ACS Chemical Biology最新文献_第9页

Blm10-Based Compounds Add to the Knowledge of How Allosteric Modulators Influence Human 20S Proteasome

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-02-05 DOI: 10.1021/acschembio.4c0034110.1021/acschembio.4c00341

Julia Witkowska, Małgorzata Giżyńska, Przemysław Karpowicz, Daria Sowik, Karolina Trepczyk, Fabian Hennenberg, Ashwin Chari, Artur Giełdoń, Karolina Pierzynowska, Lidia Gaffke, Grzegorz Węgrzyn and Elżbieta Jankowska*,

{"title":"Blm10-Based Compounds Add to the Knowledge of How Allosteric Modulators Influence Human 20S Proteasome","authors":"Julia Witkowska, Małgorzata Giżyńska, Przemysław Karpowicz, Daria Sowik, Karolina Trepczyk, Fabian Hennenberg, Ashwin Chari, Artur Giełdoń, Karolina Pierzynowska, Lidia Gaffke, Grzegorz Węgrzyn and Elżbieta Jankowska*, ","doi":"10.1021/acschembio.4c0034110.1021/acschembio.4c00341","DOIUrl":"https://doi.org/10.1021/acschembio.4c00341https://doi.org/10.1021/acschembio.4c00341","url":null,"abstract":"Proteasomes catalyze protein degradation in cells and play an integral role in cellular homeostasis. Its activity decreases with age alongside the load of defective proteins, resulting from mutations or oxidative stress-induced damage. Such proteins are prone to aggregation and, if not efficiently degraded, can form toxic oligomers and amyloid plaques. Developing an effective way to activate the proteasome could prevent such pathologies. Designing activators is not easy because they do not bind in the active site, which is well-defined and highly conserved, but away from it. The structures of proteasome complexes with natural activators can help here, but these are large proteins, some even multimeric, whose activity is difficult to replace with a small-molecule compound. Nevertheless, the use of fragments of such proteins makes it possible to accumulate knowledge about the relevance of various structural elements for efficient and selective activation. Here, we presented peptidic activators of the 20S proteasome, which were designed based on both the C-terminal sequence of the yeast proteasome activator, Blm10 protein, and the interactions predicted by molecular modeling. These Blm analogs were able to stimulate human 20S proteasome to more efficiently degrade both small fluorogenic substrates and proteins. The best activators also demonstrated their efficacy in cell lysates. X-ray crystallography indicated that an effective modulator can bind to several sites on the surface of the proteasome without causing permanent structural changes in its immediate vicinity but affecting the active sites.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 2","pages":"266–280 266–280"},"PeriodicalIF":3.5,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acschembio.4c00341","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143452599","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}

引用次数: 0

Scaffolding Activities of Pseudodeacetylase HDAC7

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-02-05 DOI: 10.1021/acschembio.4c0075310.1021/acschembio.4c00753

Ishadi K. M. Kodikara, and , Mary Kay H. Pflum*,

{"title":"Scaffolding Activities of Pseudodeacetylase HDAC7","authors":"Ishadi K. M. Kodikara,  and , Mary Kay H. Pflum*, ","doi":"10.1021/acschembio.4c0075310.1021/acschembio.4c00753","DOIUrl":"https://doi.org/10.1021/acschembio.4c00753https://doi.org/10.1021/acschembio.4c00753","url":null,"abstract":"Histone deacetylase (HDAC) enzymes remove acetyl groups from acetyllysine-containing proteins, including nucleosomal histones to control gene expression. Beyond fundamental cell biology, HDAC activity is linked to various cancers, with many HDAC inhibitors developed as anticancer therapeutics. Among the 11 metal-dependent HDAC proteins, the four class IIa isoforms (HDAC4, 5, 7, and 9) are “pseudodeacetylases” without measurable enzymatic activity due to mutation of a catalytic tyrosine. Deacetylase-related activities of class IIa HDAC proteins are attributed to scaffolding functions, where recruitment of an active HDAC isoform leads to bound substrate deacetylation. Scaffolding of class IIa proteins beyond simple recruitment of an active HDAC is only starting to emerge. This review explores the various scaffolding roles of HDAC7, including recently reported acetylation-mediated reversible scaffolding, which is a form of acetyllysine-binding reader function. Studying the functional roles of HDAC7 will provide molecular insight into normal and pathological conditions, which could facilitate drug design.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 2","pages":"248–258 248–258"},"PeriodicalIF":3.5,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143452662","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

siRNA-Mimetic Ratiometric pH (sMiRpH) Probes for Improving Cell Delivery and mRNA Knockdown

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-02-05 DOI: 10.1021/acschembio.4c0054510.1021/acschembio.4c00545

