable acetal/ketal and enzyme-cleavable linkages for endolysosomal release. These innovations include the developments of azido-acetal linkers with improved stability and hydrolysis kinetics, organocatalytic trans-isopropenylation for synthesizing asymmetric ketals and their applications in drug delivery, and enzyme-cleavable linkers activated by cathepsin B or β-galactosidase.

药物传递载体有可能提高治疗药物的疗效，包括小分子和核酸药物。然而，挑战仍然存在于开发连接，使治疗货物响应于温和的酸性环境或溶酶体酶的精确和有效的释放。本文综述了用于内溶酶体释放的酸可降解缩醛/酮和酶可切割键的最新进展。这些创新包括提高稳定性和水解动力学的叠氮-缩醛连接物的发展，用于合成不对称酮的有机催化反式异丙烯化及其在药物输送中的应用，以及由组织蛋白酶B或β-半乳糖苷酶激活的酶切割连接物。

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Peptide toxins as tools in ion channel biology 肽毒素作为离子通道生物学的工具。

IF 6.9 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Current Opinion in Chemical Biology

Pub Date : 2025-02-01 DOI: 10.1016/j.cbpa.2024.102568

Sucheta Bandyopadhyay , Satyajit Mishra , Jeet Kalia

Animal venom contains ion channel-targeting peptide toxins that inflict paralysis or pain. The high specificity and potency of these toxins for their target ion channels provides enticing opportunities for their deployment as tools in channel biology. Mechanistic studies on toxin-mediated ion channel modulation have yielded landmark breakthroughs in our understanding of channel architectures and gating mechanisms. Toxins have been recently repurposed as powerful structural biology probes to obtain structures of ion channels in elusive toxin-stabilized conformations providing unprecedented insights into channel gating. Insightful glimpses of protein–lipid interactions provided by some of these structures have served as blueprints for electrophysiology-based studies aimed at elucidating the functional roles of these interactions. Moreover, toxins appended with fluorophores have been used for clinical, biophysical, and cell biology-based studies. Herein, we summarize the contributions of ion channel-targeting toxins as tools in voltage-gated ion channel and transient receptor potential channel biology.

动物毒液含有离子通道靶向肽毒素，可造成瘫痪或疼痛。这些毒素对其目标离子通道的高特异性和效力为它们作为通道生物学工具的部署提供了诱人的机会。毒素介导离子通道调制的机制研究在我们对通道结构和门控机制的理解方面取得了里程碑式的突破。毒素最近被重新用作强大的结构生物学探针，以获得难以捉摸的毒素稳定构象的离子通道结构，为通道门控提供前所未有的见解。其中一些结构提供了对蛋白质-脂质相互作用的深刻见解，为旨在阐明这些相互作用的功能作用的基于电生理学的研究提供了蓝图。此外，与荧光团附加的毒素已被用于临床、生物物理和细胞生物学基础的研究。本文综述了离子通道靶向毒素作为工具在电压门控离子通道和瞬时受体电位通道生物学中的作用。

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Microbial metabolism of host-derived antioxidants 宿主来源抗氧化剂的微生物代谢。

IF 6.9 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Current Opinion in Chemical Biology

Pub Date : 2025-02-01 DOI: 10.1016/j.cbpa.2024.102565

Zhe Zhou , Stavroula K. Hatzios

Humans are exposed to a wide variety of small molecules with antioxidant properties that are poorly metabolized by mammalian cells. However, gastrointestinal microbes encode enzymes that convert these redox-active molecules into nutrient sources and electron acceptors to support bacterial growth in the gut. Here, we describe recent studies highlighting how microbial metabolism of host-derived antioxidants modulates interspecies interactions and provide an overview of the interdisciplinary approaches being used to map these metabolic pathways in vivo. Uncovering microbe-driven biotransformations of redox-active small molecules could create new opportunities to improve human health by modulating redox reactions at the host–microbe interface.

