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Phage Display Selection against a Mixture of Protein Targets. 针对混合蛋白靶标的噬菌体展示选择。
IF 3.5 2区 生物学
ACS Chemical Biology Pub Date : 2025-06-20 Epub Date: 2025-05-26 DOI: 10.1021/acschembio.5c00121
Xu-Dong Kong, Meng-Jie Zhang, Christian Heinis
{"title":"Phage Display Selection against a Mixture of Protein Targets.","authors":"Xu-Dong Kong, Meng-Jie Zhang, Christian Heinis","doi":"10.1021/acschembio.5c00121","DOIUrl":"10.1021/acschembio.5c00121","url":null,"abstract":"<p><p>Affinity selections by phage display or other display techniques are typically performed against single targets immobilized as a purified protein. In order to develop cross-specific binders that engage with multiple proteins, such as members of a related family, we herein propose to perform selections against mixtures of proteins as bait. Combined with follow-up selection rounds against the individual proteins, deep sequencing, and single clone enrichment analysis, we expected to distinguish binders that are cross-specific from those that are not. Indeed, applying the strategy to human and mouse coagulation factor XI (hFXI and mFXI), and thus to a situation with limited complexity due to a mixture of only two targets, allowed rapid identification of peptide-based binders along with precise information about their specificity. The study also provided insights into the dynamics and challenges of multitarget affinity selections, showing that one target can easily dominate the selection process and hinder the enrichment of binders to other proteins in a mixture.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"1288-1297"},"PeriodicalIF":3.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144148659","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 and Validation of a Novel Class of Necroptosis Inhibitors Targeting RIPK1. 一类新的靶向RIPK1的坏死性下垂抑制剂的发现和验证。
IF 3.5 2区 生物学
ACS Chemical Biology Pub Date : 2025-06-20 DOI: 10.1021/acschembio.5c00112
Lior Soday, Chotima Seripracharat, Janine L Gray, André F S Luz, Ryan T Howard, Ravi Singh, Thomas J Burden, Erika Bernardini, Miguel Mateus-Pinheiro, Jens Petersen, Anders Gunnarsson, Jenny Gunnarsson, Anna Aagaard, Tove Sjögren, Sarah Maslen, Edward J Bartlett, Abigail F Iles, David M Smith, James S Scott, Mark Skehel, Andrew M Davis, Ana S Ressurreição, Rui Moreira, Cecília M P Rodrigues, Avinash R Shenoy, Edward W Tate
{"title":"Discovery and Validation of a Novel Class of Necroptosis Inhibitors Targeting RIPK1.","authors":"Lior Soday, Chotima Seripracharat, Janine L Gray, André F S Luz, Ryan T Howard, Ravi Singh, Thomas J Burden, Erika Bernardini, Miguel Mateus-Pinheiro, Jens Petersen, Anders Gunnarsson, Jenny Gunnarsson, Anna Aagaard, Tove Sjögren, Sarah Maslen, Edward J Bartlett, Abigail F Iles, David M Smith, James S Scott, Mark Skehel, Andrew M Davis, Ana S Ressurreição, Rui Moreira, Cecília M P Rodrigues, Avinash R Shenoy, Edward W Tate","doi":"10.1021/acschembio.5c00112","DOIUrl":"10.1021/acschembio.5c00112","url":null,"abstract":"<p><p>Necroptosis is a form of programmed cell death that, when dysregulated, is associated with cancer and inflammatory and neurodegenerative diseases. Here, starting from hits identified from a phenotypic high-throughput screen for inhibitors of necroptosis, we synthesized a library of compounds containing a 7-phenylquinoline motif and validated their anti-necroptotic activity in a novel live-cell assay. Based on these data, we designed an optimized photoaffinity probe for target engagement studies and through biochemical and cell-based assays established receptor-interacting kinase 1 (RIPK1) as the cellular target, with inhibition of necroptosis arising from the prevention of RIPK1 autophosphorylation and activation. X-ray crystallography and mass spectrometry revealed that these compounds bind at the hinge region of the active conformation of RIPK1, establishing them as type I kinase inhibitors. In addition, we demonstrated <i>in vitro</i> synergy with type III kinase inhibitors, such as necrostatin-1 and found that lead compounds protected mice against acute inflammation in necroptosis models <i>in vivo</i>. Overall, we present a novel pharmacophore for inhibition of human RIPK1, a key protein involved in necroptosis, and provide a photoaffinity probe to explore RIPK1 target engagement in cells.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144332044","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
