ACS Chemical Biology最新文献

{"title":"Pseudomonas Virulence Factor Produces Autoinducer (S)-Valdiazen","authors":"Drake M. Crawford,&nbsp;Jack C. Roche,&nbsp;Qiang Guo,&nbsp;Christopher Brache and Bo Li*,&nbsp;","doi":"10.1021/acschembio.4c0083710.1021/acschembio.4c00837","DOIUrl":"https://doi.org/10.1021/acschembio.4c00837https://doi.org/10.1021/acschembio.4c00837","url":null,"abstract":"<p ><i>Pseudomonas virulence</i> <i>factor</i> (<i>pvf</i>) produces an autoinducing small-molecule signal that regulates bacterial cell-to-cell communication and virulence. While genes like <i>pvf</i> have been linked to the production of small molecules containing a diazeniumdiolate group, the specific chemical signal produced by <i>pvf</i> had not been identified. In this study, we reveal that (<i>S</i>)-valdiazen is the autoinducer produced by <i>pvf</i> in <i>Pseudomonas entomophila</i>, a model for pathogen–host interactions. The (<i>S</i>)-configuration is crucial for the signaling activity of valdiazen at physiological concentrations. We also define the (<i>S</i>)-stereochemistry of leudiazen, a similar signal produced by the plant pathogen <i>Pseudomonas syringae</i>. Using <i>pvf</i> genes needed for (<i>S</i>)-valdiazen signaling and production in <i>P. entomophila</i>, we bioinformatically identified 5383 bacterial organisms that may produce diazeniumdiolate signals. Signaling activity of valdiazen can be quenched by potassium permanganate, which oxidizes the diazeniumdiolate moiety. Identification of (<i>S</i>)-diazeniumdiolates from two bacterial species suggests stereospecific biosynthesis and transduction of these signals. Our findings set the stage for discovering diazeniumdiolate signals from other bacteria.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 5","pages":"1029–1037 1029–1037"},"PeriodicalIF":3.5,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144067646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the Potential of Homologous Recombination Protein PALB2 in Synthetic Lethal Combinations","authors":"Xinyan Lu,&nbsp;Basilius Sauter,&nbsp;Aramis Keller,&nbsp;Saule Zhanybekova and Dennis Gillingham*,&nbsp;","doi":"10.1021/acschembio.5c0011110.1021/acschembio.5c00111","DOIUrl":"https://doi.org/10.1021/acschembio.5c00111https://doi.org/10.1021/acschembio.5c00111","url":null,"abstract":"<p >Cells with defective homologous recombination (HR) are highly sensitive to poly(ADP-ribose) polymerase (PARP) inhibition. Current therapeutic approaches leverage this vulnerability by using PARP inhibitors in cells with genetically compromised HR. However, if HR factors in cancer cells could be inhibited or degraded pharmacologically, it might reveal other opportunities for synergistic combinations. In this study, we developed a model system that recapitulates PARP/HR synthetic lethality by integrating a small-molecule responsive zinc-finger degron into the HR factor Partner and Localizer of BRCA2 (PALB2). We further tested a series of peptide ligands for PALB2 based on its natural binding partners, which led to the discovery of a high affinity peptide that will support future work on PALB2 and HR. Together, our findings validate PALB2 as a promising drug target and provide the tools and starting points for developing molecules with therapeutic applications.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 5","pages":"1099–1106 1099–1106"},"PeriodicalIF":3.5,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acschembio.5c00111","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144067709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neurotoxic Implications of Human Coronaviruses in Neurodegenerative Diseases: A Perspective from Amyloid Aggregation","authors":"Thi Hong Van Nguyen,&nbsp;Francois Ferron and Kazuma Murakami*,&nbsp;","doi":"10.1021/acschembio.5c0015310.1021/acschembio.5c00153","DOIUrl":"https://doi.org/10.1021/acschembio.5c00153https://doi.org/10.1021/acschembio.5c00153","url":null,"abstract":"<p >Human coronaviruses (HCoVs) include seven species: HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1, MERS-CoV, SARS-CoV-1, and SARS-CoV-2. The last three, classified as <i>Betacoronaviruses</i>, are highly transmissible and have caused severe pandemics. HCoV infections primarily affect the respiratory system, leading to symptoms such as dry cough, fever, and breath shortness, which can progress to acute respiratory failure and death. Beyond respiratory effects, increasing evidence links HCoVs to neurological dysfunction. However, distinguishing direct neural complications from preexisting disorders, particularly in the elderly, remains challenging. This study examines the association between HCoVs and neurodegenerative diseases like Alzheimer disease, Parkinson disease, Lewy body dementia, amyotrophic lateral sclerosis, and Creutzfeldt-Jakob disease. It also presents the long-term neurological effects of HCoV infections and their differential impact across age groups and sexes. A key aspect of this study is the investigation of the sequence and structural similarities between amyloidogenic and HCoV spike proteins, which can provide insights into potential neuropathomechanisms.