Madison R. Herling, Lizeth Lopez Vazquez and Ivan J. Dmochowski*,

{"title":"siRNA-Mimetic Ratiometric pH (sMiRpH) Probes for Improving Cell Delivery and mRNA Knockdown","authors":"Madison R. Herling, Lizeth Lopez Vazquez and Ivan J. Dmochowski*, ","doi":"10.1021/acschembio.4c0054510.1021/acschembio.4c00545","DOIUrl":"https://doi.org/10.1021/acschembio.4c00545https://doi.org/10.1021/acschembio.4c00545","url":null,"abstract":"Second-generation siRNA-mimetic ratiometric pH probes (sMiRpH-2) were developed by hybridizing a 3′-FAM-labeled 2′-OMe RNA strand with a 3′-Cy5-labeled 25mer RNA strand. These duplexes demonstrated the silencing of cytoplasmic mRNA targets in HeLa cells as measured by RT-qPCR and supported by western blot analysis. Fluorescence intensity and lifetime measurements revealed that a single guanosine (G) positioned adjacent to FAM achieves substantial static quenching at pH 5, with additional collisional quenching rendering the dye almost nonemissive. A FAM-G π–π stacking interaction was evidenced by a red-shifted absorbance spectrum for FAM. Decreased quenching at near-neutral pH enhances the FAM dynamic range in the physiologic pH window and improves the differentiation in cells between endocytic entrapment and cytoplasmic release. Flow cytometric analysis of intracellular pH and uptake using sMiRpH-2 was corroborated by live cell confocal microscopy and found to be predictive of knockdown efficacy. A sMiRpH-2 probe successfully predicted the relative efficacy of two transfection agents in more challenging SK-OV-3 cells, which highlights its use for the rapid assessment of nonviral siRNA delivery vectors.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 2","pages":"309–320 309–320"},"PeriodicalIF":3.5,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143452672","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

Analogs of NIH Molecular Probe ML283 Are Potent SARS-CoV-2 Helicase Inhibitors

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-02-05 DOI: 10.1021/acschembio.4c0045810.1021/acschembio.4c00458

David N. Frick*, Robert V. Bavisotto, Nicholas C. Hopper and Wilfred T. Tysoe,

引用次数: 0

YBX1 Modulates 8-Oxoguanine Recognition and Repair in DNA

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-02-04 DOI: 10.1021/acschembio.4c0083110.1021/acschembio.4c00831

Xiaofang Zheng, Weiheng Kong, Xiaoxia Dai* and Changjun You*,

引用次数: 0

Effect of pH-Responsive Ligands on mRNA Knockdown in EGFR-Targeting Ligand-Conjugated siRNAs

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-02-03 DOI: 10.1021/acschembio.4c0050710.1021/acschembio.4c00507

Toshimasa Harumoto, Ryohei Kawai, Keiichi Motosawa, Junko Iwano, Yasuo Koda, Yuuki Hirata and Keiji Uehara*,

{"title":"Effect of pH-Responsive Ligands on mRNA Knockdown in EGFR-Targeting Ligand-Conjugated siRNAs","authors":"Toshimasa Harumoto, Ryohei Kawai, Keiichi Motosawa, Junko Iwano, Yasuo Koda, Yuuki Hirata and Keiji Uehara*, ","doi":"10.1021/acschembio.4c0050710.1021/acschembio.4c00507","DOIUrl":"https://doi.org/10.1021/acschembio.4c00507https://doi.org/10.1021/acschembio.4c00507","url":null,"abstract":"Ligand-conjugated small interfering RNAs (siRNAs) have emerged as a powerful approach to developing nucleic acid-based medicines. To achieve efficient mRNA knockdown, it is important to select targeting receptors with high expression and ligands that exhibit rapid internalization. However, the key characteristics of ligand–receptor sets involved in the postinternalization process remain largely unclear. In this study, we investigated the effect of ligand–receptor binding dissociation under low pH conditions, known as a postendocytic environment. Specifically, we chemically synthesized several modified epidermal growth factor (EGF) ligands that showed a variety of binding activities to the EGF receptor (EGFR) at low pH. Among these modified ligands, the siRNA conjugate with chemically synthesized EGF H10Y/H16Y, which is a less pH-responsive variant, exhibited reduced internalization and mRNA knockdown activity at high concentrations in EGFR-expressing cells. Additionally, we explored the use of antibody-related molecules (anti-EGFR IgG and Fab) as targeting moieties for siRNA conjugates. The anti-EGFR Fab-siRNA, which showed dissociation of EGF under low pH conditions, demonstrated stronger internalization and mRNA knockdown activity compared to the anti-EGFR IgG-siRNA, which strongly binds EGF at low pH. These data emphasize the importance of intracellular ligand–receptor dissociation and provide insights for future advancements in the field.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 2","pages":"297–308 297–308"},"PeriodicalIF":3.5,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143452573","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

Radical SAM Enzyme WprB Catalyzes Uniform Cross-Link Topology between Trp-C5 and Arg-Cγ on the Precursor Peptide

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-02-02 DOI: 10.1021/acschembio.4c0069310.1021/acschembio.4c00693

Abujunaid Habib Khan, Jabal Rahmat Haedar, Vic Kiselov, Viktors Romanuks, Gints Smits, Stefano Donadio and Chin-Soon Phan*,

