ACS Chemical Biology最新文献

{"title":"A Scavenger Hunt for a DyP-Peroxidase from a Metagenome: Curated Peroxidase Database-Assisted Primer Design and Protein Structure Elucidation.","authors":"Shaimaa Tarek, Yasmin ElMaghloob, Hong Smith, Thomas J Smith, Marwa T ElRakaiby, Mohamed H Habib","doi":"10.1021/acschembio.5c00323","DOIUrl":"https://doi.org/10.1021/acschembio.5c00323","url":null,"abstract":"<p><p>Dye-decolorizing peroxidase (DyP)-type peroxidases are heme-containing enzymes that play a role in lignin synthesis and degradation and dye decolorization. Despite numerous studies about this class of enzymes, the enzyme remains under-explored. We used 1000 DyP sequences retrieved from the NCBI database to forge a phylogenetic tree. Nodes in the tree, where sequences displayed a degree of conservation, were used to design degenerate primers to locate DyP-peroxidase sequences from the DNA extract of a tannery wastewater sample. After PCR amplification and visualization using agarose electrophoresis, a band at the expected size of a DyP peroxidase (500-700 bp) was seen. TA cloning followed by blue-white colony selection validated our finding after amplicon sequencing of the PCR product to confirm the presence of an <i>Acinetobacter</i> species DyP-peroxidase. Our metagenomic DyP displayed 99% similarity to the DyP-peroxidase sequence found in the <i>Acinetobacter baumannii</i> ATCC 19606 strain. As a result, and due to the minute differences between our found DyP and the ATCC 19606 strain DyP, we expressed the latter cloned in a pET28b(+) vector and purified it from culture medium using <i>Escherichia coli</i> SoluBl21 as a host strain. A crude oxidation assay using 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) deemed the enzyme active as shown by the formation of a green color. The crystal structure of the enzyme was solved at 2.6 Å resolution (PDB ID 9OBR) using X-ray crystallography and presented as a hexamer in solution.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144551414","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":"Phospholipase PAFAH2 Mediates Ferroptosis Surveillance and Lipid Remodeling to Promote Resistance in KEAP1 Mutant Cancers.","authors":"Stephen B Ruiz, Daniel E Tylawsky, Janki Shah, Michelle Saoi, Brandon Cuevas, Shanay Desai, Boglarka Racz, Ana Marie Perea, Arianna R Izawa-Ishiguro, Justin Cross, Daniel A Heller","doi":"10.1021/acschembio.5c00273","DOIUrl":"https://doi.org/10.1021/acschembio.5c00273","url":null,"abstract":"<p><p>Although ferroptosis resistance is prevalent among many cancer cell types, precisely how ferroptosis surveillance mechanisms are induced remains elusive due to the heterogeneity of the cellular mutational status and metabolic states. Here, we find that phospholipase PAFAH2 regulates ferroptosis through its unique ability to specifically detoxify membrane-bound oxidized phospholipids in KEAP1 mutant and NRF2-active cancer cells. We show that the genetic or chemical perturbation of PAFAH2 is sufficient to sensitize KEAP1 mutant lung adenocarcinoma cells to ferroptosis. Lipidomic analyses reveal that PAFAH2 inhibition shifts the cellular lipidome to a distinctly ferroptosis state characterized by the enrichment of key phospholipids previously identified to be important in ferroptosis, like ether-linked phosphatidylethanolamines. Finally, we comparatively assessed the antitumor efficacy of PAFAH2 inhibitor monotherapy versus cotreatment with a nanoparticle-stabilized GPX4 inhibitor formulation. Our findings support that the broad applicability of PAFAH2 inhibition can be used in ferroptosis induction and abrogation of ferroptosis resistance across cancer types.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144537385","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":"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":"https://doi.org/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":""},"PeriodicalIF":3.5,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantitative Proteomics Reveals the Role of Lysine Lactylation in Lenalidomide-Resistance in Multiple Myeloma Cells.","authors":"Xinlong Guo, Xuelian Ren, Cong Yan, He Huang","doi":"10.1021/acschembio.5c00270","DOIUrl":"https://doi.org/10.1021/acschembio.5c00270","url":null,"abstract":"<p><p>Multiple myeloma (MM) is a hematologic malignancy characterized by abnormal plasma cell proliferation, with lenalidomide emerging as a primary treatment. However, prolonged use often