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 5","pages":"983–992 983–992"},"PeriodicalIF":3.5,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144067829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of Comprehensive Screening and Assessment Assays for Small-Molecule Ligands of MALAT1 lncRNA","authors":"Mélanie Pernak,&nbsp;Claire Fleurisson,&nbsp;Cécile Delorme,&nbsp;Roba Moumné,&nbsp;Erica Benedetti,&nbsp;Laurent Micouin,&nbsp;Stéphane Azoulay*,&nbsp;Yann Foricher* and Maria Duca*,&nbsp;","doi":"10.1021/acschembio.5c0006110.1021/acschembio.5c00061","DOIUrl":"https://doi.org/10.1021/acschembio.5c00061https://doi.org/10.1021/acschembio.5c00061","url":null,"abstract":"<p >RNA targeting represents an original and promising approach to the discovery of new therapeutic tools against numerous diseases. The majority of intracellular RNAs are noncoding RNAs that play key regulatory functions in many physiological processes. Among these RNAs, long noncoding RNAs (lncRNAs) constitute the largest class of noncoding transcripts and have been shown to play important functional roles in development and disease processes. In this work, we developed a set of biochemical assays for the discovery of efficient small-molecule lncRNA ligands selective for their target, focusing on MALAT1 lncRNA. The latter bears a particular structure including a triple helical region important for its function, and it has been linked to cancer cells’ proliferation. However, its role in cancer still needs to be completely elucidated. The application of these assays to an original library of RNA binders allowed for the discovery of unprecedented ligands of the MALAT1 triple helix able to inhibit and destabilize the triple helical MALAT1 structure. The set of screening and validation assays developed could find application in the discovery of new MALAT1 binders, and the new chemical scaffolds discovered in this study represent promising chemical probes for the study of the biological role of MALAT1 in disease.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 5","pages":"1068–1076 1068–1076"},"PeriodicalIF":3.5,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144067788","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chemical Synthetic Lethality Screens Identify Selective Drug Combinations against Pseudomonas aeruginosa","authors":"Ellysia N. Overton,&nbsp;Yifan Zhang,&nbsp;Wabathi Ngecu and Mohammad R. Seyedsayamdost*,&nbsp;","doi":"10.1021/acschembio.5c0007610.1021/acschembio.5c00076","DOIUrl":"https://doi.org/10.1021/acschembio.5c00076https://doi.org/10.1021/acschembio.5c00076","url":null,"abstract":"<p >The emergence of bacterial ESKAPE pathogens presents a formidable challenge to global health, necessitating the development of innovative strategies for antibiotic discovery. Here, we leverage chemical synthetic lethality to locate therapeutic combinations of small molecules against multidrug-resistant <i>Pseudomonas aeruginosa</i>. Using a transposon screen, we identify PyrD as a target for sensitizing <i>P. aeruginosa</i> to subinhibitory doses of ceftazidime. High-throughput inhibitor screens identify two PyrD inhibitors, nordihydroguaiaretic acid (NDGA) and chlorhexidine (CHX), each of which does not significantly affect growth in isolation but exhibits chemical synthetic lethality when combined with low-dose ceftazidime. Downstream biochemical studies elucidate the mechanism of inhibition by NDGA and CHX. Remarkably, this combination is toxic to <i>P. aeruginosa</i> but leaves commensal bacteria, which are more susceptible to antibiotics, unscathed. Aside from advancing drug combinations that may be explored further in the future, our results offer a new approach for devising potent and specific drug combinations against recalcitrant pathogens.