ACS Chemical Biology最新文献

Multi-TACs: Targeting Solid Tumors with Multiple Immune Cell Co-engagers.

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-01-09 DOI: 10.1021/acschembio.4c00843

Yuxuan Zhang, Zijian Zhang, Feng Lin

引用次数: 0

The Relationship between Substrate Structure and Selectivity of Ketoreduction in Multimodular Polyketide Synthases: A Comparative Study of A-Type Ketoreductases from Late Modules Using Complex Precursor Analogues.

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-01-08 DOI: 10.1021/acschembio.4c00669

Lisa N K T Nguyen, Sebastian Derra, Frank Hahn

{"title":"The Relationship between Substrate Structure and Selectivity of Ketoreduction in Multimodular Polyketide Synthases: A Comparative Study of A-Type Ketoreductases from Late Modules Using Complex Precursor Analogues.","authors":"Lisa N K T Nguyen, Sebastian Derra, Frank Hahn","doi":"10.1021/acschembio.4c00669","DOIUrl":"https://doi.org/10.1021/acschembio.4c00669","url":null,"abstract":"Ketoreductases (KRs) are domains in the reductive loops of type I polyketide synthases (PKSs) and are responsible for the majority of stereocenters in reduced polyketides. Although the highly stereoselective reduction of ACP-bound β-ketothioester intermediates by KRs is crucial for the overall functioning of PKSs, the substrate-dependent stereoselectivity of KRs is a factor that is not yet fully understood, especially for KR domains in late PKS modules that act on biosynthetic precursors with complex polyketidic moieties. We present studies on the three KR domains FosKR7, PlmKR6, and EryKR6 from the biosynthetic pathways of fostriecin, phoslactomycin, and erythromycin by in vitro assays using close surrogates of the octaketidic FosKR7 biosynthetic precursor, complex derivatives and a diketide in the form of their biomimetic N-acetylcysteamine thioesters. Supported by molecular modeling, specific interactions of the studied KR domains with the extended polyketide moieties of their natural precursors were identified and correlated to the differences in stereoselectivity observed in the in vitro assays. These results reinforce the importance of the substrate-dependent stereoselectivity of KR domains in PKSs and suggest more detailed experimental and structural studies with isolated KRs and full PKS modules that could ultimately lead to improved results in PKS engineering.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142941420","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}

引用次数: 0

A Small-Molecule Inhibitor of Gut Bacterial Urease Protects the Host from Liver Injury.

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-01-08 DOI: 10.1021/acschembio.3c00556

Khyle C Richards-Corke, Yindi Jiang, Vladimir Yeliseyev, Yancong Zhang, Eric A Franzosa, Zhipeng A Wang, Maheeshi Yapa Abeywardana, Phillip A Cole, Curtis Huttenhower, Lynn Bry, Emily P Balskus

{"title":"A Small-Molecule Inhibitor of Gut Bacterial Urease Protects the Host from Liver Injury.","authors":"Khyle C Richards-Corke, Yindi Jiang, Vladimir Yeliseyev, Yancong Zhang, Eric A Franzosa, Zhipeng A Wang, Maheeshi Yapa Abeywardana, Phillip A Cole, Curtis Huttenhower, Lynn Bry, Emily P Balskus","doi":"10.1021/acschembio.3c00556","DOIUrl":"https://doi.org/10.1021/acschembio.3c00556","url":null,"abstract":"Hyperammonemia is characterized by the accumulation of ammonia within the bloodstream upon liver injury. Left untreated, hyperammonemia contributes to conditions such as hepatic encephalopathy that have high rates of patient morbidity and mortality. Previous studies have identified gut bacterial urease, an enzyme that converts urea into ammonia, as a major contributor to systemic ammonia levels. Here, we demonstrate use of benurestat, a clinical candidate used against ureolytic organisms in encrusted uropathy, to inhibit urease activity in gut bacteria. Benurestat inhibits ammonia production by urease-encoding gut bacteria and is effective against individual microbes and complex gut microbiota. When administered to conventional mice with liver injury induced by thioacetamide exposure, benurestat reduced gut and serum ammonia levels and rescued 100% of mice from lethal acute liver injury. Overall, this study provides an important proof-of-concept for modulating host ammonia levels and microbiota-driven risks for hyperammonemia with gut microbiota-targeted small-molecule inhibitors.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142941418","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}

引用次数: 0

2-Cyanopyrimidine-Containing Molecules for N-Terminal Selective Cyclization of Phage-Displayed Peptides.

