ACS Bio & Med Chem Au最新文献

{"title":"Structural and Functional Characterization of Cysteate Fatty Acyltransferases Involved in Bacterial Sulfonolipid Biosynthesis","authors":"Cuiping Pang,&nbsp;Meihan Liu,&nbsp;Yang Gu,&nbsp;Jiahai Zhou,&nbsp;Xiaoyu Tang","doi":"10.1021/acsbiomedchemau.6c00154","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.6c00154","url":null,"abstract":"<p>Sulfonolipids are bacterial sphingolipid-like lipidsfeaturinga sulfonated long-chain base derived from cysteate. Although severalcysteate-utilizing enzymes have been implicated in sulfonolipid biosynthesis,their phylogenetic relationships and the structural basis of cysteateutilization remain poorly understood. Here, we combined phylogeneticanalysis, biochemical characterization, X-ray crystallography, andmutagenesis to investigate cysteate fatty acyltransferase (CFAT) homologuesinvolved in bacterial sulfonolipid biosynthesis. Phylogenetic analysisrevealed that previously characterized cysteate-utilizing enzymesform a distinct branch within the broader serine palmitoyltransferase(SPT)-related pyridoxal 5′-phosphate (PLP)-dependent enzymesuperfamily. Biochemical assay on six representatives confirmed aconserved cysteate-dependent long-chain-base synthase activity anda strong preference for cysteate over serine, glycine, and alanine.To elucidate this specificity, we solved crystal structures of a representativeCFAT from <em>Capnocytophaga ochracea</em> inboth PLP-bound and PLP–cysteate-bound states, capturing a PLP–cysteateexternal aldimine intermediate. This structure reveals a compositeactive-site pocket formed across the dimer interface, where the conservedPLP-dependent catalytic scaffold is retained but the substrate-bindingpocket is significantly remodeled compared to canonical SPTs. Structure-guidedmutagenesis identified key residues important for cysteate-dependentcatalysis but failed to generate serine activity. Together, thesefindings establish CFAT homologues as a functionally coherent familyof cysteate-utilizing enzymes and provide critical molecular insightsinto bacterial sulfonolipid biosynthesis.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"6 5","pages":"723–732"},"PeriodicalIF":3.5,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure-Based Design of New Nonpeptidic Covalent Mpro Inhibitors against SARS-CoV-2 and Omicron Variants","authors":"Honglei Bao,&nbsp;Lingchen Sun,&nbsp;Shilin Gong,&nbsp;Li Qin,&nbsp;Jiawei Xu,&nbsp;Jianlin Wu,&nbsp;Chunhua Ma,&nbsp;Qinhai Ma,&nbsp;Xiaojun Yao,&nbsp;Bin Yu","doi":"10.1021/acsbiomedchemau.6c00072","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.6c00072","url":null,"abstract":"<p>The main protease (M^pro) is a prime targetfor anti-SARS-CoV-2drugs. Herein, we describe the structure-based covalent modificationsthat generate new nonpeptidic covalent M^pro inhibitors.The compounds exhibit strong inhibition against M^pro atsubmicromolar levels. The deuterated lead compound exhibits submicromolarantiviral activity against wild-type SARS-CoV-2 and Omicron variants.Biolayer interferometry analysis indicates a strong binding affinityfor M^pro. The mass spectrometry results confirm the covalentbonding of the compound with the cysteine residue of M^pro. Taken together, the data may support the deuterated compound asa new lead for developing anti-SARS-CoV-2 drugs and further revealthe feasibility of using chloroacetyl for structure-based covalentdrug design.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"6 5","pages":"658–675"},"PeriodicalIF":3.5,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221949","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Direct Observation of Structural Unraveling in PABPN1 Polyalanine Expansions","authors":"Rosa Antón,&nbsp;Javier Oroz","doi":"10.1021/acsbiomedchemau.6c00065","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.6c00065","url":null,"abstract":"<p>Above-threshold homorepeatexpansions promote alternativeconformationsand irreversible aggregation, driving the malfunction of numerousdisease-associated proteins. A detailed understanding of the structuralremodeling events in pathogenic mutants enables the identificationof key elements determining aberrant structure formation. Here, wedescribe in high resolution the structural transitions in Poly(A)Binding Protein Nuclear 1 (PABPN1), in which polyalanine expansionsbeyond a +1 single additional residue cause Oculopharyngeal MuscularDystrophy (OPMD). PABPN1’s polyalanine tract in its wild-type(containing 10 consecutive alanine residues) and +1 and +8 variantspopulate alternative polymorphs, with α-helical conformationsbeing increasingly favored and rigid upon expansion. Spontaneous slowunfolding was observed across variants in real time by Nuclear MagneticResonance (NMR) spectroscopy, indicating that increased dynamics atthe C-terminal end of the polyalanine helix emerges as an early unfoldingevent associated with functional impairment. Our data help to definekey mechanistic features in pathogenic misfunction induced by homorepeatexpansions and identify specific structural motifs as potential targetsfor fragment-based binders to restore protein functionality in polyalanineexpansion disorders.