人类接触到各种各样的具有抗氧化特性的小分子，这些小分子在哺乳动物细胞中代谢不良。然而，胃肠道微生物编码酶，将这些氧化还原活性分子转化为营养来源和电子受体，以支持肠道内的细菌生长。在这里，我们描述了最近的研究，重点介绍了宿主来源的抗氧化剂的微生物代谢如何调节物种间的相互作用，并概述了用于绘制体内这些代谢途径的跨学科方法。揭示微生物驱动的氧化还原活性小分子的生物转化可以通过调节宿主-微生物界面的氧化还原反应来改善人类健康。

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Synthetic ion channels made of DNA 由DNA合成的离子通道。

IF 6.9 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Current Opinion in Chemical Biology

Pub Date : 2025-02-01 DOI: 10.1016/j.cbpa.2024.102567

Ran Tivony

Natural ion channels have long inspired the design of synthetic nanopores with protein-like features. A significant leap towards this endeavor has been made possible using DNA origami. The exploitation of DNA as a building material has enabled the construction of biomimetic DNA nanopores with a range of pore dimensions and stimuli-responsive capabilities. However, structural fluctuations and ion leakage across the walls of DNA nanopores greatly limit their use in various applications like label-free sensing and as a research tool in functional studies of ion channels. This review outlines some of the guiding principles for biomimetic engineering of DNA-based ion channels, discusses the weaknesses of current DNA nanopore designs, and presents recent efforts to alleviate these limitations.

天然离子通道长期以来激发了具有蛋白质样特征的合成纳米孔的设计。利用DNA折纸技术，这一努力取得了重大飞跃。利用DNA作为建筑材料，可以构建具有一系列孔隙尺寸和刺激响应能力的仿生DNA纳米孔。然而，DNA纳米孔壁的结构波动和离子泄漏极大地限制了它们在各种应用中的应用，如无标记传感和作为离子通道功能研究的研究工具。本文概述了基于DNA离子通道的仿生工程的一些指导原则，讨论了当前DNA纳米孔设计的弱点，并介绍了最近为减轻这些限制所做的努力。

引用次数: 0

Development of novel indicators and molecular systems for calcium sensing through protein engineering 利用蛋白质工程开发新的钙传感指标和分子系统。

IF 6.9 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Current Opinion in Chemical Biology

Pub Date : 2025-02-01 DOI: 10.1016/j.cbpa.2024.102547

Alicia Climent-Catala, Mateo I. Sanchez

Intracellular calcium (Ca²⁺) is involved in a plethora of cell signalling processes and physiological functions. Increases in Ca²⁺ concentration are bona fide biomarkers of neuronal activity, reflecting the spike count, timing, frequency, and the intensity of synaptic input. The development of genetically encoded calcium indicators (GECIs) was a significant advancement in modern neuroscience that enabled real-time visualisation of neuronal activity at single-cell resolution. These indicators leverage the conformational changes induced by calcium-binding proteins, such as calmodulin (CaM) or troponin C (TnC). Harnessing protein engineering approaches such as directed evolution yielded new GECIs with enhanced sensitivity, kinetics, and brightness. Notably, the development of calcium-based integrators, such as scFLARE (single-chain fast light- and activity-regulated expression), convert transient raises in cytosolic Ca²⁺ into a transcriptional readout rather than an optical signal. This review summarises the latest efforts in protein engineering to develop new indicators and molecular systems to sense changes in Ca²⁺ concentrations.

细胞内钙（Ca2+）参与过多的细胞信号传导过程和生理功能。Ca2+浓度的增加是神经元活动的真正生物标志物，反映了尖峰计数、时间、频率和突触输入的强度。基因编码钙指标（GECIs）的开发是现代神经科学的一个重大进步，它使单细胞分辨率下神经元活动的实时可视化成为可能。这些指标利用钙结合蛋白（如钙调蛋白（CaM）或肌钙蛋白C (TnC)）诱导的构象变化。利用蛋白质工程方法，如定向进化，产生了新的GECIs，具有更高的灵敏度、动力学和亮度。值得注意的是，基于钙的整合子的发展，如scFLARE（单链快速光和活性调节表达），将细胞质内Ca2+的短暂升高转化为转录读数而不是光信号。本文综述了蛋白质工程在开发Ca2+浓度变化的新指标和分子系统方面的最新进展。