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-01-07 DOI: 10.1021/acschembio.4c00725

J Trae Hampton, Connor R Dobie, Demonta D Coleman, Moulay I Cherif, Sukant Das, Wenshe Ray Liu

{"title":"2-Cyanopyrimidine-Containing Molecules for N-Terminal Selective Cyclization of Phage-Displayed Peptides.","authors":"J Trae Hampton, Connor R Dobie, Demonta D Coleman, Moulay I Cherif, Sukant Das, Wenshe Ray Liu","doi":"10.1021/acschembio.4c00725","DOIUrl":"https://doi.org/10.1021/acschembio.4c00725","url":null,"abstract":"Current methods for the macrocyclization of phage-displayed peptides often rely on small molecule linkers that nonspecifically react with targeted amino acid residues. To expand tool kits for more regioselective macrocyclization of phage-displayed peptides, this study explores the unique condensation reaction between an N-terminal cysteine and nitrile along with the reactivity of an internal cysteine. Five 2-cyanopyrimidine derivatives were synthesized for this purpose and evaluated for their selective macrocyclization of a protein-fused model peptide. Among these, two novel linkers, 2-chloro-N-(2-cyanopyrimidin-5-yl)acetamide (pCAmCP) and 2-chloro-N-(2-cyanopyrimidin-4-yl)acetamide (mCAmCP), emerged as efficient molecules and were demonstrated to macrocyclize phage-displayed peptide libraries flanked by an N-terminal and an internal cysteine. Using these linkers to generate macrocyclic peptide libraries displayed on phages, peptide ligands for the ZNRF3 extracellular domain were successfully identified. One of the identified peptides, Z27S1, exhibited potent binding to ZNRF3 with a KD value of 360 nM. Notably, the selection results revealed distinct peptide enrichment patterns depending on whether mCAmCP or pCAmCP was used, underscoring the significant impact of linker choice on macrocyclic peptide identification. Overall, this study validates the development of two novel regioselective, small molecule linkers for phage display of macrocyclic peptides and highlights the benefits of employing multiple linkers during phage selections.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142941417","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}

引用次数: 0

Functional Characterization of Pathway Inhibitors for the Ubiquitin-Proteasome System (UPS) as Tool Compounds for CRBN and VHL-Mediated Targeted Protein Degradation.

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-01-03 DOI: 10.1021/acschembio.4c00450

Martin P Schwalm, Amelie Menge, Lewis Elson, Francesco A Greco, Matthew B Robers, Susanne Müller, Stefan Knapp

{"title":"Functional Characterization of Pathway Inhibitors for the Ubiquitin-Proteasome System (UPS) as Tool Compounds for CRBN and VHL-Mediated Targeted Protein Degradation.","authors":"Martin P Schwalm, Amelie Menge, Lewis Elson, Francesco A Greco, Matthew B Robers, Susanne Müller, Stefan Knapp","doi":"10.1021/acschembio.4c00450","DOIUrl":"https://doi.org/10.1021/acschembio.4c00450","url":null,"abstract":"Small molecule degraders such as PROteolysis TArgeting Chimeras (PROTACs) and molecular glues are new modalities for drug development and important tools for target validation. When appropriately optimized, both modalities lead to proteasomal degradation of the protein of interest (POI). Due to the complexity of the induced multistep degradation process, controls for degrader evaluation are critical and commonly used in the literature. However, comparative studies and evaluations of cellular potencies of these control compounds have not been published so far. Here, we investigated a diverse set of ubiquitin pathway inhibitors and evaluated their potency and utility within the CRBN and VHL-mediated degradation pathway. We used the HiBiT system to measure the level of target rescue after treatment with the control compounds. In addition, the cell health was assessed using a multiplexed high-content assay. These assays allowed us to determine nontoxic effective concentrations for control experiments and to perform rescue experiments in the absence of cellular toxicity.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142925797","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}

引用次数: 0

Exploring the Impact of Amidation Status in Meso-Diaminopimelic-Acid-Containing Disaccharide Peptidoglycan Fragments on Host Innate Immune Activation.

