ACS Chemical Biology最新文献

{"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":"1813"},"PeriodicalIF":3.5,"publicationDate":"2025-07-18","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":"Design of an Orally Bioavailable Small Molecule That Modulates the Microtubule-Associated Protein Tau's Pre-mRNA Splicing.","authors":"Peiyuan Zhang, Amirhossein Taghavi, Masahito Abe, Haruo Aikawa, Yoshihiro Akahori, Jonathan L Chen, Yuquan Tong, Jared T Baisden, Michael D Cameron, Jessica L Childs-Disney, Matthew D Disney","doi":"10.1021/acschembio.5c00260","DOIUrl":"10.1021/acschembio.5c00260","url":null,"abstract":"<p><p>Frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) is caused by the aberrant alternative pre-mRNA splicing of microtubule-associated protein tau (<i>MAPT</i>) exon 10, the inclusion of which encodes a toxic tau protein harboring four microtubule domains (4R tau). Here, we describe the design of an RNA-targeted small molecule that thermodynamically stabilizes the structure of a pre-mRNA splicing regulator element in the <i>MAPT</i> pre-mRNA exon 10-intron 10 junction to reduce the inclusion of exon 10 and hence 4R tau abundance. Structure-guided drug design was used to obtain compounds that form a network of specific interactions to the RNA, including multiple interactions between a single nucleotide (nt) A-bulge and the Hoogsteen face of a closing GC base pair, the latter of which was enabled by the design of base triple interactions. A battery of assays revealed that the compound binds the target <i>in vitro</i> and in cells and affects pre-mRNA splicing in various cellular models, including primary neurons from a human tau (htau) knock-in mouse model. The orally bioavailable compound was administered <i>per os</i> (<i>p.o.</i>), where treatment diminished exon 10 inclusion and reduced the 4R tau protein isoform. Further, the molecule mitigated cellular pathologies and behavioral phenotypes observed in the htau transgenic mouse model. This study provides a potentially general pipeline to design compounds that target RNAs, affect disease pathways, and deliver compounds that have oral bioavailability and blood-brain barrier penetrance.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"1715-1727"},"PeriodicalIF":3.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12282529/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144367623","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 of Inhibitors for Bacterial Arr Enzymes ADP-Ribosylating and Inactivating Rifamycin Antibiotics.","authors":"Juho Alaviuhkola, Sondos Abdulmajeed, Sven T Sowa, Johan Pääkkönen, Lari Lehtiö","doi":"10.1021/acschembio.5c00164","DOIUrl":"10.1021/acschembio.5c00164","url":null,"abstract":"<p><p>ADP-ribosylation is an enzymatic process where an ADP-ribose moiety is transferred from NAD⁺ to an acceptor molecule. While ADP-ribosylation is well-established as a post-translational modification of proteins, rifamycin antibiotics are its only known small-molecule targets. ADP-ribosylation of rifampicin was first identified in <i>Mycolicibacterium smegmatis</i>, whose Arr enzyme transfers the ADP-ribose moiety to the 23-hydroxy group of rifampicin preventing its interaction with the bacterial RNA polymerase thereby inactivating the antibiotic. Arr homologues are widely spread among bacterial species and present in several pathogenic species often associated with mobile genetic elements. Inhibition of Arr enzymes offers a promising strategy to overcome ADP-ribosylation mediated rifamycin resistance. We developed a high-throughput activity assay which was applied to screen an in-house library of human ADP-ribosyltransferase-targeted compounds. We identified 15 inhibitors with IC₅₀ values below 5 μM against four Arr enzymes from <i>M. smegmatis</i>, <i>Pseudomonas aeruginosa</i>, <i>Stenotrophomonas maltophilia</i>, and <i>Mycobacteroides abscessus</i>. The observed overall selectivity of the hit compounds over the other homologues indicated structural differences between the proteins. We crystallized <i>M. smegmatis</i> and <i>P. aeruginosa</i> Arr enzymes, the former in complex with its most potent hit compound with an IC₅₀ value of 1.3 μM. We observed structural differences in the NAD⁺ binding pockets of the two Arr homologues explaining the selectivity. Although the Arr inhibitors did not sensitize <i>M. smegmatis</i> to rifampicin in a growth inhibition assay, the structural information and the collection of inhibitors provide a foundation for rational modifications and further development of the compounds.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"1584-1593"},"PeriodicalIF":3.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144281662","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":"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":"1669-1682"},"PeriodicalIF":3.5,"publicationDate":"2025-07-18","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":"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":"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":"1728-1738"},"PeriodicalIF":3.5,"publicationDate":"2025-07-18","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":"","authors":"Zhanzhao Cui,&nbsp;Xiaozheng Wang,&nbsp;Lixin Yin,&nbsp;Lu Chen,&nbsp;Kai Liu,&nbsp;Yemin Wang,&nbsp;Shuangjun Lin,&nbsp;Zixin Deng,&nbsp;Min Xu* and Meifeng Tao*,&nbsp;","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 7","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":3.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschembio.5c00280","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144646174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"","authors":"Qiaoyue Kuang,&nbsp;Mizuki Endo,&nbsp;Qi Dong,&nbsp;Yang Li,&nbsp;Ying-Hsien Lee,&nbsp;Qiaojing Li and Takeaki Ozawa*,&nbsp;","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 7","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":3.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschembio.5c00096","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144646178","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"","authors":"Elisa Aquilanti,&nbsp;Sulyman Barkho,&nbsp;Vincent Bozinov,&nbsp;Lauren Kageler,&nbsp;Max Garrity-Janger,&nbsp;Michael F. Mesleh,&nbsp;Steven Horner,&nbsp;Matthew J. Ranaghan and Matthew Meyerson*,&nbsp;","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 7","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":3.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschembio.5c00244","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144646189","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 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":"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":"1609-1618"},"PeriodicalIF":3.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12281479/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An Optical Approach to Modulating Membrane Protein Endocytosis Using a Light-Responsive Tag for Recruiting β-Arrestin.","authors":"Qiaoyue Kuang, Mizuki Endo, Qi Dong, Yang Li, Ying-Hsien Lee, Qiaojing Li, Takeaki Ozawa","doi":"10.1021/acschembio.5c00096","DOIUrl":"10.1021/acschembio.5c00096","url":null,"abstract":"<p><p>Membrane receptors, particularly G protein-coupled receptors (GPCRs), are integral to numerous physiological processes. Precise control of the receptor endocytosis is essential for understanding cellular signaling pathways. In this study, we present the development of a broadly applicable optogenetic tool for light-inducible receptor internalization. This system, named E-fragment, leverages the CRY2-CIB photodimerization pair to enable blue-light-dependent recruitment of β-arrestin and subsequent receptor internalization. We showed that the E-fragment system is applicable across diverse membrane proteins, including multiple GPCRs. Furthermore, we investigated its impact on intracellular cAMP signaling in cells expressing dopamine receptor D1 and α2-adrenergic receptor. Quantitative analyses revealed that light-induced internalization led to reduced surface receptor expression and attenuated ligand-evoked cAMP responses. These findings demonstrate the versatility of the E-fragment system as a platform for studying membrane receptor function and suggest potential applications in therapeutic strategies targeting receptor trafficking and signaling modulation.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"1516-1526"},"PeriodicalIF":3.5,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144315500","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}