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"6 5","pages":"645–650"},"PeriodicalIF":3.5,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"N6-Methyladenosine RNA Modifications Influence the Stability of FUS-Dependent Biological Condensate Formation","authors":"Chamali Thalagaha Mudiyanselage,&nbsp;Milan Pandey,&nbsp;Sudeshi M. Abedeera,&nbsp;Chathurani Ekanayake,&nbsp;Aftab U. Mollah,&nbsp;Nadia Anwaar,&nbsp;Arkaprabha Konar,&nbsp;Sanjaya C. Abeysirigunawardena","doi":"10.1021/acsbiomedchemau.6c00101","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.6c00101","url":null,"abstract":"<p>Liquid–liquidphase separation (LLPS) is a processin whichproteins and nucleic acids organize into dynamic, membrane-less structureswithin cells. These structures help regulate cellular processes suchas gene expression, molecular storage, and stress responses throughweak interactions between disordered protein regions and RNA. Emergingevidence highlights a regulatory role for epitranscriptomic modifications,particularly N6-methyladenosine (m⁶A), though the underlyingmechanisms remain unclear. Here, we investigated the relationshipbetween m⁶A RNA nucleotide modification and LLPS by identifyingproteins that selectively bind methylated RNA. An RNA pull-down assayenriched 106 proteins, including 53 known RNA-binding proteins andseveral proteins that support LLPS, including FUS (Fused in sarcoma).FUS, a well-characterized phase-separating RNA-binding protein, showeda 2-fold higher binding affinity for m⁶A-modified hairpinRNA than for its unmodified counterpart. Cloud-point analysis andcoherent anti-Stokes Raman scattering (CARS) microscopy revealed enhancedthermodynamic stability at higher m⁶A levels in total RNAextracts. Quantitative CARS imaging revealed that, although the overallRNA-to-protein ratio within condensates remains largely unchanged,larger droplets under high-m⁶A conditions exhibit increasedRNA content, suggesting that m⁶A strengthens RNA–proteininteractions without significantly altering the stoichiometry. Collectively,these findings indicate that while protein–protein interactionsmay initiate LLPS, m⁶A-modulated RNA–protein interactionsgovern condensate growth and stability. Furthermore, these resultsprovide a mechanistic insight into how epitranscriptomic modificationsregulate biomolecular condensation and influence cellular organization,gene regulation, and disease processes.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"6 5","pages":"651–657"},"PeriodicalIF":3.5,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221992","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural and Combinatorial Design Principles of Emerging Drug Carriers","authors":"Jason Kantorow,&nbsp;Srirupa Chakraborty","doi":"10.1021/acsbiomedchemau.6c00095","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.6c00095","url":null,"abstract":"<p>From small moleculesand systemic administration to biologicsandtargeted drug–carrier complexes, the drug delivery field’s“toolbox” of therapeutic materials has skyrocketed inscope and sophistication over the past decade alone. The tunable properties,modularity, and structural control afforded by such materials as lipids,synthetic polymers, peptides, and polysaccharides are highly favorablenot only to the design of novel drugs but also drug carriers whichhelp guide and deliver them. While this has unlocked many more avenuestoward engineering smart, targeted drug delivery systems, the structuralcomplexity of these materials often presents a significant challengeto bench-lab design, synthesis, and experimental validation. However,computational simulation has been shown to provide a robust methodfor studying advanced drugs and their carriers, capable of sufficientlysampling this expansive design space and accounting for a full rangeof structural combinations. In this review, the current forefrontof drug carriers is explored through the lens of biomaterial structureand combinatorial potential. This is followed by a discussion of howcomputational methods promise to manage combinatorial complexity andovercome barriers to effective development of drug delivery systemsconsisting of such biomaterials.