ACS Chemical Biology最新文献

{"title":"","authors":"Maria V. Filsinger Interrante, Shaogeng Tang, Soohyun Kim, Varun R. Shanker, Brian L. Hie, Theodora U. J. Bruun, Wesley Wu, John E. Pak, Daniel Fernandez and Peter S. Kim*, ","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 7","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":3.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschembio.5c00035","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144646166","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":"","authors":"Zhe Yang, Tomoki Takahashi, Ayase Hoshino, Tatsuya Yamamoto, Hideyuki Shigemori and Yusaku Miyamae*, ","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 7","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":3.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschembio.5c00220","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144646177","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":"","authors":"Rashmi S. Bhosale, Arnab Chakraborty, Tsung-Yun Wong, Dattatraya P. Masal, Rahul Choudhury, Sonali Srivastava, D. Srinivasa Reddy, Courtney C. Aldrich, Siddhesh S. Kamat, Debasisa Mohanty and Rajesh S. Gokhale*, ","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 7","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":3.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschembio.5c00078","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144646179","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":"","authors":"Nisansala Vithanage, Rifat Hasan Apurba, Hamza Enesi Ozomarisi, Carson J. Bair, Eve L. Sugg and Victor K. Outlaw*, ","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 7","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":3.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschembio.5c00208","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144646195","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":"Borinic Acid-Based Fluorogenic Probes as an Alternative to the Amplex Red Assay for Real-Time H₂O₂ Monitoring in Live Cells.","authors":"Mathilde Pucher, Kirrthana Makenthirathasan, Hadrien Jalaber, Thomas LeSaux, Oliver Nüsse, Gilles Doisneau, Yann Bourdreux, Blaise Gatin-Fraudet, Ludovic Jullien, Boris Vauzeilles, Dominique Guianvarc'h, Marie Erard, Dominique Urban","doi":"10.1021/acschembio.5c00156","DOIUrl":"10.1021/acschembio.5c00156","url":null,"abstract":"<p><p>Hydrogen peroxide (H₂O₂) is a crucial reactive oxygen species (ROS) involved in regulating both physiological and pathological processes. Excessive H₂O₂ production can lead to oxidative stress, contributing to aging, cancer, and neurodegenerative diseases. In contrast to other ROS exhibiting short lifespans, H₂O₂ is relatively stable, and its spatial and temporal dynamics are central to understanding its pathophysiological role. Therefore, the development of fluorescent probes that are highly selective, sensitive, and capable of a rapid response is still required. To date, numerous fluorescent probes have been developed. Among them, boronic acid triggers have attracted considerable attention but often suffer from limited reactivity, preventing real-time H₂O₂ monitoring. To overcome this lack of reactivity, we report the design and synthesis of new borinic acid-based fluorogenic probes for H₂O₂ detection in cellular environments. These probes are based on a hemicyanine scaffold functionalized with the borinic acid trigger, which demonstrated superior kinetics compared to its boronic counterpart. These probes enable efficient real-time monitoring of H₂O₂ in cellular models, both extracellularly and intracellularly. The kinetics of these enzyme-free chemical probes matched that of the gold standard Amplex UltraRed/horseradish peroxidase (HRP) assay, representing a significant advancement in the field and offering a versatile and sensitive tool for studying H₂O₂-mediated cell signaling.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"1574-1583"},"PeriodicalIF":3.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144493131","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":"Utilizing Machine Learning to Improve Neutralization Potency of an HIV-1 Antibody Targeting the gp41 N-Heptad Repeat.","authors":"Maria V Filsinger Interrante, Shaogeng Tang, Soohyun Kim, Varun R Shanker, Brian L Hie, Theodora U J Bruun, Wesley Wu, John E Pak, Daniel Fernandez, Peter S Kim","doi":"10.1021/acschembio.5c00035","DOIUrl":"10.1021/acschembio.5c00035","url":null,"abstract":"<p><p>The N-heptad repeat (NHR) of the HIV-1 gp41 prehairpin intermediate (PHI) is an attractive potential vaccine target with high sequence conservation across diverse strains. However, despite the potency of NHR-targeting peptides and clinical efficacy of the NHR-targeting entry inhibitor enfuvirtide, no potently neutralizing NHR-directed monoclonal antibodies (mAbs) nor antisera have been identified