ACS Chemical Biology最新文献

{"title":"Tideglusib as a First-in-Class Chemical Probe for NatA: Identification, Mechanism, and Cellular Validation of an Allosteric, CoA-Dependent Inhibitor","authors":"Youchao Deng,&nbsp;Zhuojun Luo,&nbsp;Sarah M. Gardner,&nbsp;Emma K. Seipp,&nbsp;Taining Li,&nbsp;Michelle V. Lihon,&nbsp;Serena V. Yu,&nbsp;Ronen Marmorstein,&nbsp;Tony Hazbun,&nbsp;W. Andy Tao,&nbsp;Rong Huang","doi":"10.1021/acschembio.6c00582","DOIUrl":"10.1021/acschembio.6c00582","url":null,"abstract":"<p>N-terminal acetyltransferase A (NatA) catalyzes 40–57% of eukaryotic Nα-acetylation, a co-translational modification critical for protein stability, localization, and function, yet no validated small-molecule probe of NatA has been reported. Here, we describe the discovery and characterization of tideglusib (YD3139), a clinical-stage GSK-3β inhibitor, as the first small-molecule probe for NatA through a unprecedented catalysis-dependent mechanism. This dual-event mechanism was established through intact protein MS, rapid dilution assays, and substrate-independent IC₅₀ profiling. Tideglusib binds allosterically to <em>Saccharomyces cerevisiae</em> NatA (yNatA), whereupon the CoA released during catalysis chemically modifies tideglusib to form a reversible covalent adduct, a new paradigm for acetyltransferase inhibition. Tideglusib was identified by screening of an in-house library (∼700 compounds) and confirmed by structural optimization of the thiadiazolidinedione scaffold, yielding IC₅₀ values of 0.68–1.8 μM against yeast and human NatA with &gt;20-fold selectivity over other NAT family members. Quantitative proteomics confirmed on-target suppression of NatA-mediated Nα-acetylation in yeast. These findings establish tideglusib as a mechanistic chemical probe for NatA, reveal NatA as a previously unrecognized molecular target for a promiscuous clinical-stage investigational compound, and introduce a conceptual framework for exploiting catalysis-dependent adduct formation as a new strategy for acetyltransferase inhibitor design.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"21 10","pages":"2712–2724"},"PeriodicalIF":3.6,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148917624","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":"An Optimized Bioluminescent Lantern for RNA Imaging","authors":"Erin B. Fuller,&nbsp;Christelle E. T. Chan,&nbsp;Casey Tran,&nbsp;Katrina A. Green,&nbsp;Christoph Gohlke,&nbsp;Michelle A. Digman,&nbsp;Oswald Steward,&nbsp;Andrej Lupták,&nbsp;Jennifer A. Prescher","doi":"10.1021/acschembio.6c00479","DOIUrl":"10.1021/acschembio.6c00479","url":null,"abstract":"<p>A complete understanding of RNA dynamics requires methods to continuously image transcripts in living systems. We recently developed a panel of bioluminescent tools for multiplexed RNA detection, comprising luciferase fragments fused to RNA-binding proteins (RNA lanterns). The RNA lanterns assembled a light-emitting luciferase upon binding unique, structured RNA tags. Different colors of emission were produced via bioluminescence resonance energy transfer to fluorescent protein fusions. In this work, we systematically optimized the RNA lantern platform for enhanced performance in live cells. A luciferase-fluorescent protein linkage was identified that enabled improved energy transfer and enhanced photon outputs. The RNA lantern was further optimized for selective recognition of structured RNA tags. The new RNA lantern-tag combination is orthogonal to existing probes and enabled the first demonstration of three-color bioluminescent RNA visualization in live cells. Overall, this work expands the suite of probes for real-time, multiplexed imaging of RNA.