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Synthetic peptide scaffolds as ion channels and molecular carriers 合成多肽支架作为离子通道和分子载体。

IF 6.9 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Current Opinion in Chemical Biology

Pub Date : 2025-02-01 DOI: 10.1016/j.cbpa.2024.102563

Manuel Pérez-Pérez, Alberto Fuertes, Javier Montenegro

Transmembrane ion exchange controls biological functions and is essential for life. Over the years, a great variety of nature-inspired artificial ion channels and carriers have been synthesized to control and promote ion exchange across biological membranes. In this context, peptides emerged as ideal scaffolds for synthetic ion channels due to their biocompatibility, accessibility and chemical versatility. Peptides have already shown their potential for the construction of a range of synthetic ion transporters either alone or in combination with other molecular scaffolds. Among the great diversity of peptide-based ion transporters, we can find key examples of single-molecule and supramolecular transmembrane ion channels and ionophores. Peptide scaffolds have also found great potential for the transmembrane delivery of biomolecular cargos such as nucleic acids and proteins. This review covers some of the most relevant advances in the peptide-based ion transport field from the last few years.

跨膜离子交换控制着生物功能，对生命至关重要。多年来，人们已经合成了多种受自然启发的人工离子通道和载体，以控制和促进生物膜上的离子交换。在这种情况下，肽由于其生物相容性、可及性和化学通用性而成为合成离子通道的理想支架。肽已经显示出它们在构建一系列合成离子转运体方面的潜力，无论是单独的还是与其他分子支架结合的。在肽基离子转运体的多样性中，我们可以找到单分子和超分子跨膜离子通道和离子载体的关键例子。肽支架也发现了跨膜递送生物分子货物如核酸和蛋白质的巨大潜力。本文综述了近年来肽类离子传输领域的一些最新进展。

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Foldamer-mediated transport across phospholipid bilayers 折叠体介导的磷脂双层转运

IF 6.9 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Current Opinion in Chemical Biology

Pub Date : 2024-11-30 DOI: 10.1016/j.cbpa.2024.102549

Iqra Zubair , Luis Martínez-Crespo , Simon J. Webb

Crucial physiological processes, like neural communication and muscle contraction, are mediated by protein channels in cell membranes. These natural channels typically have a central hydrophilic pore with tightly defined dimensions, which can be opened or closed (‘gated’) by external stimuli. Mimicking natural ion channels using synthetic molecules is a long-standing goal in artificial channel research. Although current synthetic channels have not yet achieved the same combination of high activity, high selectivity, and gating as natural channels, foldamers offer a new approach. Foldamers are unnatural oligomers that fold into defined three-dimensional shapes, similar to the way that natural polypeptides fold into secondary structures. With defined shapes and often multi-nanometre dimensions, foldamers have become valuable tools to mimic the behaviour of natural proteins in membranes. This review highlights selected recent examples of foldamer channels, examples that indicate how foldamer architectures may lead to controllable channels with high activity and selectivity.

关键的生理过程，如神经通讯和肌肉收缩，是由细胞膜中的蛋白质通道介导的。这些天然通道通常具有一个具有严格定义尺寸的中央亲水孔，可以通过外部刺激打开或关闭（“门控”）。利用合成分子模拟天然离子通道是人工通道研究的长期目标。虽然目前的合成通道还没有达到与天然通道相同的高活性、高选择性和门控组合，但折叠材料提供了一种新的方法。折叠物是一种非天然的低聚物，可以折叠成明确的三维形状，类似于天然多肽折叠成二级结构的方式。由于具有明确的形状和多纳米尺寸，文件夹已成为模拟膜中天然蛋白质行为的有价值的工具。这篇综述重点介绍了最近选择的文件夹通道的例子，这些例子表明文件夹架构如何导致具有高活性和选择性的可控通道。

