ACS Chemical Biology最新文献

{"title":"","authors":"Jiangpeiyun Jin, Atharva S. Kulkarni, Andrew C. McAvoy and Neha Garg*, ","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 6","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":3.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschembio.4c00562","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144469174","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":"Identification of an Unnatural Sulfated Monosaccharide as a High-Affinity Ligand for Pan-Variant Targeting of SARS-CoV-2 Spike Glycoprotein.","authors":"Ally Thompson, Nehru Viji Sankaranarayanan, John E Chittum, Virendrasinh Mahida, Sharath S Vishweshwara, Rakesh Raigawali, Saurabh Anand, Raghavendra Kikkeri, Umesh R Desai","doi":"10.1021/acschembio.5c00206","DOIUrl":"10.1021/acschembio.5c00206","url":null,"abstract":"<p><p>Identifying smaller sulfated glycan fragments that recognize target proteins with high affinity is highly challenging. In this work, we show that microarray screening of 53 small glycan fragments helped identify distinct sulfated monosaccharide to tetrasaccharide fragments that bind to multiple isoforms of SARS-CoV-2 spike glycoprotein (SgP) with high affinity. Our library consisted of natural and unnatural glycan sequences with a wide range of sulfation levels. The unnatural features arose from the presence of phosphate or fluoro groups on the natural sulfated GAG scaffold as well as sulfate modification of idose fragments that were monomer to tetramer long. None of the natural glycans yielded much promise, which probably conveys the importance of the polymeric glycosaminoglycan chain in SgP biology. However, the unnatural idose fragments with sulfation at the 2, 3, 4, and 6 positions displayed high affinities (100-500 nM) for wild-type, Delta, and Omicron variants of SgP. The unnatural sulfated idose monosaccharide is the smallest molecule known to date that can be classified as a high-affinity, pan-variant fragment. This fragment is expected to serve as the lead for the design of pan-variant ligands with sub-nM inhibition potency.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"1394-1405"},"PeriodicalIF":3.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12186262/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143951377","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":"Novel Lipophagy Inducers as Potential Therapeutics for Lipid Metabolism Disorders.","authors":"Rachel Njeim, Bassel Awada, Haley Donow, Haley Gye, Cole Foster, Colin Kelly, Judith Molina, Sandra Merscher, Marcello Giulianotti, Alessia Fornoni, Hassan Al-Ali","doi":"10.1021/acschembio.5c00212","DOIUrl":"10.1021/acschembio.5c00212","url":null,"abstract":"<p><p>Dysregulation of lipid homeostasis is associated with a wide range of pathologies encompassing neurological, metabolic, cardiovascular, oncological, and renal disorders. We previously showed that lipid droplet (LD) accumulation in podocytes contributes to the progression of diabetic kidney disease (DKD) and reducing LDs preserves podocyte function and prevents albuminuria. Here, we sought to identify compounds that treat pathological LD accumulation. We developed a phenotypic assay using human podocytes and deployed it to screen a combinatorial library comprising over 45 million unique small molecules. This led to the identification of a compound series that effectively reduces LD accumulation in stressed podocytes. Mechanistic studies revealed that these compounds activate lipophagy, reduce LD accumulation, and rescue podocytes from cell death. In contrast, compounds known to induce general autophagy failed to mimic these effects, indicating a novel lipophagy-specific mechanism of action (MoA), which was confirmed by unbiased phenotypic profiling. An advantage of this therapeutic strategy is its potential to not only halt the progression of pathological lipid accumulation but also reverse it. These compounds will serve as tools for uncovering novel drug targets and therapeutic MoAs for treating DKD and other diseases with similar etiologies.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"1406-1416"},"PeriodicalIF":3.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144207123","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":"Comparative Metabolomics Identifies the Roles of Acyl-CoA Oxidases in the Biosynthesis of Ascarosides and a Complex Family of Secreted <i>N</i>-Acylethanolamines.","authors":"Subhradeep Bhar, Dilip V Prajapati, Melisa S Gonzalez, Chi-Su Yoon, Kevin Mai, Laura S Bailey, Kari B Basso, Rebecca A Butcher","doi":"10.1021/acschembio.5c00126","DOIUrl":"10.1021/acschembio.5c00126","url":null,"abstract":"<p><p>The nematode <i>Caenorhabditis elegans</i> produces a large family of ascaroside pheromones, which it uses in chemical communication to coordinate the development and behavior of the population. The acyl-CoA oxidase (ACOX) enzymes, which catalyze the first rate-limiting step in peroxisomal β-oxidation, act as gatekeepers for the biosynthesis of ascarosides with specific side-chain lengths. By performing unbiased comparative metabolomics on <i>acox-1.1</i>, <i>-1.2</i>, <i>-1.3</i>, <i>-1.4</i>, and <i>-3</i> mutant worms and <i>acox-1.1;acox-3</i> double mutant worms, we provide a comprehensive view of the different roles of these enzymes in ascaroside biosynthesis and implicate them in a number of additional biosynthetic pathways. Our data show that <i>acox-1.1</i> and <i>acox-3</i> are required for the biosynthesis of a broad range of medium- and long-chain ascarosides, while <i>acox-1.2</i>, <i>acox-1.3</i>, and <i>acox-1.4</i> specialize in ascarosides with specific side-chain lengths. Specific <i>acox</i> mutants accumulate a variety of modified ascarosides that are likely shunt products. Furthermore, we show that <i>acox-1.1</i> and <i>acox-3</i>, but not other <i>acox</i> genes, are required for the biosynthesis of a specific subset of <i>N</i>-acylethanolamines (NAEs), many of which have hydroxyl groups at specific positions in their fatty acyl side chains. Through stable-isotope labeling, feeding experiments, and chemical synthesis, we characterize the structures of these NAEs and show that their fatty acyl groups are derived from both bacteria and nematode sources. One of the most strongly <i>acox</i>-dependent NAEs that has a β-hydroxy fatty acyl group is attractive to <i>C. elegans</i> at attomolar concentrations, whereas a closely related NAE with a γ-hydroxy fatty acyl group is not, indicating that a subset of secreted NAEs may influence worm behavior.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"1298-1308"},"PeriodicalIF":3.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12288140/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144223699","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":"Discovery and Mechanism of 16-19F, a Novel Synthetic Lethal Inhibitor of the PRMT5•MTA Complex in MTAP-Deleted Cancer Cells.","authors":"Zhihang Shen, Xiaozhi Yang, Gustavo Seabra, Xueyong Xu, Jiawei Dong, Jason Orr Brant, Wei Zhou, Juan Guan, Wen Jiang, Chenglong Li","doi":"10.1021/acschembio.5c00160","DOIUrl":"10.1021/acschembio.5c00160","url":null,"abstract":"<p><p>Protein arginine methyltransferase 5 (PRMT5), which uniquely binds to 5'-methylthioadenosine (MTA) among the PRMT family, is emerging as an attractive epigenetic target for 5'-methylthioadenosine phosphorylase (MTAP)-deleted cancer treatments. Here, we report the discovery of a novel inhibitor 16-19F, which is a potent binder to the PRMT5•MTA, PRMT5•SAH, and PRMT5•SAM complexes and selectively inhibited MTAP-deleted cancer cell growth. Based on transcriptome analysis, we found that kinetochore metaphase signaling and cell cycle control of the chromosomal replication pathway were downregulated after 16-19F treatment in the MDA-MB-231 TNBC cell line. Additionally, we identified a new PRMT5 substrate, MCM7, an important component of DNA helicase, and figured out the potential methylation site Arg219 by site-directed mutagenesis and computational analysis. Moreover, we showed that 16-19F treatment regulated MCM7 localization, which is involved through liquid-liquid phase separation mechanisms, including the formation of stress granules. Together, we discovered a potential novel drug candidate and revealed an unknown mechanism in which PRMT5 methylation altered MCM7 localization by modulating stress granule formation.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"1333-1346"},"PeriodicalIF":3.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12210245/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144179610","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":"Localized Light-Triggered CO Delivery: Comparing the Amount of CO Delivered and Cellular Toxicity.","authors":"C Taylor Dederich, Livia S Lazarus, Abby D Benninghoff, Lisa M Berreau","doi":"10.1021/acschembio.4c00884","DOIUrl":"10.1021/acschembio.4c00884","url":null,"abstract":"<p><p>Molecules that enable the controlled delivery of carbon monoxide (CO) in biological environments are of significant current interest to probe the beneficial roles of CO for humans. Assumptions regarding the ability of molecules to reliably deliver CO continue to impact the field, including in work involving non-metal CO delivery motifs. Flavonols are drawing increasing interest as light-triggered CO release motifs due to their ease of synthesis, functionalization, and fluorescence trackability. Importantly, the light-driven CO release properties of flavonols depend on their structure and must be fully evaluated under various conditions to understand the relationship between the amount of CO delivered and the induced biological effects. Herein, we use a family of amine-functionalized π-extended flavonols to demonstrate that structural differences result in differing interactions with biomolecules, cellular uptake, and changes in subcellular localization, which can affect the amount of CO delivered intracellularly. This results in differences in the CO-induced cellular toxicity.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"1139-1144"},"PeriodicalIF":3.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144074838","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":"Discovery of IHMT-15130 as a Highly Potent Irreversible BMX Inhibitor for the Treatment of Myocardial Hypertrophy and Remodeling.","authors":"Shuang Qi, Jiangyan Cao, Ting Wu, Chenliang Shi, Junjie Wang, Beilei Wang, Ziping Qi, Hong Wu, Yun Wu, Aoli Wang, Jing Liu, Wenchao Wang, Qingsong Liu","doi":"10.1021/acschembio.4c00875","DOIUrl":"10.1021/acschembio.4c00875","url":null,"abstract":"<p><p>Cardiac hypertrophy is usually accompanied by many forms of heart disease, including hypertension, vascular disease, ischemic disease, and heart failure, and thus effectively predicts the increased cardiovascular morbidity and mortality. Bone marrow kinase in chromosome X (BMX) has been reported to be the major signaling transduction protein in cardiac arterial endothelial cells and is thought to be involved in the pathology of cardiac hypertrophy. We report here the discovery of a potent irreversible BMX kinase inhibitor, IHMT-15130, which covalently targets cysteine 496 of BMX and exhibits potent inhibitory activity against BMX kinase (IC₅₀: 1.47 ± 0.07 nM). Compared to recently approved BTK/BMX dual inhibitor Ibrutinib, IHMT-15130 displayed selectivity over CSK kinase (IC₅₀ > 25,000 nM), targeting of which may cause severe atrial fibrillation and bleeding. IHMT-15130 effectively reduced the secretion of inflammatory cytokines, inhibited the inflammatory signaling pathway in vitro and in vivo, and alleviated angiotensin II (Ang II)-induced myocardial hypertrophy in a murine model. This study provides further experimental evidence for the application of BMX kinase inhibitors in the treatment of cardiac hypertrophy.