JACS Au最新文献_第10页

Ligandability at the Membrane Interface of GPx4 Revealed through a Reverse Micelle Fragment Screening Platform 通过反向胶束片段筛选平台揭示 GPx4 膜界面的配体性

JACS Au Pub Date : 2024-06-26 DOI: 10.1021/jacsau.4c00427

Courtney L. Labrecque, Brian Fuglestad

{"title":"Ligandability at the Membrane Interface of GPx4 Revealed through a Reverse Micelle Fragment Screening Platform","authors":"Courtney L. Labrecque, Brian Fuglestad","doi":"10.1021/jacsau.4c00427","DOIUrl":"https://doi.org/10.1021/jacsau.4c00427","url":null,"abstract":"While they account for a large portion of drug targets, membrane proteins present a unique challenge for drug discovery. Peripheral membrane proteins (PMPs), a class of water-soluble proteins that bind to membranes, are also difficult targets, particularly those that function only when bound to membranes. The protein–membrane interface in PMPs is often where functional interactions and catalysis occur, making it a logical target for inhibition. However, protein–membrane interfaces are underexplored spaces in inhibitor design, and there is a need for enhanced methods for small-molecule ligand discovery. In an effort to better initiate drug discovery efforts for PMPs, this study presents a screening methodology using membrane-mimicking reverse micelles (mmRM) and NMR-based fragment screening to assess ligandability at the protein–membrane interface. The proof-of-principle target, glutathione peroxidase 4 (GPx4), is a lipid hydroperoxidase that is essential for the oxidative protection of membranes and thereby the prevention of ferroptosis. GPx4 inhibition is promising for therapy-resistant cancer therapy, but current inhibitors are generally covalent ligands with limited clinical utility. Presented here is the discovery of noncovalent small-molecule ligands for membrane-bound GPx4 revealed through the mmRM fragment screening methodology. The fragments were tested against GPx4 under bulk aqueous conditions and displayed little to no binding to the protein without embedment into the membrane. The 9 hits had varying affinities and partitioning coefficients and revealed properties of fragments that bind within the protein–membrane interface. Additionally, a secondary screen confirmed the potential to progress the fragments by enhancing the affinity from >200 to ∼15 μM with the addition of certain hydrophobic groups. This study presents an advancement of screening capabilities for membrane-associated proteins, reveals ligandability within the GPx4 protein–membrane interface, and may serve as a starting point for developing noncovalent inhibitors of GPx4.","PeriodicalId":14799,"journal":{"name":"JACS Au","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141520610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Site-Specific Cascade-Activatable Fluorogenic Nanomicelles Enable Precision and Accuracy Imaging of Pulmonary Metastatic Tumor 可层叠激活的特异位点荧光纳米细胞实现了肺转移性肿瘤的精确成像

JACS Au Pub Date : 2024-06-24 DOI: 10.1021/jacsau.4c00356

Xueqian Chen, Jiatian Liu, Yong Zhang, Xueyun Gao, Dongdong Su

{"title":"Site-Specific Cascade-Activatable Fluorogenic Nanomicelles Enable Precision and Accuracy Imaging of Pulmonary Metastatic Tumor","authors":"Xueqian Chen, Jiatian Liu, Yong Zhang, Xueyun Gao, Dongdong Su","doi":"10.1021/jacsau.4c00356","DOIUrl":"https://doi.org/10.1021/jacsau.4c00356","url":null,"abstract":"The precise localization of metastatic tumors with subtle growth is crucial for timely intervention and improvement of tumor prognosis but remains a paramount challenging. To date, site-specific activation of fluorogenic probes for single-stimulus-based diagnosis typically targets an occult molecular event in a complex biosystem with limited specificity. Herein, we propose a highly specific site-specific cascade-activated strategy to enhance detection accuracy, aiming to achieve the accurate detection of breast cancer (BC) lung metastasis in a cascade manner. Specifically, cascade-activatable NIR fluorogenic nanomicelles HPNs were constructed using ultra-pH-sensitive (UPS) block copolymers as carriers and nitroreductase (NTR)-activated fluorogenic reporters. HPNs exhibit programmable cascade response characteristics by first instantaneous dissociating under in situ tumor acidity, facilitating deep tumor penetration followed by selective fluorescence activation through NTR-mediated enzymatic reaction resulting in high fluorescence ON/OFF contrast. Notably, this unique feature of HPNs enables high-precision diagnosis of orthotopic BC as well as its lung metastases with a remarkable signal-to-background ratio (SBR). This proposed site-specific cascade activation strategy will offer opportunities for a specific diagnosis with high signal fidelity of various insidious metastatic lesions in situ across different diseases.","PeriodicalId":14799,"journal":{"name":"JACS Au","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141520613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

