Current Opinion in Chemical Biology最新文献

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Illuminating antifungal mode of action and resistance with fluorescent probes 荧光探针阐明抗真菌作用方式及耐药性

IF 6.9 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Current Opinion in Chemical Biology

Pub Date : 2025-04-01 Epub Date: 2025-02-17 DOI: 10.1016/j.cbpa.2025.102570

Moriah Jospe-Kaufman, Micha Fridman

The rise in fungal infections, driven by pathogens resistant to the limited scope of antifungal agents available, poses an increasing threat to global health and the economy. Addressing this challenge requires a thorough understanding of the mechanisms of antifungal agents and the development of advanced resistance diagnostic methods. This opinion manuscript highlights recent advancements in antifungal research, with a focus on chemical biology approaches, particularly the development of fluorescent probes derived from various antifungal agents. These probes reveal new aspects of antifungal activity and provide deeper insights into modes of action and resistance mechanisms. Live cell imaging of fungal pathogens labeled with these probes has uncovered novel strategies to enhance antifungal efficacy, understand virulence factors, and detect resistance. These unique small-molecule tools offer powerful new avenues for addressing the fungal infections crisis, harnessing chemical biology approaches to develop innovative solutions to the global challenges posed by fungi.

由于病原体对有限范围的可用抗真菌药物具有耐药性，真菌感染的增加对全球健康和经济构成越来越大的威胁。解决这一挑战需要彻底了解抗真菌药物的机制和开发先进的耐药性诊断方法。这份意见稿强调了抗真菌研究的最新进展，重点是化学生物学方法，特别是来自各种抗真菌剂的荧光探针的发展。这些探针揭示了抗真菌活性的新方面，并为作用模式和耐药机制提供了更深入的见解。用这些探针标记的真菌病原体的活细胞成像揭示了增强抗真菌功效、了解毒力因素和检测耐药性的新策略。这些独特的小分子工具为解决真菌感染危机提供了强大的新途径，利用化学生物学方法开发创新的解决方案，以应对真菌带来的全球挑战。

引用次数: 0

Recent advances in high-throughput screening methods for small molecule modulators in bacteria 细菌小分子调节剂高通量筛选方法研究进展

IF 6.9 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Current Opinion in Chemical Biology

Pub Date : 2025-04-01 Epub Date: 2025-02-14 DOI: 10.1016/j.cbpa.2025.102571

Hannah G. Addis , Erin E. Carlson

Bacterial infections, especially those that are resistant to antibiotics, constitute an increasing threat to public health. Deeper understanding about the systems that govern resistant infections, followed by the design of new therapies is crucial to minimizing morbidity and mortality due to antibacterial resistance. To this end, the discovery of small molecules capable of modulating bacterial processes is an important goal. Herein, we summarize recent developments in high-throughput screening, including the use of in vitro biochemical assays, reporter fusion read-out methods, and live cell phenotypic assays in bacteria. We also highlight key advantages and disadvantages of each assay type, as well as exciting new innovations.

细菌感染，特别是对抗生素具有耐药性的细菌感染，对公众健康构成日益严重的威胁。更深入地了解控制耐药感染的系统，然后设计新的治疗方法，对于最大限度地减少由于抗菌药物耐药性引起的发病率和死亡率至关重要。为此，发现能够调节细菌过程的小分子是一个重要的目标。在此，我们总结了高通量筛选的最新进展，包括体外生化分析、报告融合读出方法和细菌活细胞表型分析的使用。我们还强调了每种检测类型的主要优点和缺点，以及令人兴奋的新创新。

引用次数: 0

Bacterial peptidoglycan as a living polymer 细菌肽聚糖是一种活的聚合物。

IF 6.9 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Current Opinion in Chemical Biology

Pub Date : 2025-02-01 Epub Date: 2024-12-18 DOI: 10.1016/j.cbpa.2024.102562

Amr M. El-Araby, Jed F. Fisher, Shahriar Mobashery

The peptidoglycan manifests as a multifaceted component of the bacterial cell wall. Throughout the lifecycle of the bacterium, the peptidoglycan is deconstructed, rebuilt, and remodeled for bacterial cell growth and replication. Degradation products of the peptidoglycan serve as precursors for cell-wall building blocks via recycling processes and as signaling molecules. Cell-wall recycling and de novo cell-wall synthesis converge biochemically at the cytoplasmic compartment. Peptidoglycan biochemistry is finely tuned to maintain the polymer's functions and is intimately connected to antibiotic-resistance mechanisms. Cell-wall-modifying enzymes present a unique opportunity for the discovery of antibiotics and antibiotic adjuvants. The unique chemical template of the peptidoglycan has been a target of numerous chemical biology approaches for investigating its functions and modulation. In this review, we highlight the current perspective on peptidoglycan research. We present recent efforts to understand the peptidoglycan as a functional component of antibiotic resistance, and as a target for antimicrobial therapy.