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-01-03 DOI: 10.1021/acschembio.4c00700

Yaquan Liang, Christopher Adamson, Shiliu Feng, Yuan Qiao

{"title":"Exploring the Impact of Amidation Status in Meso-Diaminopimelic-Acid-Containing Disaccharide Peptidoglycan Fragments on Host Innate Immune Activation.","authors":"Yaquan Liang, Christopher Adamson, Shiliu Feng, Yuan Qiao","doi":"10.1021/acschembio.4c00700","DOIUrl":"10.1021/acschembio.4c00700","url":null,"abstract":"Bacterial peptidoglycan, the essential cell surface polymer that protects bacterial integrity, also serves as the molecular pattern recognized by the host's innate immune system. Although the minimal motifs of bacterial peptidoglycan fragments (PGNs) that activate mammalian NOD1 and NOD2 sensors are well-known and often represented by small canonical ligands, the immunostimulatory effects of natural PGNs, which are structurally more complex and potentially can simultaneously activate both the NOD1 and NOD2 signaling pathways in hosts, have not been comprehensively investigated. In particular, many bacteria incorporate additional structural modifications in peptidoglycans to evade host immune surveillance, resulting in diverse structural variations among natural PGNs that may influence their biological effects in hosts. The focus of this study is on the amidation status of γ-d-glutamic acid and meso-diaminopimelic acid (mDAP) at the second and third positions of stem peptides in peptidoglycan, which represent key structural features that vary across different bacterial species. With four synthetic mDAP-containing disaccharide PGNs of different amidation states, we systematically investigated their structure-activity relationship in stimulating host innate immune responses in vitro. Our findings revealed that the amidation of disaccharide PGNs has distinct effects on NOD1 and NOD2 induction, along with their differential immunostimulatory activities in macrophage cells. Additionally, we found that, like the canonical NOD2 ligand, natural PGNs confer immune tolerance to LPS, and amidation states do not affect this outcome. Overall, our work highlights the potential immunological implications of these differentially amidated mDAP-type disaccharide PGNs in host-microbe crosstalk.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142918802","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}

引用次数: 0

Revealing NOD1-Activating Gram-Positive Gut Microbiota via in Vivo Labeling with a meso-Diaminopimelic Acid Probe.

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-01-02 DOI: 10.1021/acschembio.4c00629

Huibin Lin, Xinying Zheng, Liyuan Lin, Chaoyong Yang, Wei Wang

{"title":"Revealing NOD1-Activating Gram-Positive Gut Microbiota via in Vivo Labeling with a meso-Diaminopimelic Acid Probe.","authors":"Huibin Lin, Xinying Zheng, Liyuan Lin, Chaoyong Yang, Wei Wang","doi":"10.1021/acschembio.4c00629","DOIUrl":"https://doi.org/10.1021/acschembio.4c00629","url":null,"abstract":"As an important receptor in a host's immune and metabolic systems, NOD1 is usually activated by Gram-negative bacteria having meso-diaminopimelic acid (m-DAP) in their peptidoglycan (PGN). But some atypical Gram-positive bacteria also contain m-DAP in their PGN, giving them the potential to activate NOD1. The prevalence of m-DAP-type Gram-positive bacteria in the gut, however, remains largely unknown. Here, we report a stem-peptide-based m-DAP-containing tetrapeptide probe for labeling and identifying m-DAP-type Gram-positive microbiota. The probe was synthesized via a five-step convergent approach and demonstrated moderate selectivity toward m-DAP-type bacteria in vitro. In vivo labeling revealed that ∼13.7% of the mouse gut microbiota (mostly Gram-positive) was selectively labeled. We then identified Oscillibacter and several other Gram-positive genera in this population, most of which were previously unknown m-DAP-type bacteria. The following functional assay showed that Oscillibacter's PGN could indeed activate NOD1, suggesting an overlooked NOD1-activating role for these Gram-positive bacteria. These findings deepen our understanding of the structural diversity of gut microbes and their interactions with the host's immune system.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142913148","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}

引用次数: 0

Strategic Acyl Carrier Protein Engineering Enables Functional Type II Polyketide Synthase Reconstitution In Vitro.