IF 3.5 2区 生物学
ACS Chemical Biology Pub Date : 2025-06-20
Marine Lacritick, Angéline Reboul, Rym Yahia Boudhar, Elodie Carlier, James W. Fairman, Tanguy Scaillet, Sandhya Subramanian, Johan Wouters, Bart Staker, Xavier De Bolle* and Stéphane P. Vincent*, 
{"title":"","authors":"Marine Lacritick,&nbsp;Angéline Reboul,&nbsp;Rym Yahia Boudhar,&nbsp;Elodie Carlier,&nbsp;James W. Fairman,&nbsp;Tanguy Scaillet,&nbsp;Sandhya Subramanian,&nbsp;Johan Wouters,&nbsp;Bart Staker,&nbsp;Xavier De Bolle* and Stéphane P. Vincent*,&nbsp;","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 6","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":3.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschembio.5c00202","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144469155","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
IF 3.5 2区 生物学
ACS Chemical Biology Pub Date : 2025-06-20
{"title":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 6","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":3.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/cbv020i006_1949688","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144469163","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
IF 3.5 2区 生物学
ACS Chemical Biology Pub Date : 2025-06-20
Quan Le,  and , John T. Ngo*, 
{"title":"","authors":"Quan Le,&nbsp; and ,&nbsp;John T. Ngo*,&nbsp;","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 6","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":3.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschembio.5c00176","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144469173","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
Bioproduction of a Large-Scale Library of Tryptamine Derivatives for Neuropsychiatric Drug Screening. 用于神经精神药物筛选的大规模色胺衍生物文库的生物生产。
IF 3.5 2区 生物学
ACS Chemical Biology Pub Date : 2025-06-20 Epub Date: 2025-05-15 DOI: 10.1021/acschembio.4c00857
Jillian M Hagel, Limei Chang, Jing Li, Xue Chen, Lisa Yu, Jonathan A Gallant, Peter J Facchini
{"title":"Bioproduction of a Large-Scale Library of Tryptamine Derivatives for Neuropsychiatric Drug Screening.","authors":"Jillian M Hagel, Limei Chang, Jing Li, Xue Chen, Lisa Yu, Jonathan A Gallant, Peter J Facchini","doi":"10.1021/acschembio.4c00857","DOIUrl":"10.1021/acschembio.4c00857","url":null,"abstract":"<p><p>Drug screening programs targeting novel indolethylamines with pharmacological properties suitable for the treatment of psychiatric and central nervous system disorders benefit from the availability of large compound libraries normally prepared using synthetic chemistry. Bioproduction strategies based on microbial metabolic engineering and fermentation generally fail to achieve the throughput, scale, or versatility of synthetic chemistry owing, in part, to a lack of efficient and promiscuous enzymes. Moreover, synthetic biology rarely extends to the purification of targeted products, which is an essential component of synthetic chemistry and drug screening regimes. A lattice of biosynthetic routes beginning with endogenous tryptophan or exogenous indole derivatives were engineered in <i>Escherichia coli</i> using heterologous genes encoding enzymes sourced from plants, mushrooms, microbes and animals. Twelve tryptophan decarboxylase candidates were screened and highly versatile top-performers from <i>Bacillus atrophaeus</i> and the gut microbiome species <i>Clostridium sporogenes</i> were identified. Seven halogenases, three tryptophan synthase β-subunits, six <i>N</i>-methyltransferases, five regioselective prenyltransferases, a cytochrome P450 oxidoreductase 5-hydroxylase, an <i>N</i>-acetyltransferase, a 4-<i>O</i>-kinase and various accessory proteins were also tested. These enzymes were used in various combinations and permutations to build <i>E. coli</i> strains capable of 344 putative biotransformations, which resulted in the formation of 279 products with only 63 targeted compounds not detected. A set of 17 novel <i>N</i>-acetylated derivatives were selected for upscaled culturing and purification to ≥95% from 0.5 to 1 L of the fermentation broth, which yielded ∼6-80 mg of each molecule. The potential of each compound for bioactivity at 14 different receptors or transporters with established or purported involvement in neuropsychiatric diseases was tested using a single ligand concentration. Nearly all the <i>N</i>-acetylated compounds showed interaction with the melatonin (MT<sub>1</sub>) receptor, and several molecules showed interaction with serotonergic receptors 5-HT<sub>2B</sub>, 5-HT<sub>2C</sub>, and 5-HT<sub>7</sub>. Overall, we show that bio-fermentation is useful in the large-scale screening of molecules with potential in drug development.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"1212-1231"},"PeriodicalIF":3.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144074835","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
