ACS 化学生物学为广泛涵盖化学和生物学之间接口的研究提供了一个快速交流的国际论坛。该期刊还作为一个论坛，促进生物学家和化学家之间的交流，从而转化为新的研究机会和发现。将发表结果，其中分子推理已被用于通过体外研究、细胞生物学方法或有机体研究来探索问题。我们欢迎对蛋白质、核酸、糖、脂质和非生物聚合物的机械研究。该杂志服务于一个大型科学界，从化学和生物学角度探索细胞功能。据了解，提交的作品是基于原始结果，之前没有发表过。

ACS Chemical Biology provides an international forum for rapid communication of research that broadly encompasses the interface between chemistry and biology. The journal serves as a platform to facilitate interactions between biologists and chemists, leading to new research opportunities and discoveries. We welcome the publication of results where molecular reasoning has been applied to explore problems through in vitro studies, cell biology methods, or organismal research. We particularly encourage mechanistic studies on proteins, nucleic acids, carbohydrates, lipids, and non-biological polymers. This journal serves a large scientific community that explores cellular functions from both chemical and biological perspectives. Please note that submitted works must be based on original results and have not been previously published.

ACS Chemical Biology 是一个国际论坛，广泛涵盖化学与生物学交叉领域的研究。该期刊旨在促进生物学家与化学家之间的交流，从而催生新的研究机会和发现。我们欢迎发表利用分子推理，通过体外研究、细胞生物学方法或有机体研究探索问题的研究成果。我们特别关注对蛋白质、核酸、糖、脂质及非生物聚合物的机制研究。该期刊服务于一个庞大的科学社区，致力于从化学和生物学的角度探索细胞功能。请注意，提交的作品必须基于原创结果，且未曾发表过。

ACS Chemical Biology

The innate immune system provides the first line of defense against pathogens through the recognition of nonspecific patterns in RNA to protect the cell in a generalized way. The human RNA-activated protein kinase, PKR, is a dsRNA binding protein and an essential sensor in the innate immune response, which recognizes viral and bacterial pathogens through their RNAs. Upon activation via RNA-dependent autophosphorylation, PKR phosphorylates the eukaryotic initiation factor eIF2α, leading to termination of translation. PKR has a well-characterized role in recognizing viral RNA, where it binds long stretches of double-stranded RNA nonsequence specifically to promote activation; however, the mechanism by which bacterial RNA activates PKR and the mode by which self RNA avoids activating PKR are unknown. We characterized activation of PKR by three functional bacterial RNAs with pseudoknots and extensive tertiary structure: the cyclic di-GMP riboswitch, the glmS riboswitch-ribozyme, and the twister ribozyme, two of which are ligand-activated. These RNAs were found to activate PKR with comparable potency to long dsRNA. Enzymatic structure mapping in the absence and presence of PKR reveals a clear PKR footprint and provides a structural basis for how these bacterial RNAs activate PKR. In the case of the cyclic di-GMP riboswitch and the glmS riboswitch-ribozyme, PKR appears to dimerize on the peripheral double-stranded regions of the native RNA tertiary structure. Overall, these results provide new insights into how PKR acts as an innate immune signaling protein for the presence of bacteria and suggest a reason for the apparent absence of protein-free riboswitches and ribozymes in the human genome.

Chelsea M. Hull

Ananya Anmangandla

Philip C. Bevilacqua

Bacterial Riboswitches and Ribozymes Potently Activate the Human Innate Immune Sensor PKR

The development of new methods for delivering proteins into cells is a central challenge for advancing both basic research and therapeutic applications. We previously reported that zinc-finger nuclease proteins are intrinsically cell-permeable due to the cell-penetrating activity of the Cys2–His2 zinc-finger domain. Here, we demonstrate that genetically fused zinc-finger motifs can transport proteins and enzymes into a wide range of primary and transformed mammalian cell types. We show that zinc-finger domains mediate protein uptake at efficiencies that exceed conventional protein transduction systems and do so without compromising enzyme activity. In addition, we demonstrate that zinc-finger proteins enter cells primarily through macropinocytosis and facilitate high levels of cytosolic delivery. These findings establish zinc-finger proteins as not only useful tools for targeted genome engineering but also effective reagents for protein delivery.

Thomas Gaj

Jia Liu

Kimberly E. Anderson

Shannon J. Sirk

Carlos F. Barbas

Protein Delivery Using Cys2–His2 Zinc-Finger Domains

使用Cys2–His2锌指结构域的蛋白质递送

Pseudomonas aeruginosa is an important nosocomial pathogen that is frequently recalcitrant to available antibiotics, underlining the urgent need for alternative therapeutic options against this pathogen. Targeting virulence functions is a promising alternative strategy as it is expected to generate less-selective resistance to treatment compared to antibiotics. Capitalizing on our nonligand-based benzamide-benzimidazole (BB) core structure compounds reported to efficiently block the activity of the P. aeruginosa multiple virulence factor regulator MvfR, here we report the first class of inhibitors shown to interfere with PqsBC enzyme activity, responsible for the synthesis of the MvfR activating ligands HHQ and PQS, and the first to target simultaneously MvfR and PqsBC activity. The use of these compounds reveals that inhibiting PqsBC is sufficient to block P. aeruginosa's acute virulence functions, as the synthesis of MvfR ligands is inhibited. Our results show that MvfR remains the best target of this QS pathway, as we show that antagonists of this target block both acute and persistence-related functions. The structural properties of the compounds reported in this study provide several insights that are instrumental for the design of improved MvfR regulon inhibitors against both acute and persistent P. aeruginosa infections. Moreover, the data presented offer the possibility of a polypharmacology approach of simultaneous silencing two targets in the same pathway. Such a combined antivirulence strategy holds promise in increasing therapeutic efficacy and providing alternatives in the event of a single target's resistance development.