leads to drug resistance, underscoring the need to understand the resistance mechanisms. Protein post-translational modifications (PTMs) play crucial roles in disease development, including chemoresistance. Here, we investigate the involvement of new types of PTMs, focusing on lysine lactylation (Kla), in lenalidomide-resistance. Glycolysis-driven elevation of Kla levels was observed in lenalidomide-resistant MM cells, and the subsequent inhibition of glycolytic activity significantly reversed the lenalidomide-resistance phenotype. Through quantitative proteome, lactylome, and acetylome analyses, we identified 7493 proteins, 1241 Kla sites, and 9313 lysine acetylation (Kac) sites, thereby revealing differential protein expression and PTM profiles in lenalidomide-resistant cells. Proteomic analysis revealed that a series of chemoresistance-related proteins were upregulated, and a number of Cullin-RING Ligase 4-Cereblon (CRL4^CRBN) regulatory factors were downregulated. Lactylome analysis revealed that numerous chemoresistance-related proteins exhibited increased Kla levels in lenalidomide-resistant MM cells, suggesting that Kla played an important role in the development of lenalidomide-resistance in LenR MM cells. Notably, histone H4K8la was associated with upregulation of chemoresistance-related genes cyclin-dependent kinase 6 (CDK6) and enoyl-CoA hydratase (ECHS1). Our findings shed light on the epigenetic mechanisms underlying lenalidomide-resistance in MM, offering insights for overcoming chemoresistance.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144537386","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":"Three-Enzyme Cascade Catalyzes Conversion of Auramycinone to Resomycin in Chartreusin Biosynthesis.","authors":"Magdalena Niemczura, Aleksi Nuutila, Rongbin Wang, Katariina Rauhanen, S Eric Nybo, Mikko Metsä-Ketelä","doi":"10.1021/acschembio.5c00205","DOIUrl":"https://doi.org/10.1021/acschembio.5c00205","url":null,"abstract":"<p><p>Chartreusin is a potent antiproliferative agent that contains a unique aromatic pentacyclic bislactone carbon scaffold. The biosynthesis of type II polyketide aglycone has been extensively investigated and shown to proceed through a tetracyclic anthracycline intermediate. The last remaining unknown steps are the conversion of auramycinone to resomycin C. Here we have discovered three enzymes that play crucial roles in two mechanistically distinct dehydration reactions. We show that ChaX is an NAD(P)H-dependent auramycinone quinone reductase that allows the cyclase-like ChaU to catalyze the formation of 9,10-dehydroauramycinone via a carbanion intermediate. In contrast, the cyclase-like ChaJ, homologous to ChaU, is responsible for subsequent 7,8-dehydration via a canonical carbocation intermediate, yielding resomycin C. The results were confirmed via assembly of the biosynthetic pathway for production of resomycin C in <i>Streptomyces coelicolor</i> M1152Δ<i>matAB</i>. The work expands the catalytic repertoire of the SnoaL protein family, which has previously been associated with anthracycline fourth-ring cyclization and two-component 1-hydroxylation.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144537387","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":"Correction to \"Thiophenyl Derivatives of Nicotinamide Are Metabolized by the NAD Salvage Pathway into Unnatural NAD Derivatives That Inhibit IMPDH and Are Toxic to Peripheral Nerve Cancers\".","authors":"Panayotis C Theodoropoulos, Holly H Guo, Wentian Wang, Eric Crossley, Giomar Rivera Cancel, Min Fang, Thu Nguyen, Hamid Baniasadi, Noelle S Williams, Joseph M Ready, Jef K De Brabander, Deepak Nijhawan","doi":"10.1021/acschembio.5c00436","DOIUrl":"10.1021/acschembio.5c00436","url":null,"abstract":"","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525304","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":"CIAA: Integrated Proteomics and Structural Modeling for Understanding Cysteine Reactivity with Iodoacetamide Alkyne.","authors":"Lisa M Boatner, Jerome Eberhardt, Flowreen Shikwana, Matthew Holcomb, Peiyuan Lee, Kendall N Houk, Stefano Forli, Keriann M Backus","doi":"10.1021/acschembio.5c00225","DOIUrl":"https://doi.org/10.1021/acschembio.5c00225","url":null,"abstract":"<p><p>Cysteine residues play key roles in protein structure and function and can serve as targets for chemical probes and even drugs. Chemoproteomic studies have revealed that heightened cysteine reactivity toward