or elicited to date. The lack of potent NHR-binding mAbs both dampens enthusiasm for vaccine development efforts at this target and presents a barrier to performing passive immunization experiments with NHR-targeting antibodies. To address this challenge, we previously developed an improved variant of the NHR-directed mAb D5, called D5_AR, which is capable of neutralizing diverse tier-2 viruses. Building on that work, here we present the 2.7Å-crystal structure of D5_AR bound to NHR mimetic peptide IQN17. We then utilize protein language models and supervised machine learning to generate small (<i>n</i> < 100) libraries of D5_AR variants that are subsequently screened for improved neutralization potency. We identify a variant with 5-fold improved neutralization potency, D5_FI, which is the most potent NHR-directed monoclonal antibody characterized to date and exhibits broad neutralization of tier-2 and -3 pseudoviruses as well as replicating R5 and X4 challenge strains. Additionally, our work highlights the ability of protein language models to efficiently identify improved mAb variants from relatively small libraries.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"1470-1480"},"PeriodicalIF":3.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12281478/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144332047","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":"Mediator Kinase Inhibitor Selectivity and Activity in Colorectal Cancer.","authors":"Maria J Ortiz-Ruiz, Olajumoke Popoola, Konstantinos Mitsopoulos, Robert Te-Poele, Rahul S Samant, Gary Box, Will Court, Alexis De Haven Brandon, Sharon Gowan, Aurelie Mallinger, Toby Roe, Kate Swabey, Melanie Valenti, Bissan Al-Lazikani, Julian Blagg, Christina Esdar, Kai Schiemann, Dirk Wienke, Suzanne A Eccles, Paul Workman, Paul A Clarke","doi":"10.1021/acschembio.5c00338","DOIUrl":"10.1021/acschembio.5c00338","url":null,"abstract":"<p><p>The Mediator complex is a regulator of gene expression, influencing chromatin structure and RNA polymerase II-mediated transcription. Its activity is controlled by a protein kinase module, which includes cyclin-dependent kinases 8 and 19, that phosphorylates RNA polymerase II and transcription factors to regulate gene expression. Using orthogonal approaches combining chemical and genetic tools, we demonstrated the selectivity of our small-molecule inhibitors derived from 3,4,5-trisubstituted pyridine and 3-methyl-1<i>H</i>-pyrazolo[3,4-<i>b</i>]pyridine chemical series in human colorectal cell culture and tumor xenograft models. The lack of activity of our inhibitors in CDK8/19 double knockout models, with respect to molecular, proliferative, and antitumor end points, revealed their specificity and dependence on these kinases. Using our chemical probes and knockout models, we explored Mediator kinase function in human colorectal cancer cells. Phospho-proteome profiling revealed substrates enriched with transcription and chromatin regulators, while promoter reporter experiments identified transcription factor binding sites, including TCF/LEF and AP1, regulated by Mediator kinases. Additionally, altered phosphorylation of several Mediator subunits suggests a mechanism for the rapid regulation of the Mediator complex. Overall, our results demonstrate that CDK8 and CDK19 play pivotal roles in regulating gene expression associated with oncogene activation and signaling pathways. Further studies are warranted to elucidate their broader cellular roles and regulatory mechanisms. The selective inhibitors validated in this study will provide valuable tools for such mechanistic investigations into Mediator kinase functions and their potential therapeutic exploitation.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"1792-1804"},"PeriodicalIF":3.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12281475/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144551415","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":"Solution NMR Analysis Reveals Synergistic β-Arrestin1 Activation by Chemically Synthesized Phosphopeptides of a C-Terminal Tail and ICL3 of NTSR1.","authors":"Zelin Li, Yi Zhang, Jun Liang, Fengyu Jia, Jiacai Song, Demeng Sun, Chaowei Shi, Changlin Tian, Pan Shi","doi":"10.1021/acschembio.5c00257","DOIUrl":"10.1021/acschembio.5c00257","url":null,"abstract":"<p><p>β-Arrestins are critical regulators of G-protein-coupled receptors (GPCRs), mediating desensitization, internalization, and activation of alternative downstream signal transduction pathways through selective binding to phosphorylated GPCRs. Although phosphorylation of C-terminal tails (C-tail) and intracellular loop 3 (ICL3) of GPCRs is essential for β-arrestin binding to GPCRs, cooperative interactions of the phosphorylated C-tail or ICL3 of GPCRs for β-arrestin recruitment remain elusive. Here, we chemically synthesized phosphorylated C-tail and