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-01-02 DOI: 10.1021/acschembio.4c00678

Kevin Li, Yae In Cho, Mai Anh Tran, Christoph Wiedemann, Shuaibing Zhang, Rebecca S Koweek, Ngọc Khánh Hoàng, Grayson S Hamrick, Margaret A Bowen, Bashkim Kokona, Pierre Stallforth, Joris Beld, Ute A Hellmich, Louise K Charkoudian

{"title":"Strategic Acyl Carrier Protein Engineering Enables Functional Type II Polyketide Synthase Reconstitution In Vitro.","authors":"Kevin Li, Yae In Cho, Mai Anh Tran, Christoph Wiedemann, Shuaibing Zhang, Rebecca S Koweek, Ngọc Khánh Hoàng, Grayson S Hamrick, Margaret A Bowen, Bashkim Kokona, Pierre Stallforth, Joris Beld, Ute A Hellmich, Louise K Charkoudian","doi":"10.1021/acschembio.4c00678","DOIUrl":"10.1021/acschembio.4c00678","url":null,"abstract":"Microbial polyketides represent a structurally diverse class of secondary metabolites with medicinally relevant properties. Aromatic polyketides are produced by type II polyketide synthase (PKS) systems, each minimally composed of a ketosynthase-chain length factor (KS-CLF) and a phosphopantetheinylated acyl carrier protein (holo-ACP). Although type II PKSs are found throughout the bacterial kingdom, and despite their importance to strategic bioengineering, type II PKSs have not been well-studied in vitro. In cases where the KS-CLF can be accessed via E. coli heterologous expression, often the cognate ACPs are not activatable by the broad specificity Bacillus subtilis surfactin-producing phosphopantetheinyl transferase (PPTase) Sfp and, conversely, in systems where the ACP can be activated by Sfp, the corresponding KS-CLF is typically not readily obtained. Here, we report the high-yield heterologous expression of both cyanobacterial Gloeocapsa sp. PCC 7428 minimal type II PKS (gloPKS) components in E. coli, which allowed us to study this minimal type II PKS in vitro. Initially, neither the cognate PPTase nor Sfp converted gloACP to its active holo state. However, by examining sequence differences between Sfp-compatible and -incompatible ACPs, we identified two conserved residues in gloACP that, when mutated, enabled high-yield phosphopantetheinylation of gloACP by Sfp. Using analogous mutations, other previously Sfp-incompatible type II PKS ACPs from different bacterial phyla were also rendered activatable by Sfp. This demonstrates the generalizability of our approach and breaks down a longstanding barrier to type II PKS studies and the exploration of complex biosynthetic pathways.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142918804","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}

引用次数: 0

High-Throughput Computer Screen Aids Discovery of Methotrexate as miR-20b Inhibitor to Suppress Nonsmall Cell Lung Cancer Progression.

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2024-12-30 DOI: 10.1021/acschembio.4c00706

Xiaorui Shi, Chong Hu, Liangli Fan, Bin Guo, Jingyu Zhang, Chu Tang, Fu Wang

{"title":"High-Throughput Computer Screen Aids Discovery of Methotrexate as miR-20b Inhibitor to Suppress Nonsmall Cell Lung Cancer Progression.","authors":"Xiaorui Shi, Chong Hu, Liangli Fan, Bin Guo, Jingyu Zhang, Chu Tang, Fu Wang","doi":"10.1021/acschembio.4c00706","DOIUrl":"https://doi.org/10.1021/acschembio.4c00706","url":null,"abstract":"MicroRNAs (miRNAs) play a significant role in tumor progression, and regulating miRNA expression with small molecules may offer a new approach to cancer therapy. Among them, miRNA-20b has been found to be dysregulated in several cancers, including nonsmall cell lung cancer (NSCLC). Herein, an in silico high-throughput computer screen was conducted to identify small molecules that downregulate miR-20b using the three-dimensional structure of the Dicer binding site on pre-miR-20b. Among 1058 small molecule compounds, Methotrexate (MTX), was discovered to be a potential miR-20b-specific inhibitor, which has been found to suppress miR-20b by specifically blocking Dicer processing in p53 wild-type A549 NSCLC cells but not in H1299 cells with p53 depletion. MTX effectively inhibited the proliferation, survival, migration, and invasion of A549 cells in a dose-dependent manner. Furthermore, the treatment of MTX up-regulated the expression of miR-20b target genes PTEN, STAT3, and HIF1α. Notably, MTX also significantly inhibited tumor growth in a mouse xenograft tumor model of NSCLC, with no observed tissue toxicity. Our findings indicate that MTX may have a novel role as an established drug in p53 wild-type NSCLC tumor therapy by down-regulating miR-20b expression. These findings are expected to provide preclinical evidence for miR-20b-targeting NSCLC therapeutic strategies.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142906176","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}

引用次数: 0

Click Chemistry Methodology: The Novel Paintbrush of Drug Design.

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2024-12-27 DOI: 10.1021/acschembio.4c00608

Ioana Oprea, Terry K Smith

引用次数: 0