ACS Chemical Biology最新文献

{"title":"Well-Defined Catalytic System for Integrating Homogeneous and Heterogeneous Catalysis","authors":"Hongli Wang,&nbsp;Jiashu Sun,&nbsp;Dongcheng He,&nbsp;Kang Zhao,&nbsp;Bo Qian and Feng Shi*,&nbsp;","doi":"10.1021/acscatal.4c0370110.1021/acscatal.4c03701","DOIUrl":"https://doi.org/10.1021/acscatal.4c03701https://doi.org/10.1021/acscatal.4c03701","url":null,"abstract":"<p >Catalysis is an eternal theme in chemical research because it is indispensable in the chemical industry. Homogeneous and heterogeneous catalysts possess their individual advantages and disadvantages, which are significantly complementary. Therefore, it is highly desirable to develop an effective and practical method for merging the benefits of homogeneous and heterogeneous catalysis. Recently, the application of organic ligands to modify heterogeneous supported catalysts has emerged as an important method to combine the advantages of heterogeneous catalysis with those of homogeneous catalysis. Ligands modified supported catalysts offer the potential to overcome major challenges in tunability and stability for supported catalysts. This Viewpoint discusses the recent progress in the synthesis and application of ligand modified supported metal catalysts in organic reactions that merge the advantages of homo- and heterogeneous catalysis. We discuss the preparation and characterization, the origin of enhanced activities, and the structure–activity relationship of ligand modified supported metal catalysts. The challenges and perspectives for future progress in this field will be given. This viewpoint provides important insights into the development of well-defined heterogeneous catalysts for integrating homogeneous and heterogeneous catalysis.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"14 21","pages":"16025–16043 16025–16043"},"PeriodicalIF":11.3,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142560408","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":"A van der Waals–Covalent Bonding-Inspired Typical Coordination with Ultrahigh Lattice Mismatch as Active Sites for Hydrogen Electrosynthesis","authors":"Xinying Luo,&nbsp;Junjie Xiong,&nbsp;Xiaolong Liu,&nbsp;Zhichang Xiao*,&nbsp;Qinghua Zhang,&nbsp;Yuchen Cai,&nbsp;Bowen Liu,&nbsp;Yang Gao,&nbsp;Tao Liang,&nbsp;Qiang Zheng,&nbsp;Jichen Dong*,&nbsp;Ting Tan*,&nbsp;Zhenxing Wang,&nbsp;Yunqi Liu and Bin Wang*,&nbsp;","doi":"10.1021/acscatal.4c0404610.1021/acscatal.4c04046","DOIUrl":"https://doi.org/10.1021/acscatal.4c04046https://doi.org/10.1021/acscatal.4c04046","url":null,"abstract":"<p >We report a van der Waals–covalent bonding interface with boosted hydrogen evolution reaction (HER) catalytic activity compared to the well-known edge defects for two-dimensional catalysts. The central region of a chemical-vapor-deposition-grown multilayer MoS₂ is transformed to Mo₅N₆, thus forming a van der Waals–covalent (v–c) interface that has high structural strain due to the large lattice mismatch of 10.5% between the two different phases. The large structural distortion creates several kinds of stretched sites that show ideal HER catalytic activities theoretically, such as the S sites coordinated by 2 Mo atoms and the 3-coordinated N atoms. In experiments, the v–c interface bonding and coordination variations were observed, and a number-of-layers-dependent MoS₂-to-Mo₅N₆ transformation mechanism was found. Using the on-chip electrochemical micromeasurements, the catalytic activity of the atoms at the v–c interface was demonstrated to be higher than the edge atoms of either MoS₂ or Mo₅N₆ sheets. Further macrotests using the as-synthesized powder materials showed greatly enhanced HER performance of the v–c structure than MoS₂ or Mo₅N₆ sheets. This comprehensive study of the v–c structure shows the synthesis route and a clear bonding interface, establishes the number-of-layers-dependent transformation principles, exhibits high-priority HER activities, and explains the strain/coordination-variation-induced catalytic mechanism.