electrophilic probes, such as iodoacetamide alkyne (IAA), is indicative of likely residue functionality. However, while the cysteine coverage of chemoproteomic studies has increased substantially, these methods still provide only a partial assessment of proteome-wide cysteine reactivity, with cysteines from low-abundance proteins and tough-to-detect peptides still largely refractory to chemoproteomic analysis. Here, we integrate cysteine chemoproteomic reactivity data sets with structure-guided computational analysis to delineate key structural features of proteins that favor elevated cysteine reactivity toward IAA. We first generated and aggregated multiple descriptors of cysteine microenvironment, including amino acid content, solvent accessibility, residue proximity, secondary structure, and predicted p<i>K</i>_a. We find that no single feature is sufficient to accurately predict the reactivity. Therefore, we developed the CIAA (Cysteine reactivity toward IodoAcetamide Alkyne) method, which utilizes a Random Forest model to assess cysteine reactivity by incorporating descriptors that characterize the three-dimensional (3D) structural properties of thiol microenvironments. We trained the CIAA model on existing and newly generated cysteine chemoproteomic reactivity data paired with high-resolution crystal structures from the Protein Data Bank (PDB), with cross-validation against an external data set. CIAA analysis reveals key features driving cysteine reactivity, such as backbone hydrogen bond donor atoms, and reveals still underserved needs in the area of computational predictions of cysteine reactivity, including challenges surrounding protein structure selection data set curation. Thus, our work provides a strong foundation for deploying artificial intelligence (AI) on cysteine chemoproteomic data sets.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525303","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":"Enzymatic Pathway for Kupyaphore Degradation in <i>Mycobacterium tuberculosis</i>: Mechanism of Metal Homeostasis and Turnover.","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, Rajesh S Gokhale","doi":"10.1021/acschembio.5c00078","DOIUrl":"https://doi.org/10.1021/acschembio.5c00078","url":null,"abstract":"<p><p>Metallophores are essential for metal homeostasis, regulating availability, and mediating host-pathogen interactions. Kupyaphores are specialized metallophores produced by <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) that primarily chelate zinc to support bacterial survival. Elevated kupyaphore levels early in infection highlight their importance, while their rapid decline, despite increasing bacterial loads, indicates tightly regulated mechanisms of production, consumption, and degradation. However, the processes driving kupyaphore catabolism and their role in preventing zinc toxicity in <i>Mtb</i> remain unclear. Here, we show that covalent modification of the isonitrile moiety in kupyaphores releases zinc, triggering degradation through a sequential three-step enzymatic pathway encoded by <i>Mtb</i>. Isonitrile hydratase converts isonitrile groups into formamides, which are subsequently processed into amines by <i>N</i>-substituted formamide deformylase and ultimately oxidized to β-ketoesters by amine oxidases. The biological significance of this pathway is underscored by the upregulation of these genes under metal-depleted and biofilm-forming conditions. Mutant <i>Mtb</i> strains lacking these genes exhibit impaired growth in metal-limiting environments and reduced levels of biofilm formation. Catalytic intermediates detected in <i>Mtb</i> cultures and infected mouse lung tissues confirm the pathway's in vivo activity. Further, genome mining reveals that similar enzymes are conserved across organisms producing isonitrile-containing metabolites, emphasizing the broader importance of this pathway. Understanding these processes could pave the way for novel therapeutic strategies targeting kupyaphore catabolism.