Structural Insights into Spare-Tire DNA G-Quadruplex from the Human VEGF Promoter. 从人VEGF启动子对备用轮胎DNA g -四重体的结构见解。
IF 3.5 2区 生物学
ACS Chemical Biology Pub Date : 2025-06-20 Epub Date: 2025-05-16 DOI: 10.1021/acschembio.5c00226
Ines Burkhart, Vivien Rose McKenney, Julia Wirmer-Bartoschek, J Tassilo Grün, Alexander Heckel, Harald Schwalbe
{"title":"Structural Insights into Spare-Tire DNA G-Quadruplex from the Human <i>VEGF</i> Promoter.","authors":"Ines Burkhart, Vivien Rose McKenney, Julia Wirmer-Bartoschek, J Tassilo Grün, Alexander Heckel, Harald Schwalbe","doi":"10.1021/acschembio.5c00226","DOIUrl":"10.1021/acschembio.5c00226","url":null,"abstract":"<p><p>The vascular endothelial growth factor (<i>VEGF</i>) promoter region, which is involved in cancer progression, contains guanine-rich sequences capable of forming G-quadruplex (G4) structures. G4s play a critical role in transcriptional regulation and genomic stability and exhibit high structural polymorphism. The major <i>VEGF</i> G4 adopts a parallel topology involving the first four of five G-tracts (<i>VEGF</i>1234), while a potential \"spare-tire\" mechanism suggests the formation of <i>VEGF</i>1245 in response to oxidative damage. Here, we characterize this alternative G4 (<i>VEGF</i>1245), formed by excluding the third G-tract, using circular dichroism and nuclear magnetic resonance spectroscopy. Structural analysis reveals that <i>VEGF</i>1245 folds in a hybrid conformation. Different from the other five tracts containing G4s, for which various strand topologies can rapidly interconvert, <i>VEGF</i>1245 remains thermodynamically metastable and does not refold spontaneously into <i>VEGF</i>1234 at physiological temperatures. Further trapping of the <i>VEGF</i>1245 conformation by a photolabile protecting group and its in situ release documents that the transition to <i>VEGF</i>1234 requires elevated temperatures, implicating kinetic barriers in the refolding process and the delineation of <i>VEGF</i>1245 as a prominent metastable conformation. Our findings provide new insights into transcriptional regulation and DNA repair for cancer-related <i>VEGF</i>-G4.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"1417-1425"},"PeriodicalIF":3.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12186258/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144074840","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
Trihydroxybenzaldoximes are Redox Cycling Inhibitors of ThDP-Dependent DXP Synthase. 三羟基苯甲醛肟是thdp依赖性DXP合成酶的氧化还原循环抑制剂。
IF 3.5 2区 生物学
ACS Chemical Biology Pub Date : 2025-06-20 Epub Date: 2025-05-18 DOI: 10.1021/acschembio.5c00025
Charles R Nosal, Ananya Majumdar, Netzahualcóyotl Arroyo-Currás, Caren L Freel Meyers
{"title":"Trihydroxybenzaldoximes are Redox Cycling Inhibitors of ThDP-Dependent DXP Synthase.","authors":"Charles R Nosal, Ananya Majumdar, Netzahualcóyotl Arroyo-Currás, Caren L Freel Meyers","doi":"10.1021/acschembio.5c00025","DOIUrl":"10.1021/acschembio.5c00025","url":null,"abstract":"<p><p>Pathogenic bacteria must swiftly adapt to dynamic infection environments in order to survive and colonize in the host. 1-Deoxy-d-xylulose-5-phosphate synthase (DXPS) is thought to play a critical role in bacterial adaptation during infection and is a promising drug target. DXPS utilizes a thiamine diphosphate (ThDP) cofactor to catalyze the decarboxylative condensation of pyruvate and d-glyceraldehyde-3-phosphate (d-GAP) to form DXP, a precursor to isoprenoids and B vitamins. DXPS follows a ligand-gated mechanism in which pyruvate reacts with ThDP to form a long-lived lactyl-ThDP (LThDP) adduct which is coordinated by an active-site network of residues. d-GAP binding ostensibly disrupts this network to activate LThDP for decarboxylation. Our lab previously reported trihydroxybenzaldoxime inhibitors which are competitive with respect to d-GAP, and uncompetitive with respect to pyruvate, suggesting they bind after E-LThDP complex formation. Here, we