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"14 21","pages":"16074–16085 16074–16085"},"PeriodicalIF":11.3,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142560392","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":"Selective Association Enforced by the Confinement Effect To Boost the Regioselectivity of Vinyl Acetate Hydroformylation","authors":"Guoqing Wang,&nbsp;Miao Jiang,&nbsp;Benhan Fan,&nbsp;Zhao Sun,&nbsp;Leilei Qian,&nbsp;Guangjun Ji,&nbsp;Lei Ma,&nbsp;Cunyao Li,&nbsp;Zhaozhan Wang,&nbsp;Guifa Long*,&nbsp;Yong Yang*,&nbsp;Li Yan* and Yunjie Ding*,&nbsp;","doi":"10.1021/acscatal.4c0393210.1021/acscatal.4c03932","DOIUrl":"https://doi.org/10.1021/acscatal.4c03932https://doi.org/10.1021/acscatal.4c03932","url":null,"abstract":"<p >1,3-Propanediol derived from vinyl acetate through hydroformylation/hydrogenation has always been considered the most promising strategy to substitute the current technology. So far, the linear aldehyde regioselectivity of vinyl acetate hydroformylation is still far from satisfactory. Herein, we prepare a series of single-site catalysts with a confinement effect, in which different second-shell atoms (C, O, and N) are bonded with the P atom. The Rh–P–N-POPs catalyst, in which two N and one O atoms are bonded with a P atom, delivers not only a good aldehyde yield but also attractive regioselectivity (l/b = 1.5), outperforming Rh–P–C-POPs (l/b = 0.007), Rh–P–O-POPs (l/b = 0.01), and all previously reported optimizing Rh catalysts (l/b = 0.8). Characterizations and DFT calculations suggest that the enhanced performance is mainly ascribed to selective association enforced by the confinement effect and electron-deficient properties. The confinement effect, which is imposed by the ligand, hinders the chelating effect of acetate and facilitates the selective association of Rh with the terminal carbon of olefins. Meanwhile, N as second-shell atoms in the Rh–P–N-POPs catalyst endows Rh active sites with an electron-deficient coordination environment and accelerates the linear aldehyde forming rate. This work offers an effective strategy to regulate the hydroformylation performance by the confinement effect for the modulation of a second-shell atom, which sheds light on designing heterogeneous catalysts with high regioselectivity for the hydroformylation of functional olefins.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"14 21","pages":"16014–16024 16014–16024"},"PeriodicalIF":11.3,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142560393","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":"Boosting Enzyme Activity in Biomass Conversion by Modulating the Hydrolysis Process of Cellobiohydrolases","authors":"Han Liu,&nbsp;Yu Ding,&nbsp;Scott Mazurkewich,&nbsp;Wenwen Pei,&nbsp;Xiuxin Wei,&nbsp;Johan Larsbrink,&nbsp;Christophe Chipot*,&nbsp;Zhangyong Hong*,&nbsp;Wensheng Cai* and Zhiyou Zong*,&nbsp;","doi":"10.1021/acscatal.4c0539310.1021/acscatal.4c05393","DOIUrl":"https://doi.org/10.1021/acscatal.4c05393https://doi.org/10.1021/acscatal.4c05393","url":null,"abstract":"<p >Cellobiohydrolases (CBHs) are the most significant cellulose-degrading enzymes, the performance of which determines the cost-effective utilization of renewable lignocellulosic resources. Most engineering strategies for improving CBH hydrolysis are currently focused on accelerating the noncatalytic enzyme–substrate dissociation by increasing the flexibility of eight substrate-enclosing loops (SELs), which does not take the catalysis into account or even deteriorates it. Here, in the model <i>Trichoderma reesei</i> CBHI, we identified a key SEL that affects the dissociation by examining enzyme–enzyme/substrate interactions. Furthermore, through analyzing the hydrogen-bonding network for the catalytic region, we detected a crucial residue D262. Root-mean-square-fluctuation analysis indicates that its replacement with valine (D262V) markedly improves the stability of the catalytic triad. Through QM/MM simulations, we determined that this mutation diminished the free-energy barrier against catalysis by 2.3 kcal/mol and increased <i>k</i>_cat by 53.1%, as determined in kinetic experiments. Additionally, the substitution caused a significant enhancement of SEL flexibility and led to a lowered dissociation barrier by 2.1 kcal/mol. The cellobiose yield was increased by 49.8%, owing to the impact of the single valine replacement on the enzyme hydrolysis. This work unlocks a brand-new engineering direction for industrially important CBHs, contributing to more efficient depolymerization of renewable lignocellulose.