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"6 5","pages":"522–543"},"PeriodicalIF":3.5,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149222081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lipoyl Synthase in Focus: Radical SAM Chemistry and the Biosynthesis of Lipoic Acid","authors":"Olga E. Esakova,&nbsp;Caitlin D. Palmer,&nbsp;Douglas M. Warui,&nbsp;Erin L. McCarthy,&nbsp;Squire J. Booker","doi":"10.1021/acsbiomedchemau.6c00104","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.6c00104","url":null,"abstract":"<p>Lipoic acid (1,2-dithiolane-3-pentanoicacid or 6,8-thioctic acid)is a sulfur-containing cofactor essential for central metabolism,where it functions in oxidative decarboxylation reactions catalyzedby the 2-oxoacid dehydrogenase complexes and glycine degradation catalyzedby the glycine cleavage system. Beyond its canonical metabolic roles,the redox-active disulfide/dithiol pair of lipoic acid has attractedconsiderable interest because of its proposed therapeutic relevancein ailments associated with oxidative stress and inflammation, suchas Alzheimer’s and Parkinson’s disease. Despite thebroad biological importance of this cofactor, the molecular detailsof its biosynthesis remained elusive for many years because of theunusual chemistry required for sulfur insertion into unactivated carboncenters. Recent advances have subsequently expanded the understandingof this pathway, particularly through mechanistic and structural studiesof lipoyl synthase, a radical <em>S</em>-adenosylmethionineenzyme that catalyzes sulfur incorporation during cofactor assembly.This perspective highlights current insights into lipoic acid biosynthesisand lipoyl synthase, with an emphasis on emerging mechanistic paradigms,lipoyl synthase auxiliary cluster function and regeneration, and thebroader biochemical context of radical-mediated sulfur insertion.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"6 5","pages":"495–507"},"PeriodicalIF":3.5,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221870","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Thermodynamic and Mechanistic Aspects of Small-Ring Formation Mediated by Nonheme-Iron and 2-Oxoglutarate Dependent Enzymes","authors":"Mark W. Ruszczycky,&nbsp;Wei-chen Chang","doi":"10.1021/acsbiomedchemau.6c00102","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.6c00102","url":null,"abstract":"<p>The biological formation of three-membered rings catalyzedby nonheme-ironand 2-oxoglutarate dependent (Fe/2OG) enzymes incurs a thermodynamiccost paid by the four-electron reduction of molecular oxygen. Inspection,however, suggests that this chemistry is closely related to the Fentonreaction, where the central ferryl complex serves as a more reactivesurrogate for hydrogen peroxide. While this sacrifices some of theoxidative power of O₂ to heat, sufficient chemical potentialis retained to make small-ring cyclization strongly exergonic whilealso reducing kinetic barriers to reaction. At the same time, mechanisticfeatures must be introduced that raise the relative activation energiesfor alternative reaction pathways. Current study of Fe/2OG catalyzedsmall ring cyclization is helping to identify these features includingsubstrate–cofactor disposition, ferric stabilization and activesite preorganization among others that likely work together to definereaction channels and thus determine the reaction outcome.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"6 5","pages":"484–494"},"PeriodicalIF":3.5,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phenazine Biosynthesis Inhibitors as Pseudomonas aeruginosa Antivirulence Agents","authors":"Maria Handke,&nbsp;Janosch Baumgarten,&nbsp;Marie Thiemann,&nbsp;Moritz Zimmermann,&nbsp;Martin Empting,&nbsp;Lars E. P. Dietrich,&nbsp;Conrad Kunick,&nbsp;Wulf Blankenfeldt,&nbsp;Matthias Schiedel","doi":"10.1021/acsbiomedchemau.6c00146","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.6c00146","url":null,"abstract":"<p>Phenazines are redox-active secondary metabolites producedby avariety of bacteria, including <em>Pseudomonas aeruginosa</em>, a Gram-negative opportunistic pathogen associated with severe,often chronic infections