conducted mechanistic studies to determine if these compounds inhibit DXPS by preventing LThDP activation or if they act as inducers of LThDP activation. We discovered that the catechol moiety of the trihydroxybenzaldoxime scaffold undergoes oxidation under alkaline aerobic conditions, and inhibitory potency is reduced under oxygen restriction. Leveraging long-range <sup>1</sup>H-<sup>15</sup>N HSQC NMR and electrochemical measurements, we demonstrated that the oxidized form of the trihydroxybenzaldoxime induces LThDP decarboxylation and accepts electrons from the resulting carbanion, resulting in reduction to the catechol and formation of acetyl-ThDP which hydrolyzes to form acetate. Under aerobic conditions the catechol is reoxidized. Thus, these compounds act as redox cycling, substrate-wasting inhibitors of DXP formation. These findings uncover a novel activity and mechanism of DXPS inhibition which may have implications for DXPS-mediated redox activity in bacteria. Further exploration of redox active DXPS probes may provide new insights for inhibition strategies and selective probe development.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":"1195-1211"},"PeriodicalIF":3.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144092072","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
IF 3.5 2区 生物学
ACS Chemical Biology Pub Date : 2025-06-20
C. Taylor Dederich, Livia S. Lazarus, Abby D. Benninghoff and Lisa M. Berreau*, 
{"title":"","authors":"C. Taylor Dederich,&nbsp;Livia S. Lazarus,&nbsp;Abby D. Benninghoff and Lisa M. Berreau*,&nbsp;","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":"20 6","pages":"XXX-XXX XXX-XXX"},"PeriodicalIF":3.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acschembio.4c00884","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144343651","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
Utilizing Machine Learning to Improve Neutralization Potency of an HIV-1 Antibody Targeting the gp41 N-Heptad Repeat. 利用机器学习提高靶向gp41 N-Heptad重复序列的HIV-1抗体的中和效力
IF 3.5 2区 生物学
ACS Chemical Biology Pub Date : 2025-06-20 DOI: 10.1021/acschembio.5c00035
Maria V Filsinger Interrante, Shaogeng Tang, Soohyun Kim, Varun R Shanker, Brian L Hie, Theodora U J Bruun, Wesley Wu, John E Pak, Daniel Fernandez, Peter S Kim
{"title":"Utilizing Machine Learning to Improve Neutralization Potency of an HIV-1 Antibody Targeting the gp41 N-Heptad Repeat.","authors":"Maria V Filsinger Interrante, Shaogeng Tang, Soohyun Kim, Varun R Shanker, Brian L Hie, Theodora U J Bruun, Wesley Wu, John E Pak, Daniel Fernandez, Peter S Kim","doi":"10.1021/acschembio.5c00035","DOIUrl":"10.1021/acschembio.5c00035","url":null,"abstract":"<p><p>The N-heptad repeat (NHR) of the HIV-1 gp41 prehairpin intermediate (PHI) is an attractive potential vaccine target with high sequence conservation across diverse strains. However, despite the potency of NHR-targeting peptides and clinical efficacy of the NHR-targeting entry inhibitor enfuvirtide, no potently neutralizing NHR-directed monoclonal antibodies (mAbs) nor antisera have been identified or elicited to date. The lack of potent NHR-binding mAbs both dampens enthusiasm for vaccine development efforts at this target and presents a barrier to performing passive immunization experiments with NHR-targeting antibodies. To address this challenge, we previously developed an improved variant of the NHR-directed mAb D5, called D5_AR, which is capable of neutralizing diverse tier-2 viruses. Building on that work, here we present the 2.7Å-crystal structure of D5_AR bound to NHR mimetic peptide IQN17. We then utilize protein language models and supervised machine learning to generate small (<i>n</i> < 100) libraries of D5_AR variants that are subsequently screened for improved neutralization potency. We identify a variant with 5-fold improved neutralization potency, D5_FI, which is the most potent NHR-directed monoclonal antibody characterized to date and exhibits broad neutralization of tier-2 and -3 pseudoviruses as well as replicating R5 and X4 challenge strains. Additionally, our work highlights the ability of protein language models to efficiently identify improved mAb variants from relatively small libraries.</p>","PeriodicalId":11,"journal":{"name":"ACS Chemical Biology","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144332047","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
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