肽聚糖是细菌细胞壁的多层面组成部分。在细菌的整个生命周期中，肽聚糖被分解、重建和重塑，以促进细菌细胞的生长和复制。肽聚糖的降解产物通过再循环过程成为细胞壁结构单元的前体和信号分子。细胞壁再循环和细胞壁从头合成在细胞质区进行生化交汇。肽聚糖的生物化学经过精细调整，以维持聚合物的功能，并与抗生素耐药性机制密切相关。细胞壁修饰酶为发现抗生素和抗生素佐剂提供了一个独特的机会。肽聚糖的独特化学模板一直是众多化学生物学方法研究其功能和调节的目标。在本综述中，我们将重点介绍肽聚糖研究的现状。我们介绍了最近为了解肽聚糖作为抗生素耐药性功能成分和抗菌治疗靶点所做的努力。

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引用次数: 0

Developing photoactivated artificial enzymes for sustainable fuel production 开发用于可持续燃料生产的光激活人工酶。

IF 6.9 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Current Opinion in Chemical Biology

Pub Date : 2025-02-01 Epub Date: 2024-12-29 DOI: 10.1016/j.cbpa.2024.102553

Ashlee E. Wertz , Hannah S. Shafaat

Enzymes catalyze molecular reactions with remarkable efficiency and selectivity under mild conditions. Photoactivated enzymes make use of a light-absorbing chromophore to drive chemical transformations, ideally using sunlight as an energy source. The direct attachment of a chromophore to native enzymes is advantageous, as information on the underlying catalytic mechanisms can be obtained. Artificial enzyme development seeks to mimic natural enzymes to generate valuable products with high efficiency in a simplified, robust framework. Light-initiated artificial enzymatic catalysis combines these strategies and represents a promising avenue for sustainable generation of value-added products. Furthermore, while early systems often combined three components for catalysis-- the enzyme, a photosensitizer, and a sacrificial electron donor-- we describe an adaptation of this approach in which the chromophore is immobilized on the enzyme, removing the need for diffusional collision. The latter is advantageous as it provides deeper insight into the catalytic mechanism and facilitates further optimization of the designed construct. In this opinion, we highlight several examples of light-driven, artificial metalloenzymes, and suggest that ongoing and future efforts should leverage prior mechanistic studies on native enzymes as a foundation for strategic design of next-generation photoactivated protein-based catalysts.

酶在温和条件下催化分子反应具有显著的效率和选择性。光激活酶利用吸收光的发色团来驱动化学转化，理想情况下使用阳光作为能量来源。发色团与天然酶的直接连接是有利的，因为可以获得有关潜在催化机制的信息。人工酶的发展旨在模仿天然酶，在简化、健壮的框架内高效地产生有价值的产品。光引发的人工酶催化结合了这些策略，代表了可持续产生增值产品的有前途的途径。此外，虽然早期的系统通常结合三种成分进行催化-酶，光敏剂和牺牲电子供体-我们描述了这种方法的适应性，其中发色团固定在酶上，消除了扩散碰撞的需要。后者是有利的，因为它提供了对催化机制的更深入的了解，并有利于进一步优化所设计的结构。在这种观点下，我们强调了几个光驱动的人工金属酶的例子，并建议正在进行的和未来的努力应该利用现有的天然酶的机制研究作为下一代光激活蛋白催化剂战略设计的基础。

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引用次数: 0

Corrigendum to “Drug discovery targeting Nav1.8: Structural insights and therapeutic potential” [Curr Opin Chem Biol 83 (2024) 102538] 针对 Nav1.8 的药物发现：结构见解和治疗潜力》[Curr Opin Chem Biol 83 (2024) 102538] 更正

IF 6.9 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Current Opinion in Chemical Biology

Pub Date : 2025-02-01 Epub Date: 2024-11-25 DOI: 10.1016/j.cbpa.2024.102546

Huan Wang , Jian Huang , Jie Zang , Xueqin Jin , Nieng Yan

引用次数: 0

Synthetic ion channels in biomembranes 生物膜中的合成离子通道。

IF 6.9 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Current Opinion in Chemical Biology

Pub Date : 2025-02-01 Epub Date: 2024-11-20 DOI: 10.1016/j.cbpa.2024.102544

Ai Kohata , Kazushi Kinbara

Ion transport across cell membranes is crucial in maintaining ion homeostasis in cells. Synthetic molecules that can mimic the functions of natural ion channel proteins would possess great potential as therapeutic agents by promoting apoptosis or interfering with autophagic processes through perturbing the intracellular pH or inducing oxidative and osmotic stresses. However, little is known about the underlying mechanisms in terms of direct correlation between ion transport and biological functions. This review summarizes recent progress in the area of synthetic transmembrane ion transport systems, focusing on the channel type, with an emphasis on their bioapplications as anticancer agents.