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"1181-1194"},"PeriodicalIF":3.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144100959","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":"Expansion Microscopy Provides Nanoscale Insight into Nucleolar Reorganization and Nuclear Foci Formation during Nucleolar Stress.","authors":"Katelyn R Alley, Katelyn M Wyatt, Adam C Fries, Victoria J DeRose","doi":"10.1021/acschembio.5c00104","DOIUrl":"10.1021/acschembio.5c00104","url":null,"abstract":"<p><p>The nucleolus, a membraneless organelle crucial for ribosome production, has a unique nanoscale structure whose organization is responsive to cell signals and disease progression. Here, we highlight the potential of Expansion Microscopy (ExM) for capturing intricate spatial and functional information about membraneless organelles such as the nucleolus and nuclear foci. We apply dual protein Expansion Microscopy (dual-proExM) in combination with click Expansion Microscopy (click-ExM) to capture images at the highest resolution reported for the nucleolus of ∼45 ± 2 nm. Inhibition of nucleolar processes triggers a nucleolar stress response, causing distinct structural rearrangements whose molecular basis is an area of active investigation. We investigate time-dependent changes in nucleolar structure and function under nucleolar stress induced by oxaliplatin, actinomycin D, and other platinum-based compounds. Our findings reveal new stages that occur prior to the complete sequestration of RNA Pol I into nucleolar caps, shedding light on the early mechanisms of the nucleolar stress response. RNA transcription is linked to nanoscale protein rearrangements using a combination of click-ExM and pro-ExM, revealing locations of active transcripts during the early stages of nucleolar stress reorganization. With prolonged stress, fibrillarin and NPM1 segregate from the nucleolus into nucleoplasmic foci that are for the first time imaged at nanometer resolution. In addition to revealing new morphological information about the nucleolus, this study demonstrates the potential of ExM for imaging membraneless organelles with nanometer-scale precision.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"1232-1246"},"PeriodicalIF":3.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109036","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":"Discovery and Identification of a Novel PORCN Inhibitor via Structure-Based Virtual Screening.","authors":"Xinyu Yang, Yanbei Li, Jingyi Zhou, Yuanyang Zhou, Kexin Lin, Shuqing Chu, Jingyi Meng, Xinyi Ma, Yuan Zhu, Xutong Li, Dan Teng, Mingyue Zheng, Sulin Zhang","doi":"10.1021/acschembio.5c00155","DOIUrl":"10.1021/acschembio.5c00155","url":null,"abstract":"<p><p>Dysregulated activation of the Wnt pathway is closely associated with oncogenesis and the progression of various cancers. Palmitoylation catalyzed by porcupine (PORCN) is essential for the secretion of Wnts and the activation of the Wnt pathway. Given its critical role in regulating Wnt signaling, PORCN has been recognized as a promising therapeutic target for cancers driven by aberrant Wnt pathway activation. Herein, we explored the binding modes of reported inhibitors with different scaffolds using molecular docking and molecular dynamics simulations, establishing an optimized structure-based virtual screening model, which discovered a novel PORCN inhibitor, <b>Y-99</b>. <b>Y-99</b> demonstrated promising inhibitory activity against the Wnt/β-catenin signaling pathway (IC₅₀ = 155.4 nM) and exhibited high binding affinity to PORCN (<i>K</i>_D = 33.1 nM). Notably, <b>Y-99</b> exerted a significant antiproliferation effect in Wnt-addicted tumor cell lines, accompanied by reduced LRP6 phosphorylation and downregulation of Wnt-related gene expression, including <i>AXIN2</i> and <i>CCND1.</i> Taken together, these findings highlight that <b>Y-99</b>, which was identified through <i>in silico</i> screening and validated <i>in vitro</i>, is a promising PORCN inhibitor, which has the potential for further research and development.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"1319-1332"},"PeriodicalIF":3.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144140887","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":"","authors":"Ally Thompson,&nbsp;Nehru Viji Sankaranarayanan,&nbsp;John E. Chittum,&nbsp;Virendrasinh Mahida,&nbsp;Sharath S. Vishweshwara,&nbsp;Rakesh Raigawali,&nbsp;Saurabh Anand,&nbsp;Raghavendra Kikkeri and Umesh R. Desai*,&nbsp;","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 6","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":3.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschembio.5c00206","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144469162","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}