Damien Maura

Steffen L. Drees

Arunava Bandyopadhaya

Tomoe Kitao

Michele Negri

Melissa Starkey

Biliana Lesic

Sylvain Milot

Eric Déziel

Robert Zahler

Mike Pucci

Antonio Felici

Susanne Fetzner

François Lépine

Laurence G. Rahme

Polypharmacology Approaches against the Pseudomonas aeruginosa MvfR Regulon and Their Application in Blocking Virulence and Antibiotic Tolerance

针对铜绿假单胞菌MvfR调控子的多重药理学方法及其在阻断毒力和抗生素耐受中的应用

Methods for the delivery of exogenous substances to specific organelles are important because each organelle functions according to its own role. Specifically, mitochondria play an important role in energy production. Recently, plant mitochondrial transformation via delivery methods to mitochondria has been actively researched. Mitochondrial targeting sequences (MTSs) are essential for transporting bioactive molecules, such as nucleic acids, to mitochondria. However, the selectivity and efficacy of MTSs as carrier molecules in plants are not yet sufficient. In this study, we developed an effective MTS in plants via a quantitative comparison of the targeting functions of several MTSs. The presequence of HSP60 from Nicotiana tabacum, which is highly similar to that of several other model plants, showed high mitochondrial-targeting ability among the MTSs tested. This result suggests the applicability of the HSP60 presequence for MTSs in various plants. We further investigated this HSP60 presequence through stepwise shortening on the basis of secondary structure prediction, aiming to simplify synthesis and increase the solubility of the peptides. As shown by assessment of the mitochondrial targeting ability, the 15 residues from the N-terminus of the HSP60 presequence for the MTS, which is particularly conserved among various model plants, retained a targeting efficacy comparable to that of the full-length HSP60 presequence. This developed sequence from the HSP60 sequence is a promising MTS for transfection into plant mitochondria.

Naoya Abe

Masaki Odahara

Shamitha Rao Morey

Keiji Numata

Development of a Versatile Plant-Derived Mitochondrial Targeting Sequence Based on a Reporter Protein Sorting Analysis and Biological Information

基于报告蛋白分选分析和生物信息学的多功能植物源线粒体定位序列的开发

Small-molecule fluorescent probes embody an essential facet of chemical biology. Although numerous compounds are known, the ensemble of fluorescent probes is based on a modest collection of modular "core" dyes. The elaboration of these dyes with diverse chemical moieties is enabling the precise interrogation of biochemical and biological systems. The importance of fluorescence-based technologies in chemical biology elicits a necessity to understand the major classes of small-molecule fluorophores. Here, we examine the chemical and photophysical properties of oft-used fluorophores and highlight classic and contemporary examples in which utility has been built upon these scaffolds.

Luke D. Lavis

Ronald T. Raines

ACS Chem. Biol.

Bright Ideas for Chemical Biology

化学生物学中的创新思路

Xiaodong Tian

Yiyu Zhang

Hui-Wang Ai

PEGylated ATP-Independent Luciferins for Noninvasive High-Sensitivity High-Speed Bioluminescence Imaging

聚乙二醇化ATP非依赖型荧光素用于非侵入性高灵敏度高速生物发光成像

Noncanonical base pairs play an important role in enabling the structural and functional complexity of RNA. Molecular recognition of such motifs is challenging because of their diversity, significant deviation from the Watson-Crick structures, and dynamic behavior, resulting in alternative conformations of similar stability. Triplex-forming peptide nucleic acids (PNAs) have emerged as excellent ligands for the recognition of Watson-Crick base-paired double helical RNA. The present study extends the recognition potential of PNA to RNA helices having noncanonical GoU, AoC, and tandem GoA/AoG base pairs. The purines of the noncanonical base pairs formed M

Sara Farshineh Saei

Vladislavs Baskevics

Martins Katkevics

Eriks Rozners

Recognition of Noncanonical RNA Base Pairs Using Triplex-Forming Peptide Nucleic Acids