ICL3 peptides of neurotensin receptor 1 (NTSR1) and investigated the conformational dynamics of β-arrestin1 during its interaction with the phosphopeptides. Two-dimensional ¹H-¹³C nuclear magnetic resonance (NMR) spectroscopy of ¹³C^εH3-methionine labeled β-arrestin1 revealed that the phosphorylated C-tail (C-tail-NC 6P), N-cluster of C-tail (C-tail-N 3P), or ICL3 4P triggered conformational changes of β-arrestin1, whereas the C-cluster of the C-tail (C-tail-C 3P) exhibited negligible influence. Additionally, analysis of successive binding of C-tail-NC 6P and ICL3 4P of NTSR1 to β-arrestin1 implied noncompetitive binding of the two segments and displayed allosteric modulation of C-tail or ICL3 in β-arrestin1. These 2D ¹³C-methyl-Met NMR data provide direct evidence for interactions between β-arrestin1 and phosphorylated segments of GPCRs, offering a framework to decode the details of β-arrestin signaling.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"1464-1469"},"PeriodicalIF":3.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144473282","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":"Engineering H₂S-Activatable Aptameric Binders for Tailored Cell Manipulation.","authors":"Jieyu Wang, Jialong Peng, Ming Cai, Yangbing Li, Fang He, Hong-Hui Wang, Zhou Nie","doi":"10.1021/acschembio.5c00201","DOIUrl":"10.1021/acschembio.5c00201","url":null,"abstract":"<p><p>Cell surface receptors play a crucial role in mediating cellular communication and precisely regulating cellular functions. Dysregulation of these receptors is closely associated with various diseases. To enable precise and dynamic receptor control, we developed a gas-responsive aptameric binder based on a chemically masked configuration, enabling stimulus-triggered reactivation. Specifically, the receptor-targeting activity of the aptamer is sterically blocked via azide modifications at critical residues, with selective restoration of function upon exposure to hydrogen sulfide (H₂S), enabling precise receptor modulation. Using this strategy, we successfully achieved H₂S-triggered receptor dimerization, leading to controlled activation of downstream signaling pathways and regulation of cellular behaviors such as migration and proliferation. Furthermore, we extended this approach to facilitate highly selective receptor degradation. By harnessing gasotransmitter cues for molecular switching, this system expands the toolkit for receptor engineering and holds great potential for targeted therapeutic interventions in regenerative medicine and oncology.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"1619-1626"},"PeriodicalIF":3.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144582598","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":"SARS-CoV-2 Omicron Variant Spike Glycoprotein Mutation Q954H Enhances Fusion Core Stability.","authors":"Nisansala Vithanage, Rifat Hasan Apurba, Hamza Enesi Ozomarisi, Carson J Bair, Eve L Sugg, Victor K Outlaw","doi":"10.1021/acschembio.5c00208","DOIUrl":"10.1021/acschembio.5c00208","url":null,"abstract":"<p><p>The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant-of-concern has rapidly spread across the globe to become the dominant form of COVID-19 infection. The Omicron Spike (S) glycoprotein, which mediates viral entry into cells, possesses up to 34 mutations that contribute to the variant's increased transmissibility and decreased susceptibility to antibody-mediated immunity from vaccines or prior infections. One of those mutations, Q954H, occurs within the N-terminal heptad repeat (HR1) domain. During viral entry, the HR1 domain coassembles with the C-terminal heptad repeat (HR2) domain to form a stable six-helix bundle or \"fusion core\" structure, which brings the viral envelope and host membrane into proximity and thermodynamically drives membrane fusion. Here, we demonstrate that the Q954H mutation enhances the interaction between the HR1 and HR2 domains, thereby stabilizing the fusion core assembly relative to prior variants. We also report the first X-ray crystal structure of the Omicron S fusion core, which reveals that the Q954H side chain forms a N···H-O hydrogen bond with the side chain hydroxyl of S1175 within the HR2 domain, as well as an unexpected C-H···O hydrogen bonding interaction with the backbone carbonyl of N1173. Co-assembly with a synthetic depsipeptide, in which the amide of N1173 is replaced with an ester, results in a decreased assembly stability, providing evidence to support the importance of the observed hydrogen bond network. These insights will be valuable for analyzing the factors that drive viral evolution and for the development of inhibitors of SARS-CoV-2 entry.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"1627-1634"},"PeriodicalIF":3.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144574336","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}