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"21 10","pages":"2622–2629"},"PeriodicalIF":3.6,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148954543","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":"Syringotoxin Biosynthetic Gene Cluster Required for Antiamoebal Defense in Pseudomonas syringae","authors":"Ying Huang,&nbsp;Shuaibing Zhang,&nbsp;Lisa Reimer,&nbsp;Grit Walther,&nbsp;Karsten Willing,&nbsp;Pierre Stallforth","doi":"10.1021/acschembio.6c00589","DOIUrl":"10.1021/acschembio.6c00589","url":null,"abstract":"<p>Syringotoxins are chlorinated cyclic lipopeptides from <em>Pseudomonas syringae</em> that were structurally characterized more than three decades ago. The corresponding biosynthetic gene cluster required for their production, however, has not been experimentally assigned. Based on targeted genetics, metabolite profiling, and structure analysis, we identify a divergent syringomycin-type nonribosomal peptide synthetase gene cluster in <em>P. syringae</em> DSM 1242 and show that <em>psyt</em> is the syringotoxin biosynthetic gene cluster. Deletion of <em>psyt</em> abolishes syringotoxin production and renders the mutant susceptible to grazing by the amoebal predator <em>Dictyostelium discoideum</em>. Besides nanomolar amoebicidal activity, syringotoxin B shows strong antifungal activity, particularly against <em>Candida</em> pathogens. Comparative genomic and structural analyses place <em>psyt</em> within the syringomycin-type lipopeptide family, while the activity loss after macrolactone opening links syringotoxin bioactivity to its cyclic lipopeptide architecture. Together, this work assigns the biosynthetic origin of syringotoxin and establishes this cyclic lipopeptide as a defense factor required for full resistance of <em>P. syringae</em> to amoebal predation.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"21 10","pages":"2734–2742"},"PeriodicalIF":3.6,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149100918","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":"Mapping of Metabolic Glycan Labeling Tolerance Based on SERS-Imaging of N-Substituted Unnatural Sugar Analogs in the Hexosamine Biosynthetic Pathway","authors":"Madhukrishnan Murali,&nbsp;Vishnu Priya Murali,&nbsp;Purushothaman C Harikrishnan,&nbsp;Prathapan Abeesh,&nbsp;Sumayya Basheer,&nbsp;Kaustabh Kumar Maiti","doi":"10.1021/acschembio.6c00596","DOIUrl":"10.1021/acschembio.6c00596","url":null,"abstract":"<p>Unnatural forms of sialic acid can be introduced to mammalian cell surfaces by the metabolic transformation of glycan precursors of <em>N</em>-acetylhexosamine (ManNAc and GlcNAc). Previous studies have shown that mannosamine analogs with <em>N</em>-acyl groups, whether unacetylated or acetylated, containing up to five carbon atoms, and <em>N</em>-alkyl glucosamine derivatives (GlcNPhAlk) can be recognized by the biosynthetic machinery and converted into sialoglycoconjugates on the cell surface. These structural changes to cell surface glycans can be used to investigate carbohydrate-dependent cellular phenomena pertinent to advanced diagnostics by tracking the changes in cell surface glycans. Herein, we report the tolerance levels of the hexosamine biosynthetic pathway (HBP) based on structural alterations of the <em>N</em>-acyl, <em>N</em>-alkyl, and <em>N</em>-acyloxy substituents of mannosamine and glucosamine. A series of analogs has been synthesized with <em>N</em>-acyl, <em>N</em>-alkyl, and <em>N</em>-acyloxy groups of hexosamines (GlcNPhAlk, ManNPhAlk, GlcNAcPhAlk, ManNAcPhAlk, GlcNAcOPhAlk, and ManNAcOPhAlk) and examined their metabolic conversion to cell surface glycans using the metabolic glycan labeling coupled surface-enhanced Raman scattering (MGL-SERS) mapping technique. We observed that ManNAcPhAlk imposed the highest glycan labeling efficiency-based SERS-mapped images in the cell-surface milieu, followed by ManNPhAlk and GlcNPhAlk, while GlcNAcOPhAlk, ManNAcOPhAlk, and GlcNAcPhAlk are subsequently less efficiently metabolized by the biosynthetic machinery. Furthermore, these findings have been validated through far western blot analysis using azide-PEG3-biotin, which consistently complemented the outcome of the MGL-SERS technique. Subsequently, inhibitor studies using <em>N</em>-glycan and <em>O</em>-glycan inhibitors with MGL-SERS techniques revealed that all these glycan analogs are mostly labeling <em>N</em>-glycans, which was further substantiated by the same far-western blot analysis. Finally, azido naphthalimide fluorophore was utilized to complement the alkyne-tag of the highest labeling precursor ManNAcPhAlk, enabling click chemistry to generate a triazole product with an intense fluorescence and reconfirmed mapped images on the cell surface. Collectively, the key structural requirements for substrate recognition within the HBP provide a clear understanding of its metabolic tolerance to design novel chemical tools for glycoengineering.