引用次数: 0

Discovering microbiota functions via chemical probe incorporation for targeted sequencing 通过化学探针结合发现微生物群功能，用于靶向测序

IF 6.9 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Current Opinion in Chemical Biology

Pub Date : 2024-11-30 DOI: 10.1016/j.cbpa.2024.102551

Natalie Falco , Matthew E. Griffin

Our microbiota plays crucial roles in immune development and homeostasis and has been implicated in virtually all major diseases of the 21st century. Nevertheless, our understanding of the exact microbial functions that underlie these correlations remains extremely limited, due in large part to the difficulty of profiling cellular activities within non-model organisms and complex communities. Over the past decade, new flow cytometric approaches have been developed to distinguish specific microbial populations based on their interactions with metabolite analogs, modified biomolecules, and reactive compounds. By selecting and separating active microbes via fluorescence-activated cell sorting, PRobe INcorporation for Targeted sequencing (PRINT-seq) has inspired innovative approaches to identify and characterize functional members of our microbiota. Here, we provide a broad overview of this evolving technology and summarize how this method has been recently employed as a diagnostic fingerprint for diverse microbial activities.

我们的微生物群在免疫发育和体内平衡中起着至关重要的作用，并与21世纪几乎所有主要疾病有关。然而，我们对这些相关性背后的确切微生物功能的理解仍然非常有限，这在很大程度上是由于在非模式生物和复杂群落中分析细胞活动的困难。在过去的十年里，新的流式细胞术方法已经被开发出来，根据它们与代谢物类似物、修饰生物分子和活性化合物的相互作用来区分特定的微生物种群。通过荧光活化细胞分选选择和分离活性微生物，PRobe incorporated for Targeted sequencing （PRINT-seq）激发了识别和表征微生物群功能成员的创新方法。在这里，我们提供了这种不断发展的技术的广泛概述，并总结了这种方法最近如何被用作多种微生物活动的诊断指纹。

引用次数: 0

Forty sites of TRP channel regulation 40个TRP通道调控位点

IF 6.9 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Current Opinion in Chemical Biology

Pub Date : 2024-11-30 DOI: 10.1016/j.cbpa.2024.102550

Irina A. Talyzina, Kirill D. Nadezhdin, Alexander I. Sobolevsky

Transient receptor potential (TRP) channels are polymodal molecular sensors that integrate chemical, thermal, mechanical and electrical stimuli and convert them into ionic currents that regulate senses of taste, smell, vision, hearing, touch and contribute to perception of temperature and pain. TRP channels are implicated in the pathogenesis of numerous human diseases, including cancers, and represent one of the most ardently pursued drug targets. Recent advances in structural biology, particularly associated with the cryo-EM “resolution revolution”, yielded numerous TRP channel structures in complex with ligands that might have therapeutic potential. In this review, we describe the recent progress in TRP channel structural biology, focusing on the description of identified binding sites for small molecules, their relationship to membrane lipids, and interaction of TRP channels with other proteins. The characterized binding sites and interfaces create a diversity of druggable targets and provide a roadmap to aid in the design of new molecules for tuning TRP channel function in disease conditions.

瞬态受体电位（TRP）通道是多模态分子传感器，整合化学、热、机械和电刺激，并将其转化为离子电流，调节味觉、嗅觉、视觉、听觉、触觉，并有助于感知温度和疼痛。色氨酸通道与包括癌症在内的许多人类疾病的发病机制有关，是最受关注的药物靶点之一。结构生物学的最新进展，特别是与低温电镜“分辨率革命”相关的进展，产生了许多与配体复合物的TRP通道结构，这些结构可能具有治疗潜力。本文综述了TRP通道结构生物学的最新进展，重点介绍了小分子结合位点的描述、它们与膜脂的关系以及TRP通道与其他蛋白质的相互作用。表征的结合位点和界面创造了多种可药物靶点，并为帮助设计在疾病条件下调节TRP通道功能的新分子提供了路线图。

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