引用次数: 0

Discovery of Dual ROCK1/2 Inhibitors from Nocardiopsis sp. under Metal Stress

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-02-02 DOI: 10.1021/acschembio.4c0073610.1021/acschembio.4c00736

Thinh T. M. Bui, Hyejin Ko, Soohyun Um, Hyeongju Jeong, Suk Woo Kang, Hasun Kim, Dae-geun Song, Sang Hoon Jung* and Kyuho Moon*,

{"title":"Discovery of Dual ROCK1/2 Inhibitors from Nocardiopsis sp. under Metal Stress","authors":"Thinh T. M. Bui, Hyejin Ko, Soohyun Um, Hyeongju Jeong, Suk Woo Kang, Hasun Kim, Dae-geun Song, Sang Hoon Jung* and Kyuho Moon*, ","doi":"10.1021/acschembio.4c0073610.1021/acschembio.4c00736","DOIUrl":"https://doi.org/10.1021/acschembio.4c00736https://doi.org/10.1021/acschembio.4c00736","url":null,"abstract":"Rho-associated protein kinase (ROCK) inhibitors are promising therapeutic agents for reducing elevated intraocular pressure in patients with glaucoma. We explored new ROCK inhibitors derived from bioactive metabolites produced by microbes, specifically cryptic metabolites from Nocardiopsis sp. MCY7, using a liquid chromatography–mass spectrometry-based chemical analysis approach integrated with metal stress-driven isolation. This strategy led to the identification of two previously undescribed linear peptides, nocarnickelamides A and B (1 and 2), and an unreported cittilin derivative, cittilin C (3). The planar structures of 1–3 were elucidated using UV spectroscopy, high-resolution mass spectrometry, and nuclear magnetic resonance. The absolute configurations of 1 and 2 were assigned using the advanced Marfey’s method. Biological assays demonstrated that nocarnickelamides (1 and 2) exhibited dual inhibitory activity against ROCK1 (IC50 29.8 and 14.9 μM, respectively) and ROCK2 (IC50 27.0 and 21.9 μM, respectively), with molecular simulations suggesting binding to the ATP-binding site. In human trabecular meshwork cells, 2 significantly inhibited the activation of ROCK-regulated cytoskeletal contraction markers such as the myosin light chain. Nocarnickelamide B (2) is a novel dual ROCK1/2 inhibitor and a potential pharmacophore for designing new therapeutic agents to reduce intraocular pressure in glaucoma.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 2","pages":"432–441 432–441"},"PeriodicalIF":3.5,"publicationDate":"2025-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143452446","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

Discovery of DCAF16 Binders for Targeted Protein Degradation

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-01-30 DOI: 10.1021/acschembio.4c0079910.1021/acschembio.4c00799

Miguel A. Campos, Isabella A. Riha, Chenlu Zhang, Chen Mozes, Karl A. Scheidt* and Xiaoyu Zhang*,

{"title":"Discovery of DCAF16 Binders for Targeted Protein Degradation","authors":"Miguel A. Campos, Isabella A. Riha, Chenlu Zhang, Chen Mozes, Karl A. Scheidt* and Xiaoyu Zhang*, ","doi":"10.1021/acschembio.4c0079910.1021/acschembio.4c00799","DOIUrl":"https://doi.org/10.1021/acschembio.4c00799https://doi.org/10.1021/acschembio.4c00799","url":null,"abstract":"Conventional small-molecule drugs primarily operate by inhibiting protein function, but this approach is limited when proteins lack well-defined ligand-binding pockets. Targeted protein degradation (TPD) offers an alternative approach by harnessing cellular degradation pathways to eliminate specific proteins. Recent studies have expanded the potential of TPD by identifying additional E3 ligases, with DCAF16 emerging as a promising candidate for facilitating protein degradation through both proteolysis-targeting chimera (PROTAC) and molecular glue mechanisms. In this study, we revisited a previously reported compound and discovered that it covalently binds to DCAF16. We further optimized it into a FKBP12-targeting PROTAC, MC-25B. This PROTAC engages DCAF16 at cysteines C177–179, leading to the degradation of nuclear-localized FKBP12. We further demonstrated the versatility of this DCAF16 recruiter by degrading additional endogenous proteins. Compared to the first-generation DCAF16-based PROTAC, which was derived from a fragment electrophile, this DCAF16 recruiter-based PROTAC exhibits improved proteome-wide selectivity.","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 2","pages":"479–488 479–488"},"PeriodicalIF":3.5,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143452454","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

Chemoproteomic Profiling of Clickable Fumarate Probes for Target Identification and Mechanism of Action Studies

IF 3.5 2区生物学

ACS Chemical Biology Pub Date : 2025-01-28 DOI: 10.1021/acschembio.4c0061710.1021/acschembio.4c00617

Lu Zhang*, Jeffrey G. Martin, Benbo Gao, Weike Zeng, Shalise Couvertier and Douglas S. Johnson*,

引用次数: 0