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"21 10","pages":"2743–2754"},"PeriodicalIF":3.6,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149035685","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":"ZDHHC13 Is a Catalytically Deficient Protein S-Acyltransferase That Functions via a Noncanonical Mechanism","authors":"Andrey A. Petropavlovskiy,&nbsp;Alysha M. Church,&nbsp;Amelia H. Doerksen,&nbsp;Rahul Raina,&nbsp;Denver A. Bakhareva,&nbsp;Étienne P. Sellar,&nbsp;Nisandi N. Herath,&nbsp;Anirban Banerjee,&nbsp;Shaun S. Sanders","doi":"10.1021/acschembio.6c00384","DOIUrl":"10.1021/acschembio.6c00384","url":null,"abstract":"<p>S-Acylation is the addition of fatty acids to cysteine residues to regulate protein function and localization. S-Acylation is catalyzed by ZDHHC (Asp–His–His–Cys) protein <em>S</em>-acyltransferases (PATs), which S-acylate protein substrates by first auto-S-acylating the catalytic cysteine of the DHHC active site followed by transfer to the substrate. ZDHHC13 and ZDHHC17 are related ankyrin repeat domain (ANK) PATs that S-acylate neuronal proteins, including Huntingtin (HTT), the protein mutated in Huntington disease. However, unlike ZDHHC17 and other human PATs, ZDHHC13 possesses a noncanonical DQHC active site. As the first histidine is essential for auto-S-acylation, it is unclear if ZDHHC13 is catalytically active. Our phylogenetic analysis of eukaryotic ANK PATs showed that while the DHHC of ZDHHC17 orthologues is highly conserved, the motif is variable among ZDHHC13 orthologues, suggesting evolution independent of catalytic activity. We found that the ZDHHC13 catalytic cysteine is indeed S-acylated in cells, albeit substantially less than ZDHHC17 or ZDHHC20. We also confirmed minimal autoacylation activity <em>in vitro</em> with purified ZDHHC13. While wild-type (WT) ZDHHC13 increased S-acylation of an HTT^1-588 fragment in cells, surprisingly, catalytically dead DQHS ZDHHC13 facilitated HTT^1-588 S-acylation equally. This suggests that the ZDHHC13 catalytic cysteine is not required for substrate S-acylation and instead ZDHHC13 contributes to S-acylation via an indirect mechanism. Furthermore, ZDHHC13 was identified in a high-molecular-weight complex, suggesting a scaffolding or accessory role in S-acylation. This work broadens our understanding of this noncanonical PAT and lays the foundation for future mechanistic and structural studies.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"21 10","pages":"2550–2559"},"PeriodicalIF":3.6,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148917584","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":"Facile Siderophore Assembly Enables Bacterial Delivery of Nucleic Acid Therapeutics","authors":"Harshitha Ramu,&nbsp;Peter Kuijken,&nbsp;Georgia Poulladofonou,&nbsp;Mathijs J. Pals,&nbsp;Daniel Summerton,&nbsp;Yong-Fu Li,&nbsp;Willem Arend Velema","doi":"10.1021/acschembio.6c00323","DOIUrl":"10.1021/acschembio.6c00323","url":null,"abstract":"<p>Antibiotic resistance is an increasing threat to modern medicine that calls for the discovery of new antibiotics. RNA targeting is a promising approach for antibiotic development. In particular, antisense antibiotics, dubbed ASObiotics, are an exciting class of oligomers that show promise as powerful antibiotic agents. However, limited bacterial uptake has hampered their widespread use. Exploiting bacteria’s own machinery in transporting cargo into the cell through siderophore-mediated delivery can address this obstacle. Here, we report the design of a tris-catechol-type siderophore that allows for the assembly on the backbone of antisense therapeutics during their solid-phase peptide synthesis. This approach fully negates the need for challenging siderophore synthesis and conjugation to the antisense therapeutic. The resulting ASObiotics display potent submicromolar activity against <em>Escherichia coli</em>. Through a series of competition and knockout experiments, we elucidated that ASObiotic delivery is accomplished through the Fiu receptor. On-target engagement was established through RT-qPCR, <em>lacZ</em> reporter assays, and Western blot. We further demonstrate the potential use of these siderophore-antisense conjugates as antibiotics against <em>Bacillus subtilis</em> and <em>Acinetobacter baumannii</em>.