离子在细胞膜上的转运是维持细胞离子平衡的关键。能模拟天然离子通道蛋白功能的合成分子通过扰乱细胞内 pH 值或诱导氧化和渗透压力，促进细胞凋亡或干扰自噬过程，具有很大的治疗潜力。然而，人们对离子转运与生物功能直接相关的内在机制知之甚少。本综述总结了合成跨膜离子转运系统领域的最新进展，重点是通道类型，并着重介绍了它们作为抗癌剂的生物应用。

引用次数: 0

Illuminating anions in biology with genetically encoded fluorescent biosensors 用基因编码荧光生物传感器照亮生物学中的阴离子。

IF 6.9 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Current Opinion in Chemical Biology

Pub Date : 2025-02-01 Epub Date: 2024-12-09 DOI: 10.1016/j.cbpa.2024.102548

Mariah A. Cook , Shelby M. Phelps , Jasmine N. Tutol , Derik A. Adams, Sheel C. Dodani

Anions are critical to all life forms. Anions can be absorbed as nutrients or biosynthesized. Anions shape a spectrum of fundamental biological processes at the organismal, cellular, and subcellular scales. Genetically encoded fluorescent biosensors can capture anions in action across time and space dimensions with microscopy. The firsts of such technologies were reported more than 20 years for monoatomic chloride and polyatomic cAMP anions. However, the recent boom of anion biosensors illuminates the unknowns and opportunities that remain for toolmakers and end users to meet across the aisle to spur innovations in biosensor designs and applications for discovery anion biology. In this review, we will canvas progress made over the last three years for biologically relevant anions that are classified as halides, oxyanions, carboxylates, and nucleotides.

阴离子对所有生命形式都至关重要。阴离子可以作为营养物被吸收或被生物合成。阴离子在有机体、细胞和亚细胞尺度上塑造了一系列基本的生物过程。基因编码的荧光生物传感器可以通过显微镜捕捉在时间和空间维度上的阴离子。这类技术的首次报道是在20多年前对单原子氯离子和多原子cAMP阴离子进行的。然而，最近阴离子生物传感器的蓬勃发展为工具制造商和最终用户提供了未知和机会，以刺激生物传感器设计和应用的创新，以发现阴离子生物学。在这篇综述中，我们将回顾过去三年在生物相关阴离子方面取得的进展，这些阴离子被分类为卤化物、氧阴离子、羧酸盐和核苷酸。

引用次数: 0

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 : 2025-02-01 Epub 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

Enabling structural biological electron paramagnetic resonance spectroscopy in membrane proteins through spin labelling 通过自旋标记实现膜蛋白结构生物电子顺磁共振波谱。

IF 6.9 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Current Opinion in Chemical Biology

Pub Date : 2025-02-01 Epub Date: 2024-12-21 DOI: 10.1016/j.cbpa.2024.102564

Anokhi Shah , Joshua L. Wort , Yue Ma , Christos Pliotas

Pulsed dipolar electron paramagnetic resonance spectroscopy (PDS), combined with site-directed spin-labelling, represents a powerful tool for the investigation of biomacromolecules, emerging as a keystone approach in structural biology. Increasingly, PDS is applied to study highly complex integral membrane protein systems, such as mechanosensitive ion channels, transporters, G-protein coupled receptors, ion pumps, and outer membrane proteins elucidating their dynamics and revealing conformational ensembles. Indeed, PDS offers a platform to study intermediate or lowly-populated states that are otherwise invisible to other modern methods, such as X-ray crystallography, cryo-EM, and hydrogen-deuterium exchange-mass spectrometry. Importantly, advances in spin labelling strategies welcome a new era of membrane protein investigation under near-native or in-cell conditions. Here, we review recent integral membrane protein PDS applications, and highlight well-suited, emerging spin labelling strategies that show promise for future studies.

脉冲偶极电子顺磁共振波谱（PDS）与定点自旋标记相结合，是研究生物大分子的有力工具，是结构生物学研究的重要手段。PDS越来越多地被应用于研究高度复杂的整体膜蛋白系统，如机械敏感离子通道、转运体、g蛋白偶联受体、离子泵和外膜蛋白，以阐明它们的动力学和揭示构象集合。事实上，PDS提供了一个研究中间或低密度态的平台，否则其他现代方法是看不见的，如x射线晶体学，低温电子显微镜和氢-氘交换质谱法。重要的是，自旋标记策略的进步迎来了近天然或细胞内条件下膜蛋白研究的新时代。在这里，我们回顾了最近的整体膜蛋白PDS应用，并强调了适合的，新兴的自旋标记策略，显示出未来研究的希望。

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 : 2025-02-01 Epub 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。

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