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Antibiotic target discovery by integrated phenotypic and activity-based profiling of electrophilic fragments

IF 6.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Chemical Biology

Pub Date : 2025-03-20 DOI: 10.1016/j.chembiol.2025.02.001

Yizhen Jin , Sadhan Jana , Mikail E. Abbasov , Hening Lin

The emergence of antibiotic resistance necessitates the discovery of novel bacterial targets and antimicrobial agents. Here, we present a bacterial target discovery framework that integrates phenotypic screening of cysteine-reactive fragments with competitive activity-based protein profiling to map and functionally characterize the targets of screening hits. Using this approach, we identify β-ketoacyl-acyl carrier protein synthase III (FabH) and MiaA tRNA prenyltransferase as primary targets of a hit fragment, 10-F05, that confer bacterial stress resistance and virulence in Shigella flexneri. Mechanistic investigations elucidate that covalent C112 modification in FabH, an enzyme involved in bacterial fatty acid synthesis, results in its inactivation and consequent growth inhibition. We further demonstrate that irreversible C273 modification at the MiaA RNA-protein interaction interface abrogates substrate tRNA binding, attenuating resistance and virulence through decreased translational accuracy. Our findings underscore the efficacy of integrating phenotypic and activity-based profiling of electrophilic fragments to accelerate the identification and pharmacologic validation of new therapeutic targets.

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引用次数: 0

Development of an FKBP12-recruiting chemical-induced proximity DNA-encoded library and its application to discover an autophagy potentiator fkbp12募集化学诱导邻近dna编码文库的建立及其在发现自噬增强剂中的应用

IF 6.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Chemical Biology

Pub Date : 2025-03-20 DOI: 10.1016/j.chembiol.2024.12.002

Zher Yin Tan , Joel K.A. Adade , Xiebin Gu , Cody J.S. Hecht , Michael Salcius , Bingqi Tong , Shuang Liu , Seungmin Hwang , Frédéric J. Zécri , Daniel B. Graham , Stuart L. Schreiber , Ramnik J. Xavier

Chemical inducers of proximity (CIPs) are molecules that recruit one protein to another and introduce new functionalities toward modulating protein states and activities. While CIP-mediated recruitment of E3 ligases is widely exploited for the development of degraders, other therapeutic modalities remain underexplored. We describe a non-degrader CIP-DNA-encoded library (CIP-DEL) that recruits FKBP12 to target proteins using non-traditional acyclic structures, with an emphasis on introducing stereochemically diverse and rigid connectors to attach the combinatorial library. We deployed this strategy to modulate ATG16L1 T300A, which confers genetic susceptibility to Crohn’s disease (CD), and identified a compound that stabilizes the variant protein against caspase-3 (Casp3) cleavage in a FKBP12-independent manner. We demonstrate in cellular models that this compound potentiates autophagy, and reverses the xenophagy defects as well as increased cytokine secretion characteristic of ATG16L1 T300A. This study provides a platform to access unexplored chemical space for CIP design to develop therapeutic modalities guided by human genetics.

化学接近诱导剂（Chemical inductors of proximity, cip）是一种将一种蛋白质招募到另一种蛋白质并引入新功能来调节蛋白质状态和活性的分子。虽然cip介导的E3连接酶募集被广泛用于降解物的开发，但其他治疗方式仍未得到充分探索。我们描述了一个非降解的cip - dna编码文库（CIP-DEL），它使用非传统的无环结构招募FKBP12来靶向蛋白质，重点是引入立体化学多样性和刚性连接器来连接组合文库。我们采用这种策略来调节ATG16L1 T300A，它赋予克罗恩病（CD）的遗传易感性，并鉴定了一种化合物，该化合物以不依赖于fkbp12的方式稳定变异蛋白，防止Casp3切割。我们在细胞模型中证明，这种化合物增强了自噬，逆转了ATG16L1 T300A的异种吞噬缺陷以及增加的细胞因子分泌特征。这项研究为CIP设计提供了一个未经探索的化学空间，以开发由人类遗传学指导的治疗方式。

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引用次数: 0

NAPE-PLD is target of thiazide diuretics

IF 6.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Chemical Biology

Pub Date : 2025-03-20 DOI: 10.1016/j.chembiol.2025.01.008

Sara Chiarugi , Francesco Margheriti , Valentina De Lorenzi , Elisa Martino , Eleonora Germana Margheritis , Aldo Moscardini , Roberto Marotta , Antonio Chaves-Sanjuan , Cristina Del Seppia , Giuseppe Federighi , Dominga Lapi , Tiziano Bandiera , Simona Rapposelli , Rossana Scuri , Martino Bolognesi , Gianpiero Garau