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"21 10","pages":"2542–2549"},"PeriodicalIF":3.6,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148785362","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":"Omics-Scale Capture of Electrophilic Metabolites","authors":"Allen F. Schroeder,&nbsp;Yan Yu,&nbsp;Ali Turk,&nbsp;Henry H. Le,&nbsp;Matthew LeClair,&nbsp;Marissa A. Fontaine,&nbsp;Nicholas W. Cheng,&nbsp;Saeideh Azad,&nbsp;Christopher N. Parkhurst,&nbsp;Jason Pan,&nbsp;David Artis,&nbsp;Meng Wang,&nbsp;Frank C. Schroeder","doi":"10.1021/acschembio.6c00711","DOIUrl":"10.1021/acschembio.6c00711","url":null,"abstract":"<p>The majority of metabolic pathways rely on the production of activated electrophilic intermediates, e.g., coenzyme-A esters, and their chemical structures and abundances are central to understanding enzyme function and biochemical mechanisms. However, most electrophilic metabolites are lost in traditional metabolomic analysis and thus remain poorly characterized. Here, we introduce a biochemical probe, <em>O</em>-(trimethylammoniobutyl)-hydroxylamine (TAMOHA), that enables comprehensive profiling of electrophilic species such as coenzyme-A esters, ketones, and aldehydes. TAMOHA incorporates a highly nucleophilic hydroxylamine that reacts quickly with electrophilic species upon tissue lysis, trapping them as stable derivatives that feature a tetraalkylammonium moiety whose constitutive charge and characteristic MS² fragmentation fingerprint enable their highly sensitive detection. Using TAMOHA to survey the electrophilomes of <em><em>E. coli,</em> <em>C. elegans</em></em>, and mice revealed several thousand electrophilic metabolites, most of which have not been characterized. We then demonstrate trapping of electrophilic metabolites with TAMOHA in the context of specific biochemical pathways, confirming previously proposed functions of two fatty acid metabolism enzymes, detecting formaldehyde production in mice, and providing new insights into the biosynthesis of ascaroside pheromones in <em>C. elegans</em>. We anticipate that use of TAMOHA for the profiling of electrophilic species will help clarify enzyme function and uncover previously elusive biochemical mechanisms in a wide range of biological systems.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"21 10","pages":"2787–2799"},"PeriodicalIF":3.6,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149100941","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":"Covalent-Allosteric Akt Inhibitors: Targeting Akt3 through Molecular Hybridization and Expanding the Isoform-Selective Toolbox","authors":"Kosmas Alexandros Pervanidis,&nbsp;Giovanni Danilo D’Angelo,&nbsp;Ioannis Athanasiadis,&nbsp;Hannah Jantzen,&nbsp;Andrea Scrima,&nbsp;Katharina Schäfer,&nbsp;Lena Quambusch,&nbsp;Matthias P. Müller,&nbsp;Daniel Rauh","doi":"10.1021/acschembio.6c00415","DOIUrl":"10.1021/acschembio.6c00415","url":null,"abstract":"<p>Akt is a central serine/threonine kinase in the PI3K/Akt/mTOR pathway that regulates cell survival, growth, and metabolic homeostasis. Although Akt1, Akt2, and Akt3 share high sequence homology, they perform distinct physiological and pathological functions, motivating the development of small-molecule isoform-selective chemical probes. Here, we first applied a molecular hybridization strategy to combine structural features that lead to Akt3-selectivity with the covalent pharmacophore of established covalent-allosteric Akt inhibitors, enabling selective and covalent targeting of Akt3. We then expanded the chemical space of covalent-allosteric Akt inhibitors to investigate how subtle structural differences influence selectivity across all three isoforms. Guided by structure–activity relationships and high-resolution co-crystal structures, systematic modifications of substituent patterns, linker geometry, and scaffold architecture revealed distinct isoform-selectivity profiles. Biochemical target inhibition, cellular target engagement, and covalent-binding studies further characterized these compounds and their selectivity. Collectively, these findings expand the covalent-allosteric Akt inhibitor toolbox, provide insight into the structural determinants governing Akt isoform selectivity, and establish molecular hybridization as a strategy for selective covalent targeting of Akt3.