使用三链形成肽核酸识别非经典RNA碱基对

Flavin-dependent azoreductases have been applied to a wide range of tasks from decolorizing numerous azo dyes to releasing azo-conjugated prodrugs. A general narrative reiterated in much of the literature suggests that this enzyme promotes sequential reduction of both the azo-containing substrate and its corresponding hydrazo product to release the aryl amine components while consuming two equivalents of NAD(P)H. Indeed, such aryl amines can be formed by incubation of certain azo compounds with azoreductases, but the nature of the substrates capable of this apparent azo bond lysis remained unknown. We have now prepared a set of azobenzene derivatives and characterized their turnover and products after treatment with azoreductase from Escherichia coli to discover the structural basis regulating aryl amine formation. Without resonance donation by aryl substituents, reduction ceases at the hydrazo product. This indicates that azoreductases do not act on the hydrazo bond. Instead, aryl amine formation depends on a spontaneous hydrazo bond lysis that is promoted by resonance stabilization and subsequent reduction of the quinone-like intermediate by azoreductase. Experimental and computational approaches confirm the substituent dependence of this process. With knowledge of this requirement, full release of aryl amines from azo-conjugates can now be designed and applied with confidence.

Yu-Ju Peng

Bing Xu

Steven E. Rokita

Breaking the Myth of Enzymatic Azoreduction

打破酶促偶氮还原的神话

Although methods for Cys-specific bioconjugation and functionalization of proteins have been developed and widely utilized in biomolecule engineering and therapeutic development, reagents for this purpose are generally designed to accomplish bioconjugation only. Consequently, additional clickable groups must be attached to these reagents to accomplish functionalization. Herein, we describe a new, simple, dual-performing bioconjugation–functionalization reagent, VMeTz, which possesses an electron-withdrawing tetrazine (Tz) substituted vinyl (V) moiety to serve as both a Michael receptor for selective conjugation with Cys and a site for click with TCO derivatives to introduce functionality. Critically, VMeTz contains a methyl group that prevents the formation of multiple Tz-containing Cys-adducts. Reactions of VMeTz with Cys-containing peptides and proteins both in vitro and in live cells produce single stable Michael adducts with high selectivity. Moreover, the Cys-VMeTz peptide and protein conjugates undergo facile click reactions with TCO-functionalized reagents for labeling and protein profiling. Furthermore, VMeTz selectively activates and delivers the TCO-caged toxic substances Dox and PROTAC ARV-771 to cancer cells to produce therapeutic effects that are comparable to those of the parent drugs. Collectively, the studies demonstrate that VMeTz is a useful reagent for therapeutically significant Cys-specific protein bioconjugation and functionalization.

Mengyang Chang

Hang Xu

Yue Dong

Giri Gnawali

Fangchao Bi

Wei Wang

Dual-Performing Vinyltetrazine for Rapid, Selective Bioconjugation and Functionalization of Cysteine Proteins

用于快速、选择性生物偶联和半胱氨酸蛋白功能化的双功能乙烯四唑

Oligonucleotides are a rapidly emerging class of therapeutics. Their most well-known examples are informational drugs that modify gene expression by binding mRNA. Despite inducing proximity between biological machinery and mRNA when applied to modulating gene expression, oligonucleotides are not typically labeled as "proximity-inducing" in literature. Yet, they have recently been explored as building blocks for multispecific proximity-inducing drugs (MPIDs). MPIDs are unique because they can direct endogenous biological machinery to destroy targeted molecules and cells, in contrast to traditional drugs that inhibit only their functions. The unique mechanism of action of MPIDs has enabled the targeting of previously "undruggable" molecular entities that cannot be effectively inhibited. However, the development of MPIDs must ensure that these molecules will selectively direct a potent, destruction-based mechanism of action toward intended targets over healthy tissues to avoid causing life-threatening toxicities. Oligonucleotides have emerged as promising building blocks for the design of MPIDs because they are sequence-controlled molecules that can be rationally designed to program multispecific binding interactions. In this Review, we examine the emergence of oligonucleotide-containing MPIDs in the proximity induction space, which has been dominated by antibody and small molecule MPID modalities. Moreover, examples of oligonucleotides developed as MPID candidates in immunotherapy and protein degradation are discussed to demonstrate the utility of oligonucleotides in expanding the scope and selectivity of the MPID toolbox. Finally, we discuss the utility of programming "AND" gates into oligonucleotide scaffolds to encode conditional responses that have the potential to be incorporated into MPIDs, which can further enhance their selectivity, thus increasing the scope of this drug category.

Kevin Xiao Tong Zhou

Katherine E. Bujold

The Emergence of Oligonucleotide Building Blocks in the Multispecific Proximity-Inducing Drug Toolbox of Destruction

寡核苷酸构建模块在破坏性多特异性邻近诱导药物工具箱中的出现

Abbreviation	ACS Chem. Biol.
Journal Impact	3.38
Quartiles(Global)	BIOCHEMISTRY & MOLECULAR BIOLOGY(Q2)

ISSN	1554-8929, 1554-8937
h-index	135

Publication Information	Publisher: American Chemical Society，Publishing cycle: Monthly，Journal Type: journal，Open Access Journals: No
Basic data	Year of publication: 2006，Proportion of original research papers: 97.46%，Self Citation Rate:2.90%， Gold OA Rate: 14.94%
Average review cycle	网友分享经验：平均3.3个月
Average recruitment ratio	网友分享经验：较易

ACS Chemical Biology

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