Thiazide and thiazide-like diuretics are among the most efficacious and used drugs for the treatment of hypertension, edema, and major cardiovascular outcomes. Despite more then than six decades of clinical use, the molecular target and mechanism of action by which these drugs cure hypertension after long-term use have remained mysterious. Here we report the discovery and validation of a previously unknown renal and extrarenal target of these antihypertensives, the membrane-associated phospholipase N-acylphosphatidylethanolamine-specific phospholipase D (NAPE-PLD) of the endocannabinoid system. Structural and functional insights, together with preclinical studies in hypertensive rats, disclose the molecular and physiological basis by which thiazides cause acute diuresis and, at the same time, the distinctive chronic reduction of vascular resistance. Our results shed light on the mechanism of treatment of hypertension and will be useful for developing more efficacious medications for the management of vascular risk factors, as well as associated leukoencephalopathies and myelin disorders.

{"title":"NAPE-PLD is target of thiazide diuretics","authors":"Sara Chiarugi , Francesco Margheriti , Valentina De Lorenzi , Elisa Martino , Eleonora Germana Margheritis , Aldo Moscardini , Roberto Marotta , Antonio Chaves-Sanjuan , Cristina Del Seppia , Giuseppe Federighi , Dominga Lapi , Tiziano Bandiera , Simona Rapposelli , Rossana Scuri , Martino Bolognesi , Gianpiero Garau","doi":"10.1016/j.chembiol.2025.01.008","DOIUrl":"10.1016/j.chembiol.2025.01.008","url":null,"abstract":"<div><div>Thiazide and thiazide-like diuretics are among the most efficacious and used drugs for the treatment of hypertension, edema, and major cardiovascular outcomes. Despite more then than six decades of clinical use, the molecular target and mechanism of action by which these drugs cure hypertension after long-term use have remained mysterious. Here we report the discovery and validation of a previously unknown renal and extrarenal target of these antihypertensives, the membrane-associated phospholipase N-acylphosphatidylethanolamine-specific phospholipase D (NAPE-PLD) of the endocannabinoid system. Structural and functional insights, together with preclinical studies in hypertensive rats, disclose the molecular and physiological basis by which thiazides cause acute diuresis and, at the same time, the distinctive chronic reduction of vascular resistance. Our results shed light on the mechanism of treatment of hypertension and will be useful for developing more efficacious medications for the management of vascular risk factors, as well as associated leukoencephalopathies and myelin disorders.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 3","pages":"Pages 449-462.e5"},"PeriodicalIF":6.6,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143477580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Epigenetic fluidity meets phenotypic malleability in intestinal epithelial cells

IF 6.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Chemical Biology

Pub Date : 2025-03-20 DOI: 10.1016/j.chembiol.2025.02.007

Swarnabh Bhattacharya , Ramesh A. Shivdasani

Differentiated progenitors in intestinal crypts react to stem cell attrition by reverting to the multipotent state. In the February issue of Nature Cell Biology, Pashos et al.¹ reveal a role for H3K36 methylation at cell-type-restricted genes in helping maintain differentiated cell states, hence regulating cell plasticity and regenerative responses.

引用次数: 0

De novo designed Hsp70 activator dissolves intracellular condensates

IF 6.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Chemical Biology

Pub Date : 2025-03-20 DOI: 10.1016/j.chembiol.2025.01.006

Jason Z. Zhang , Nathan Greenwood , Jason Hernandez , Josh T. Cuperus , Buwei Huang , Bryan D. Ryder , Christine Queitsch , Jason E. Gestwicki , David Baker

Protein quality control (PQC) is carried out in part by the chaperone Hsp70 in concert with adapters of the J-domain protein (JDP) family. The JDPs, also called Hsp40s, are thought to recruit Hsp70 into complexes with specific client proteins. However, the molecular principles regulating this process are not well understood. We describe the de novo design of Hsp70 binding proteins that either inhibit or stimulate Hsp70 ATPase activity. An ATPase stimulating design promoted the refolding of denatured luciferase in vitro, similar to native JDPs. Targeting of this design to intracellular condensates resulted in their nearly complete dissolution and revealed roles as cell growth promoting signaling hubs. The designs inform our understanding of chaperone structure-function relationships and provide a general and modular way to target PQC systems to regulate condensates and other cellular targets.