and particularly notorious for its multipleresistance mechanisms. A major contributor to <em>P. aeruginosa</em> virulence and resistance is the production of phenazine-derivedmetabolites such as pyocyanin, which play central roles in biofilmformation, redox homeostasis, and host tissue damage. Consequently,inhibition of phenazine biosynthesis may be an attractive pathoblockerstrategy aimed at attenuating bacterial virulence without exertingbactericidal pressure, thus reducing the development of drug resistance.Over the past years, considerable progress has been made in the identificationand characterization of small-molecule inhibitors targeting this pathway.These advances have been driven by interdisciplinary efforts, withmedicinal chemistry, chemical biology, and structural biology providingkey insights into target tractability, ligand binding modes, and structure–activityrelationships. In this review, we summarize recent developments inphenazine biosynthesis inhibition, highlighting representative inhibitorsand discussing biological and structural data for enzymes across thepathway.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"6 5","pages":"626–644"},"PeriodicalIF":3.5,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cellular Morphological Profiling of PROTAC Degraders of the m6A RNA Methyltransferase METTL3","authors":"Mao Jiang,&nbsp;Chukwudi T. Ugwu,&nbsp;Laura Wortmann,&nbsp;Jeffrey L. Schloßhauer,&nbsp;Christian Begemann,&nbsp;Sonja Sievers,&nbsp;Katarzyna W. Kliza,&nbsp;Peng Wu","doi":"10.1021/acsbiomedchemau.6c00136","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.6c00136","url":null,"abstract":"<p>Methylation of N6-adenosineis the most abundant RNA modification,which is mainly installed on mRNA by the methyltransferase METTL3–METTL14complex. Dysregulation of the catalytic activity of METTL3 has beenassociated with many human diseases, especially in acute myeloid leukemiaand other cancers. Therefore, both monovalent small-molecule inhibitorsand bivalent heterobifunctional proteolysis-targeting chimera (PROTAC)degraders have been pursued to address METTL3 for therapeutic development.In this study, we report the structure-based design and synthesisof new METTL3-targeting PROTACs, as well as the first applicationof unbiased morphological profiling of the obtained METTL3 PROTACsin the cell painting assay to obtain phenotypic characterization datafor the further development of METTL3 PROTAC degraders.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"6 5","pages":"708–722"},"PeriodicalIF":3.5,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of a Screening Workflow for the Halogenation of Nitrogen Heterocycles with Vanadium-Dependent Haloperoxidases","authors":"Carter U. Brzezinski,&nbsp;Sergio A. Solis,&nbsp;Hannah S. Slocumb,&nbsp;John Bacsa,&nbsp;Kyle F. Biegasiewicz","doi":"10.1021/acsbiomedchemau.6c00157","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.6c00157","url":null,"abstract":"<p>The halogenationof nitrogen heterocycles is a privileged transformationfor accessing important synthetic intermediates and biologically activetargets in medicinal chemistry. Despite the importance of N-heterocyclehalogenation, current methods rely on reagents or catalysts that arelargely unselective and produce a significant number of waste products.With an emerging interest in using halogenating enzymes to addressthese challenges, the vanadium-dependent haloperoxidase class of enzymeshas emerged as a powerful platform for halogenation reactions undera uniquely broad set of reaction conditions. Herein, we report thedevelopment of a screening workflow for the halogenation of heterocycleswith chloroperoxidase from <em>Curvularia inaequalis</em> (<em>Ci</em>VCPO). Using a high-throughput screening strategy,representative model heterocycles are screened for direct chlorinationand bromination reactions, and the optimized conditions are translatedto an extended substrate scope in moderate to high yields. The volumeof high-throughput data obtained allowed for the development of apredictive model for the substrate halogenation conditions. This screeningplatform is applied to established industrial intermediates and tothe discovery of previously undiscovered enzymatic nitrogen-chlorinebond formation and decarboxylative halogenation reactions.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"6 5","pages":"733–743"},"PeriodicalIF":3.5,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149221872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}