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 5","pages":"1077–1086 1077–1086"},"PeriodicalIF":3.5,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144067781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biosynthesis of Physcion and Identification of an O-Methyltransferase with C6–OH Selectivity in Aspergillus chevalieri BYST01","authors":"Zhong-di Huang,&nbsp;Shu-xiang Zhang,&nbsp;Ye Wang,&nbsp;Zhi-wen Song,&nbsp;Wei-yu Wang,&nbsp;Cai-ping Yin and Ying-lao Zhang*,&nbsp;","doi":"10.1021/acschembio.5c0000410.1021/acschembio.5c00004","DOIUrl":"https://doi.org/10.1021/acschembio.5c00004https://doi.org/10.1021/acschembio.5c00004","url":null,"abstract":"<p >Physcion, a polyketide natural product derived from plants and microorganisms, has been commercially approved as an agricultural fungicide for the prevention and treatment of powdery mildew. However, the long planting period and complex extraction process from plants limit the yield of physcion. Here, the <i>Phy</i> biosynthetic gene cluster responsible for physcion biosynthesis was identified from the genome of high-yield physcion strain <i>Aspergillus chevalieri</i> BYST01. We reconstructed the biosynthesis of physcion via heterologous expression of <i>PhyFGL</i> in <i>Aspergillus oryzae</i> NSAR1. Of note, the PT domain of <i>PhyG</i> catalyzes the selective ring closure to form two distinct polyketide scaffolds (<b>1</b> and <b>7</b>) and for the first time to report the biosynthetic pathway of compound pannorin C (<b>1</b>). In addition, in vitro and in vivo enzymatic assays demonstrated that PhyL had the capability to catalyze the stereoselective methylation of C6–OH. The physiological biosynthetic pathway was further rationally engineered by improving the catalytic efficiency of O-methyltransferase (OMT)-PhyL by 2.64-fold through site-directed mutagenesis. Subsequently, the titer of physcion reached 152.81 mg/L in shake-flask fermentation through optimizing the cultivation conditions and alkaline treatment of the fermentation broth. Furthermore, the novel CYP-PhyE could with regioselectivity catalyze symmetrically oxidative phenol coupling (OPC) of monomeric polyketone to form 10,10′-dimers. Finally, differential expression analysis of transcriptome between <i>AO-PhyGF</i> and <i>AO-PhyGFL</i> revealed that the expression of the <i>PhyL</i> gene led to extensive alterations in the secondary metabolism of <i>A. oryzae</i> NSAR1 and upregulating the expression level of ABC transporters, promoting the translocation of host metabolites. Thus, our study provides a foundation for further improving the production of physcion via a highly efficient route.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 5","pages":"1048–1058 1048–1058"},"PeriodicalIF":3.5,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144067787","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elucidating the Role of the Competence Regulon Quorum Sensing Circuitry in Streptococcus cristatus","authors":"Alec A. Brennan,&nbsp;Steven C. Tata,&nbsp;Clay P. Renshaw and Yftah Tal-Gan*,&nbsp;","doi":"10.1021/acschembio.5c0018010.1021/acschembio.5c00180","DOIUrl":"https://doi.org/10.1021/acschembio.5c00180https://doi.org/10.1021/acschembio.5c00180","url":null,"abstract":"<p ><i>Streptococcus cristatus</i> belongs to the Mitis group of streptococci and is an early colonizer of the human oral cavity. This species has recently been reclassified from <i>Streptococcus oligofermentans</i>, and as such, much information regarding the competence regulon and its regulatory role in modulating downstream phenotypes remains unknown. In this work, we set out to investigate the role of the competence-stimulating peptide (CSP) in competence regulon activation and modulation, as well as define the resultant transcriptomic and phenotypic effects of CSP exposure. To this end, following confirmation of the CSP identity, structure activity relationship (SAR) analyses were conducted and revealed residues integral for CSP::ComD binding and activation, as well as provided insights about the CSP secondary structure. The ability of synthesized CSP analogs to modulate the competence regulon was quantified with the aid of a newly developed luciferase-based reporter strain, after which the biological activity was correlated with peptide secondary structure derived through CD analysis. Furthermore, RNA-seq was utilized to gain broader insights about subsequent transcriptomic changes following CSP incubation, while phenotypic assays helped with visualizing resultant expression profiles. Lastly, to further explore the potential of <i>S. cristatus</i> as a potential biotherapeutic against the oral pathogen, <i>Streptococcus mutans</i>, interspecies competition assays were used to evaluate interactions between these two species.