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"14 21","pages":"16044–16054 16044–16054"},"PeriodicalIF":11.3,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142571119","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":"2-Deoxy-4-epi-scyllo-inosose (DEI) is the Product of EboD, a Highly Conserved Dehydroquinate Synthase-like Enzyme in Bacteria and Eustigmatophyte Algae","authors":"Samuel Tanoeyadi,&nbsp;Wei Zhou,&nbsp;Andrew R. Osborn,&nbsp;Takeshi Tsunoda,&nbsp;Arash Samadi,&nbsp;Sachin Burade,&nbsp;Ty J. Waldo,&nbsp;Melanie A. Higgins and Taifo Mahmud*,&nbsp;","doi":"10.1021/acschembio.4c0051010.1021/acschembio.4c00510","DOIUrl":"https://doi.org/10.1021/acschembio.4c00510https://doi.org/10.1021/acschembio.4c00510","url":null,"abstract":"<p >A cryptic cluster of genes, known as the ebo cluster, has been found in a variety of genomic contexts among bacteria and algae. In <i>Pseudomonas fluorescens</i> NZI7, the ebo cluster (a.k.a. EDB cluster) is involved in the bacterial repellent mechanism against nematode grazing. In cyanobacteria, the cluster plays a role in the transport of the scytonemin monomer from the cytosol to the periplasm. Despite their broad distribution and interesting phenotypes, neither the pathway nor the functions of the enzymes are known. Here we show that EboD proteins from the ebo clusters in <i>Nostoc punctiforme</i> and <i>Sporocytophaga myxococcoides</i> catalyze the cyclization of mannose 6-phosphate to a novel cyclitol, 2-deoxy-4-<i>epi</i>-<i>scyllo</i>-inosose. The enzyme product is postulated to be a precursor of a signaling molecule or a transporter in the organisms. This study sheds the first light onto ebo/EDB pathways and established a functionally distinct enzyme that extends the diversity of sugar phosphate cyclases.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"19 11","pages":"2277–2283 2277–2283"},"PeriodicalIF":3.5,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142641113","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 and Synthesis of Artificial FAD Cofactors for the Light-Triggered Covalent Flavinylation of Flavoenzymes†","authors":"Clemens Cziegler,&nbsp;Florian Csarman,&nbsp;Erik Breslmeyer,&nbsp;Su Ma,&nbsp;Hannes Meinert,&nbsp;Roland Ludwig*,&nbsp;Florian Rudroff* and Marko D. Mihovilovic,&nbsp;","doi":"10.1021/acscatal.4c0354410.1021/acscatal.4c03544","DOIUrl":"https://doi.org/10.1021/acscatal.4c03544https://doi.org/10.1021/acscatal.4c03544","url":null,"abstract":"<p >Flavoenzymes are versatile biocatalysts with extraordinary properties. They are not only vital to life by orchestrating complex transformations in biological processes but offer numerous biocatalytic opportunities. Most flavoenzymes have a noncovalently bound flavin cofactor. The cofactor is responsible for the catalytic versatility and prowess of flavoenzymes and is essential for their structure and stability. The dissociation of noncovalently bound flavin adenine dinucleotide (FAD) results in an immediate loss of activity and often an unstable apoenzyme, which reduces turnover stability and limits the broader application of flavoenzymes in the industry. Herein, we present a proof-of-concept for the light-induced covalent flavinylation of the three flavoenzymes glucose oxidase (GOx), cellobiose dehydrogenase (CDH), and cyclohexanone monooxygenase (CHMO). We designed and synthesized seven FAD analogs bearing a diazirine group, allowing the light-triggered covalent anchoring of the cofactor. One of the photoclickable FAD analogs (<b>diazFAD4</b>) could be integrated successfully into all flavoenzymes of interest, achieving activities comparable to those of the native FAD. The covalent bond formation was initiated by ultraviolet (UV) light irradiation and could be confirmed via fluorescence imaging. By expanding the photoaffinity labeling technique, we provide a novel method for the covalent and functional incorporation of cofactors into biocatalysts.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"14 21","pages":"15988–15996 15988–15996"},"PeriodicalIF":11.3,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acscatal.4c03544","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142560377","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":"A Dynamic Loop in Halohydrin Dehalogenase HheG Regulates Activity and Enantioselectivity in Epoxide Ring Opening","authors":"Marcel Staar,&nbsp;Lina Ahlborn,&nbsp;Miquel Estévez-Gay,&nbsp;Katharina Pallasch,&nbsp;Sílvia Osuna* and Anett Schallmey*,&nbsp;","doi":"10.1021/acscatal.4c0481510.1021/acscatal.4c04815","DOIUrl":"https://doi.org/10.1021/acscatal.4c04815https://doi.org/10.1021/acscatal.4c04815","url":null,"abstract":"<p >Halohydrin dehalogenase HheG and its homologues are remarkable enzymes for the efficient ring opening of sterically demanding internal epoxides using a variety of nucleophiles. The enantioselectivity of the respective wild-type enzymes, however, is usually insufficient for application and frequently requires improvement by protein engineering. We herein demonstrate that the highly flexible N-terminal loop of HheG, comprising residues 39 to 47, has a tremendous impact on the activity as well as enantioselectivity of this enzyme in the ring opening of structurally diverse epoxide substrates. Thus, highly active and enantioselective HheG variants could be accessed through targeted engineering of this loop. In this regard, variant M45F displayed almost 10-fold higher specific activity than wild type in the azidolysis of cyclohexene oxide, yielding the corresponding product (1<i>S</i>,2<i>S</i>)-2-azidocyclohexan-1-ol in 96%ee_P (in comparison to 49%ee_P for HheG wild type). Moreover, this variant was also improved regarding activity and enantioselectivity in the ring opening of cyclohexene oxide with other nucleophiles, demonstrating even inverted enantioselectivity with cyanide and cyanate. In contrast, a complete loop deletion yielded an inactive enzyme. Concomitant computational analyses of HheG M45F in comparison to wild type enzyme revealed that mutation M45F promotes the productive binding of cyclohexene oxide and azide in the active site by establishing noncovalent C–H ··π interactions between epoxide and F45. These interactions further position one of the two carbon atoms of the epoxide ring closer to the azide, resulting in higher enantioselectivity. Additionally, stable and enantioselective cross-linked enzyme crystals of HheG M45F were successfully generated after combination with mutation D114C. Overall, our study highlights that a highly flexible loop in HheG governs the enzyme’s activity and selectivity in epoxide ring opening and should thus be considered in future protein engineering campaigns of HheG.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"14 21","pages":"15976–15987 15976–15987"},"PeriodicalIF":11.3,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acscatal.4c04815","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142560379","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":"Screening Ir-Free Trimetallic Alloys with Consideration of Metal Electronegativity and Oxophilicity toward Ammonia Electrooxidation","authors":"Zhengwei Zhang,&nbsp;Hao Shen,&nbsp;Yongying Wang,&nbsp;Zhaozhao Dong,&nbsp;Tieyu Hu,&nbsp;Zhongti Sun*,&nbsp;Juan Yang* and Yi Li*,&nbsp;","doi":"10.1021/acscatal.4c0518510.1021/acscatal.4c05185","DOIUrl":"https://doi.org/10.1021/acscatal.4c05185https://doi.org/10.1021/acscatal.4c05185","url":null,"abstract":"<p >Ir-contained alloys represent the state-of-the-art ammonia oxidation reaction (AOR) electrocatalysts for direct ammonia fuel cells, but they are greatly impeded by their high cost. Here, we rationally design and synthesize Ir-free trimetallic alloys with the consideration of metal electronegativity and oxophilicity that govern the reactivity of the alloy surface. By introducing a metal (i.e., Pd) with an electronegativity like Ir and oxophilic metals (i.e., Mn, Fe, Co, or Ni) into Pt, we have screened a high-performance Ir-free trimetallic electrocatalyst system. Among others, Pt₃PdNi was experimentally selected as an optimal AOR electrocatalyst, showing an onset potential of ∼0.45 V versus the reversible hydrogen electrode, lower than those of Pt, Pt₃Pd, and Pt₃RuNi controls and much closer to commercial PtIr/C. Further carbon support selection has resulted in the optimal Pt₃PdNi deposited onto carboxyl-functionalized carbon black displaying the highest peak current density of 252.9 A g_Pt^–1. Density functional theory calculations further demonstrated that PdNi atoms in Pt decrease the reaction energy barrier of electrochemical dehydrogenation of *NH₂ to *NH, resulting in enhanced catalytic activity for the AOR. Moreover, the hydrazine electrooxidation experiments indicate that NH₃ adsorption and activation before N–N dimerization is kinetically sluggish.