引用次数: 0

An affinity-based depletion strategy for evaluating the effects of ergothioneine on bacterial physiology

IF 6.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Chemical Biology

Pub Date : 2025-03-20 DOI: 10.1016/j.chembiol.2025.02.004

Anna B. Seminara , Stavroula K. Hatzios

Ergothioneine (EGT) is a thiol-based antioxidant synthesized by certain fungal and bacterial species that is prevalent in the human diet. Recently, an EGT-specific transporter, EgtUV, was discovered in bacteria that are incapable of EGT biosynthesis, including the gastric pathogen Helicobacter pylori. However, EGT is naturally abundant in the complex media required to culture H. pylori and many other host-associated microbes, complicating efforts to understand how this molecule influences microbial physiology. Using the solute-binding domain of H. pylori EgtUV, we generated an EGT-chelating resin that depletes EGT from nutrient-rich media. We determined that wild-type H. pylori requires EGT to outcompete a transporter-deficient strain in vitro. Furthermore, EGT induces transcription of genes encoding outer-membrane transporters that may regulate intracellular EGT content upstream of the inner-membrane-localized EgtUV transporter. Our work establishes a method for tuning exposure to an abundant antioxidant in vitro, enabling future studies of EGT in diverse microbial strains and communities.

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引用次数: 0

Lipid it up: Freed fats drive ferroptosis

IF 6.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Chemical Biology

Pub Date : 2025-03-20 DOI: 10.1016/j.chembiol.2025.02.008

Madison S. Mortensen , Jennifer L. Watts

Polyunsaturated fats promote ferroptosis through their propensity to form toxic lipid peroxides. In this issue of Cell Chemical Biology, Sokol et al.¹ report that extracellular lipid depletion leads to increased cell death by ferroptosis. This occurs because fats liberated from triglycerides are modified and incorporated into cellular phospholipids.

多不饱和脂肪可形成有毒的脂质过氧化物，从而促进铁变态反应。在本期《细胞化学生物学》（Cell Chemical Biology）杂志上，索科尔（Sokol）等人1 报告说，细胞外脂质耗竭会导致细胞因铁中毒而死亡。这是因为从甘油三酯中释放出的脂肪被修饰并融入细胞磷脂中。

引用次数: 0

Ligand-induced assembly of antibody variable fragments for the chemical regulation of biological processes

IF 6.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Chemical Biology

Pub Date : 2025-03-20 DOI: 10.1016/j.chembiol.2025.01.007

Erik Rihtar , Tina Fink , Tina Lebar , Duško Lainšček , Živa Kolenc , Lucija Kadunc Polajnar , Roman Jerala

Precise control of biological processes by the application of small molecules can increase the safety and efficiency of therapies. Adverse side effects of small molecule signals and/or immunogenicity of regulatory domains hinder their biomedical utility. Here, we designed small molecule-responsive switches, based on the conditional reassembly of human antibody variable fragments, called Fv-CID switches. The principle was validated using high-affinity antibodies against nicotine and β-estradiol to construct chemically responsive transcription factors. Further, we developed an Fv-CID switch responsive to bio-inert, clinically approved compound fluorescein, which was used to control the activity of chimeric antigen receptor (CAR) T cells and bispecific T cell engagers (BiTEs) in vivo. This study provides a framework to regulate the expression of endogenous genes, combine multiple chemical signals, and regulate T cell-based immunotherapy in an animal cancer model using a clinically approved small molecule regulator that could be customized for regulating therapeutic proteins or cells.

{"title":"Ligand-induced assembly of antibody variable fragments for the chemical regulation of biological processes","authors":"Erik Rihtar , Tina Fink , Tina Lebar , Duško Lainšček , Živa Kolenc , Lucija Kadunc Polajnar , Roman Jerala","doi":"10.1016/j.chembiol.2025.01.007","DOIUrl":"10.1016/j.chembiol.2025.01.007","url":null,"abstract":"<div><div>Precise control of biological processes by the application of small molecules can increase the safety and efficiency of therapies. Adverse side effects of small molecule signals and/or immunogenicity of regulatory domains hinder their biomedical utility. Here, we designed small molecule-responsive switches, based on the conditional reassembly of human antibody variable fragments, called Fv-CID switches. The principle was validated using high-affinity antibodies against nicotine and β-estradiol to construct chemically responsive transcription factors. Further, we developed an Fv-CID switch responsive to bio-inert, clinically approved compound fluorescein, which was used to control the activity of chimeric antigen receptor (CAR) T cells and bispecific T cell engagers (BiTEs) <em>in vivo</em>. This study provides a framework to regulate the expression of endogenous genes, combine multiple chemical signals, and regulate T cell-based immunotherapy in an animal cancer model using a clinically approved small molecule regulator that could be customized for regulating therapeutic proteins or cells.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 3","pages":"Pages 474-485.e5"},"PeriodicalIF":6.6,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Disrupting neuron-tumor networking connections