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 5","pages":"1123–1136 1123–1136"},"PeriodicalIF":3.5,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144067780","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Escherichia coli yybP-ykoY Riboswitch as a Tandem Riboswitch Regulated by Mn2+ and pH","authors":"Wenwen Xiao,&nbsp;Guangfeng Liu,&nbsp;Ting Chen,&nbsp;Yunlong Zhang,&nbsp;Ailong Ke*,&nbsp;Rujie Cai* and Changrui Lu*,&nbsp;","doi":"10.1021/acschembio.4c0071510.1021/acschembio.4c00715","DOIUrl":"https://doi.org/10.1021/acschembio.4c00715https://doi.org/10.1021/acschembio.4c00715","url":null,"abstract":"<p >The <i>Escherichia</i><i>coli</i> <i>yybP-ykoY</i> riboswitch regulates <i>mntP</i> and <i>alx</i> gene expression on the translation level. It contains two tandem domains regulated by Mn²⁺ and pH. This study investigates the tertiary structure and conformational dynamics of the <i>E. coli</i> <i>yybP-ykoY</i> riboswitch using a combination of crystallography, small-angle X-ray scattering (SAXS), and chemical probing. Our crystal structure of the aptamer domain at 3.8 Å reveals that the <i>yybP-ykoY</i> riboswitch aptamer domain forms a coaxial superhelix containing three helices connected by a three-way junction (3WJ), with L1 and L3 creating a pocket-like structure that binds Mg²⁺ and Mn²⁺. SHAPE probing and SAXS show that the <i>yybP-ykoY</i> riboswitch maintains a consistent conformation across pH conditions without Mn²⁺ but exhibits significant conformational changes under alkaline conditions when Mn²⁺ is present. These findings align with our proposed model, where Mn²⁺ binding induces a transition from an “OFF” to an “ON” state in alkaline conditions, while the Mn²⁺ remains bound to the aptamer independent of pH. This regulatory mechanism allows for more sophisticated control of gene expression, providing a finely tuned adaptive response to environmental changes.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 5","pages":"1010–1019 1010–1019"},"PeriodicalIF":3.5,"publicationDate":"2025-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144067774","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Amber Codon Mutational Scanning and Bioorthogonal PEGylation for Epitope Mapping of Antibody Binding Sites on Human Arginase-1.","authors":"Jaime Fernández de Santaella, Nikolaj G Koch, Lorenz Widmer, Michael A Nash","doi":"10.1021/acschembio.4c00692","DOIUrl":"10.1021/acschembio.4c00692","url":null,"abstract":"<p><p>Epitope mapping is crucial for understanding immunological responses to protein therapeutics. Here, we combined genetic code expansion and bacterial surface display to incorporate S-allylcysteine (SAC) into human arginase-1 (hArg1) via <i>Methanococcoides burtonii</i> pyrrolysyl-tRNA synthetase. Using an amber codon deep mutational scanning and sequencing workflow, we mapped SAC incorporation efficiency across the hArg1 sequence, providing insights into structural and sequence dependencies of noncanonical amino acid incorporation. We used mutually bioorthogonal allyl/tetrazine and azide/DBCO chemistries to achieve site-specific PEGylation and fluorescent labeling of hArg1, revealing insights into SAC side chain reactivity and solvent accessibility of residues in hArg1. This system was further applied to determine the binding epitope of a monoclonal antibody on the surface of hArg1, providing high-resolution data on the impact of PEGylation residue position on antibody binding. Our method produces high dimensional data of noncanonical amino acid incorporation efficiency, site-specific functionalization enabled by mutually bioorthogonal chemistries, and epitope mapping of therapeutic proteins.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"791-801"},"PeriodicalIF":3.5,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bringing Histidine Phosphorylation into Light: Role of Chemical Tools.","authors":"Solbee Choi, Shin Hyeon Lee, Jung-Min Kee","doi":"10.1021/acschembio.5c00103","DOIUrl":"10.1021/acschembio.5c00103","url":null,"abstract":"<p><p>Histidine phosphorylation is a historically underexplored post-translational modification (PTM). Once deemed \"elusive\" due to its chemical lability, phosphohistidine (pHis) has recently come to light thanks to emerging chemical tools─including stable pHis analogs, pHis-specific antibodies, and tailored proteomics workflows─that enable its detection and functional analysis. Together, these innovations have led to a surge in the identification of pHis sites and raised awareness of their roles in both bacterial and mammalian systems. New assay systems have also facilitated the characterization of histidine kinases and phosphatases. This Review summarizes recent breakthroughs in pHis research tools, examines the limitations of current approaches, and outlines future tools needed to fully unravel the potential of histidine phosphorylation.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"778-790"},"PeriodicalIF":3.5,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143784356","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}