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"14 21","pages":"15965–15975 15965–15975"},"PeriodicalIF":11.3,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142560374","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":"A “Goldilocks Zone” for Recruiting BET Proteins with Bromodomain-1-Selective Ligands","authors":"Ashraf Mohammed,&nbsp;Kelly Churion,&nbsp;Adithi Danda,&nbsp;Steven J. Philips and Aseem Z. Ansari*,&nbsp;","doi":"10.1021/acschembio.4c0050510.1021/acschembio.4c00505","DOIUrl":"https://doi.org/10.1021/acschembio.4c00505https://doi.org/10.1021/acschembio.4c00505","url":null,"abstract":"<p >Synthetic genome readers/regulators (SynGRs) are bifunctional molecules that are rationally designed to bind specific genomic sequences and engage cellular machinery that regulates the expression of targeted genes. The prototypical SynGR1 targets GAA trinucleotide repeats and recruits the BET family of transcriptional regulatory proteins via a flexibly tethered ligand, JQ1. This pan-BET ligand binds both tandem bromodomains of BET proteins (BD1 and BD2). Second-generation SynGRs, which substituted JQ1 with bromodomain-selective ligands, unexpectedly revealed that BD1-selective ligands failed to functionally engage BET proteins in living cells despite displaying the ability to bind BD1 in vitro. Mechanistically, recruiting a BET protein via BD1- or BD2-selective SynGRs should have resulted in indistinguishable functional outcomes. Here we report the conversion of inactive BD1-targeting SynGRs into functional gene regulators by a structure-guided redesign of the chemical linker that bridges the DNA-binding molecule to the highly selective BD1 ligand GSK778. The results point to an optimal zone for positioning the BD1-selective ligand for functional engagement of BET proteins on chromatin, consistent with the preferred binding of BD1 domains to distal acetyllysine residues on histone tails. The results not only resolve the mechanistic conundrum but also provide insight into domain-selective targeting and nuanced design of chemo probes and therapeutics.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"19 11","pages":"2268–2276 2268–2276"},"PeriodicalIF":3.5,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142641040","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":"Discovery of Antinociceptive α9α10 Nicotinic Acetylcholine Receptor Antagonists by Stable Receptor Expression","authors":"Kyle M. Kremiller,&nbsp;Gauri C. Kulkarni,&nbsp;Lauren M. Harris,&nbsp;Hirushi Gunasekara,&nbsp;Yavnika Kashyap,&nbsp;Giokdjen Ilktach,&nbsp;Angela Nguyen,&nbsp;Alison E. Ondrus,&nbsp;Ying S. Hu,&nbsp;Zaijie J. Wang,&nbsp;Andrew P. Riley* and Christian J. Peters*,&nbsp;","doi":"10.1021/acschembio.4c0033010.1021/acschembio.4c00330","DOIUrl":"https://doi.org/10.1021/acschembio.4c00330https://doi.org/10.1021/acschembio.4c00330","url":null,"abstract":"<p >Chronic neuropathic pain is an increasingly prevalent societal issue that responds poorly to existing therapeutic strategies. The α9α10 nicotinic acetylcholine receptor (nAChR) has emerged as a potential target to treat neuropathic pain. However, challenges in expressing functional α9α10 nAChRs in mammalian cell lines have slowed the discovery of α9α10 ligands and studies into the relationship between α9α10 nAChRs and neuropathic pain. Here, we develop a cell line in the HEK293 background that stably expresses functional α9α10 nAChRs. By also developing cell lines expressing only α9 and α10 subunits, we identify distinct receptor pharmacology between homomeric α9 or α10 and heteromeric α9α10 nAChRs. Moreover, we demonstrate that incubation with nAChR ligands differentially regulates the expression of α9- or α10-containing nAChRs, suggesting a possible mechanism by which ligands may modify receptor composition and trafficking in α9- and α10-expressing cells. We then apply our α9α10 cell line in a screen of FDA-approved and investigational drugs to identify α9α10 ligands that provide new tools to probe α9α10 nAChR function. We demonstrate that one compound from this screen, diphenidol, possesses antinociceptive activity in a murine model of neuropathic pain. These results expand our understanding of α9α10 receptor pharmacology and provide new starting points for developing efficacious neuropathic pain treatments.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"19 11","pages":"2291–2303 2291–2303"},"PeriodicalIF":3.5,"publicationDate":"2024-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142641069","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}