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"21 10","pages":"2572–2596"},"PeriodicalIF":3.6,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149072819","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 Requirements for microRNA-Mediated Upregulation Enables Reengineering of Upregulatory Sites","authors":"Helia Dehghan Harati,&nbsp;Thusini Uggalla Arachchige,&nbsp;Xinghai Liu,&nbsp;Lara K. Mahal","doi":"10.1021/acschembio.6c00503","DOIUrl":"10.1021/acschembio.6c00503","url":null,"abstract":"<p>The post-transcriptional regulation of protein expression by miRNA has given rise to new technologies for therapeutic interventions and synthetic biology. To date, these technologies assume that miRNAs are repressors of protein expression; however, emerging evidence has shown that miRNA regulation of proteins is bidirectional. Although it is now clear that upregulation by miRNAs is a common event, the molecular requirements remain poorly characterized. To address this gap, we utilized the miRFluR assay, a genetically encoded dual-fluorescence reporter assay previously developed in our laboratory, to systematically explore upregulation. Using upregulation of the enzyme B3GLCT by miR-891b as a model system, we find that upregulation requires both specific sequence elements and RNA secondary structure. Mutagenesis and truncation analyses revealed that the effect is context-dependent and influenced by the local UTR structure. We also find that sites can be reengineered to be triggered by alternate miRNA, opening the door to synthetic biology manipulations. Our study provides a new perspective on upregulation by miRNA and sets the stage for further exploration of the bidirectional nature of miRNA action.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"21 10","pages":"2650–2661"},"PeriodicalIF":3.6,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148954582","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":"Dynamics of Anti-ABO(H) Antibody Expression in SARS-CoV-2-Infected Patients","authors":"Tianwei Jia,&nbsp;Akul Y. Mehta,&nbsp;Kashyap R. Patel,&nbsp;Kelsey M Charon,&nbsp;Jamie Heimburg-Molinaro,&nbsp;John D. Roback,&nbsp;Sean R. Stowell,&nbsp;Richard D. Cummings","doi":"10.1021/acschembio.6c00447","DOIUrl":"10.1021/acschembio.6c00447","url":null,"abstract":"<p>The association between ABO(H) blood groups and COVID-19 susceptibility and severity has been studied throughout the pandemic. However, the comprehensively tracked dynamic changes of antibodies to ABO(H) over the course of COVID-19 infection remain poorly characterized. Here, we present a longitudinal cohort study that tracked changes in anti-ABO(H) antibody levels and isotypes in serum of 65 COVID-19 patients. Sera were collected at (1) time of hospital admission, (2) 2–3 weeks after symptom onset, and (3) just before hospital discharge or death. Anti-ABO(H) glycan-specific IgG, IgM, and IgA isotypes were profiled using high-throughput Luminex assays, employing beads derivatized with glycans representing the major ABO(H) antigens. While each patient demonstrated unique repertoires of anti-ABO(H) antibodies, unexpected changes in isotypes were observed, indicating varied impact on naturally occurring antibody levels following SARS-CoV-2 infection. Interestingly, blood group O patients showed a higher likelihood of possessing anti-ABO(H) IgA than other blood types. Additionally, we identified autoantibodies against non-blood-group self-glycans in a small proportion of the cohort. Data suggest that exposure to virus represents an underappreciated factor influencing anti-ABO(H) antibody profiles. These results provide a deeper understanding of the potential interplay between anti-ABO(H) antibodies and progression of SARS-CoV-2 infection.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"21 10","pages":"2597–2610"},"PeriodicalIF":3.6,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149056640","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}