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525305","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":"Tryptamine Metabolism and Functionalization in Gut Commensal Bacteria Expand Human Tryptamine Signaling Responses.","authors":"Hyun Bong Park, Deguang Song, Mytien Nguyen, Noah W Palm, Jason M Crawford","doi":"10.1021/acschembio.5c00313","DOIUrl":"https://doi.org/10.1021/acschembio.5c00313","url":null,"abstract":"<p><p>Gut microbes secrete specialized small molecules that broadly influence human physiology. Despite their potential significance, the variety of functional small molecules known in the gut is relatively limited. Here, we screened the supernatants from human fecal-derived bacterial cultures to explore their agonist effects on the human G protein-coupled receptors (GPCRs), melatonin receptor types 1A and 1B (MTNR1A, MTNR1B). Chemical analysis of the supernatant-soluble molecules of <i>Clostridium sporogenes</i>, a prominent gut commensal identified in the screen, led to the characterization of agonists for these two melatonin receptors. Specifically, through bioactivity-assisted isolation and characterization, we identified three small molecules, <b>1</b>-<b>3</b>, including two previously uncharacterized metabolites, which were synthesized to confirm their structures. While the structure of <b>1</b> features a urea core symmetrically disubstituted with tryptamine moieties, <b>2</b> and <b>3</b> harbor a monomeric tryptamine functionalized with methyl carbamate and <i>N</i>-acetyl groups, respectively. These structural characterization efforts illuminated downstream functional consequences of tryptamine metabolism in <i>C. sporogenes</i>. Additional GPCR screening analyses revealed that <b>2</b> activates melatonin receptors and the purinergic P2RY11 receptor, whereas <b>1</b> serves as an agonist for the semiorphan receptor GPR55. Interestingly, <b>1</b> also exhibits significant inhibitory activity against inflammatory soluble epoxide hydrolase with a half-maximal inhibitory concentration of 420 nM. Single-cell RNA sequencing analysis of the gut tissue from mice orally treated with <b>1</b> relative to the solvent vehicle control revealed that <b>1</b> specifically decreased the frequency of GPR55- and granzyme K-expressing effector-like CD8 T cells in the intraepithelial lymphocyte population. Overall, this study broadens our understanding of tryptamine-derived signaling at the human-microbe interface.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144511248","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":"Identification of an Induced Orthosteric Pocket in IL-23: A New Avenue for Non-biological Therapeutic Targeting.","authors":"Fabien C Lecomte, Jeremiah S Joseph, Jacek Stalewski, Qingliang Shen, Eric Arnoult, Vandana Sridhar, Mengjie Liu, Yingxia Hu, Jovylyn Gatchalian Gasendo, Hagit Ben Arie, Nurit Keinan, Liraz Keidar, Israel Aviv, Emil Ruvinov, Julia Grandjean, Paulo Roberto Dores-Silva, Annie Mak, Buyung Santoso, Suzie Kim, Vikram Shende, Walter J Wever, Tara Mirzadegan, Zhaoning Zhu, Bryan Fuchs, Philippe Pinton, Rose Szabady","doi":"10.1021/acschembio.5c00181","DOIUrl":"https://doi.org/10.1021/acschembio.5c00181","url":null,"abstract":"<p><p>Interleukin 23 (IL23) is a key driver of autoimmune inflammatory pathology and has been successfully targeted by therapeutic antibodies for the treatment of psoriasis and ulcerative colitis. Identifying small-molecule inhibitors of IL23 signaling is of potential interest for drug development. We report the identification of an induced-fit orthosteric binding pocket on the IL23p19 subunit that may be suitable for small-molecule inhibition. X-ray crystallography was used to determine the structure of the IL23 heterodimer when bound to inhibitory peptide 23-446 and to confirm peptide binding to the IL23p19 subunit at the location of its interface with the IL23 receptor (IL23R). We then applied structure-based design to modify peptide 23-446. This process involved identifying key residues responsible for inhibitory activity and generating structure-activity relationship-optimized peptides with low nanomolar affinity for IL-23 and corresponding inhibitory potency against IL-23R binding. These optimized peptides show promise as potential therapeutic candidates in their own right and may also serve as valuable starting points for further discovery. The most potent of these peptides was used to develop a fluorescence polarization probe and to design a high-throughput screening assay, which was validated through a pilot screen using a small fragment-based compound library. This screening strategy has the potential to support the discovery of peptides or small molecules that bind to the orthosteric pocket, thereby blocking the IL-23R interaction and downstream signaling.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144493132","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}