IF 6.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Chemical Biology

Pub Date : 2025-03-20 DOI: 10.1016/j.chembiol.2025.02.006

Cheng-En Shen , Alesandra S. Echeandía Marrero , Yuan Pan

Neurons are key to brain tumor pathogenesis. Though direct synaptic connections between neurons and glioblastoma cells had been revealed, the nature of such connections remained enigmatic. In a recent issue of Cell, Tetzlaff et al.¹ leveraged monosynaptic retrograde tracing to pinpoint these interactions, demonstrating new therapeutic strategies for targeting malignant neuron-glioma crosstalk.

引用次数: 0

VIPER-TACs leverage viral E3 ligases for disease-specific targeted protein degradation

IF 6.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Chemical Biology

Pub Date : 2025-03-20 DOI: 10.1016/j.chembiol.2025.02.002

Kyle Mangano , Robert G. Guenette , Spencer Hill , Shiqian Li , Jeffrey J. Liu , Cory M. Nadel , Suresh Archunan , Arghya Sadhukhan , Rajiv Kapoor , Seung Wook Yang , Kate S. Ashton , Patrick Ryan Potts

In targeted protein degradation (TPD) a protein of interest is degraded by chemically induced proximity to an E3 ubiquitin ligase. One limitation of using TPD therapeutically is that most E3 ligases have broad tissue expression, which can contribute to toxicity via target degradation in healthy cells. Many pathogenic and oncogenic viruses encode E3 ligases (vE3s), which de facto have strictly limited expression to diseased cells. Here, we provide proof-of-concept for viral E3 pan-essential removing targeting chimeras (VIPER-TACs) that are bi-functional molecules that utilize viral E3 ubiquitin ligases to selectively degrade pan-essential proteins and eliminate diseased cells. We find that the human papillomavirus (HPV) ligase E6 can degrade the SARS1 pan-essential target protein in a model of HPV-positive cervical cancer to selectively kill E6 expressing cancer cells. Thus, VIPER-TACs have the capacity to dramatically increase the therapeutic window, alleviate toxicity concerns, and ultimately expand the potential target space for TPD.

{"title":"VIPER-TACs leverage viral E3 ligases for disease-specific targeted protein degradation","authors":"Kyle Mangano , Robert G. Guenette , Spencer Hill , Shiqian Li , Jeffrey J. Liu , Cory M. Nadel , Suresh Archunan , Arghya Sadhukhan , Rajiv Kapoor , Seung Wook Yang , Kate S. Ashton , Patrick Ryan Potts","doi":"10.1016/j.chembiol.2025.02.002","DOIUrl":"10.1016/j.chembiol.2025.02.002","url":null,"abstract":"<div><div>In targeted protein degradation (TPD) a protein of interest is degraded by chemically induced proximity to an E3 ubiquitin ligase. One limitation of using TPD therapeutically is that most E3 ligases have broad tissue expression, which can contribute to toxicity via target degradation in healthy cells. Many pathogenic and oncogenic viruses encode E3 ligases (vE3s), which <em>de facto</em> have strictly limited expression to diseased cells. Here, we provide proof-of-concept for viral E3 pan-essential removing targeting chimeras (VIPER-TACs) that are bi-functional molecules that utilize viral E3 ubiquitin ligases to selectively degrade pan-essential proteins and eliminate diseased cells. We find that the human papillomavirus (HPV) ligase E6 can degrade the SARS1 pan-essential target protein in a model of HPV-positive cervical cancer to selectively kill E6 expressing cancer cells. Thus, VIPER-TACs have the capacity to dramatically increase the therapeutic window, alleviate toxicity concerns, and ultimately expand the potential target space for TPD.</div></div>","PeriodicalId":265,"journal":{"name":"Cell Chemical Biology","volume":"32 3","pages":"Pages 423-433.e9"},"PeriodicalIF":6.6,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143547031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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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