De Novo Engineering of Pd-Metalloproteins and Their Use as Intracellular Catalysts 钯金属蛋白新工程及其作为细胞内催化剂的应用

JACS Au Pub Date : 2024-06-23 DOI: 10.1021/jacsau.4c00379

Soraya Learte-Aymamí, Laura Martínez-Castro, Carmen González-González, Miriam Condeminas, Pau Martin-Malpartida, María Tomás-Gamasa, Sandra Baúlde, José R. Couceiro, Jean-Didier Maréchal, Maria J. Macias, José L. Mascareñas, M. Eugenio Vázquez

引用次数: 0

Electrocatalytic Reduction of Carbon Dioxide in Acidic Electrolyte with Superior Performance of a Metal–Covalent Organic Framework over Metal–Organic Framework 在酸性电解质中电催化还原二氧化碳，金属-共价有机框架的性能优于金属-有机框架

JACS Au Pub Date : 2024-06-21 DOI: 10.1021/jacsau.4c00246

Chang-Pu Wan, Hui Guo, Duan-Hui Si, Shui-Ying Gao, Rong Cao, Yuan-Biao Huang

{"title":"Electrocatalytic Reduction of Carbon Dioxide in Acidic Electrolyte with Superior Performance of a Metal–Covalent Organic Framework over Metal–Organic Framework","authors":"Chang-Pu Wan, Hui Guo, Duan-Hui Si, Shui-Ying Gao, Rong Cao, Yuan-Biao Huang","doi":"10.1021/jacsau.4c00246","DOIUrl":"https://doi.org/10.1021/jacsau.4c00246","url":null,"abstract":"CO2 electroreduction (CO2RR) to generate valuable chemicals in acidic electrolytes can improve the carbon utilization rate in comparison to that under alkaline conditions. However, the thermodynamically more favorable hydrogen evolution reaction under an acidic electrolyte makes the CO2RR a big challenge. Herein, robust metal phthalocyanine(Pc)-based (M = Ni, Co) conductive metal-covalent organic frameworks (MCOFs) connected by strong metal tetraaza[14]annulene (TAA) linkage, named NiPc–NiTAA and NiPc–CoTAA, are designed and synthesized to apply in the CO2RR in acidic electrolytes for the first time. The optimal NiPc–NiTAA exhibited an excellent Faradaic efficiency (FECO) of 95.1% and a CO partial current density of 143.0 mA cm–2 at −1.5 V versus the reversible hydrogen electrode in an acidic electrolyte, which is 3.1 times that of the corresponding metal–organic framework NiPc–NiN4. The comparison tests and theoretical calculations reveal that in-plane full π–d conjugation MCOF with a good conductivity of 3.01 × 10–4 S m–1 accelerates migration of the electrons. The NiTAA linkage can tune the electron distribution in the d orbit of metal centers, making the d-band center close to the Fermi level and then activating CO2. Thus, the active sites of NiPc and NiTAA collaborate to reduce the *COOH formation energy barrier, favoring CO production in an acid electrolyte. It is a helpful route for designing outstanding conductive MCOF materials to enhance CO2 electrocatalysis under an acidic electrolyte.","PeriodicalId":14799,"journal":{"name":"JACS Au","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141520614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Parsimonious Topology Based on Frank-Kasper Polyhedra in Metal–Organic Frameworks 基于金属有机框架中弗兰克-卡斯帕多面体的解析拓扑结构

JACS Au Pub Date : 2024-06-20 DOI: 10.1021/jacsau.4c00285

Soochan Lee, Sungmin Lee, Yuna Kwak, Masood Yousaf, Eunchan Cho, Hoi Ri Moon, Sung June Cho, Noejung Park, Wonyoung Choe

引用次数: 0

Exploring the Chemical Space of the Exposome: How Far Have We Gone? 探索暴露体的化学空间：我们走了多远？

JACS Au Pub Date : 2024-06-20 DOI: 10.1021/jacsau.4c00220

Saer Samanipour, Leon Patrick Barron, Denice van Herwerden, Antonia Praetorius, Kevin V. Thomas, Jake William O’Brien

{"title":"Exploring the Chemical Space of the Exposome: How Far Have We Gone?","authors":"Saer Samanipour, Leon Patrick Barron, Denice van Herwerden, Antonia Praetorius, Kevin V. Thomas, Jake William O’Brien","doi":"10.1021/jacsau.4c00220","DOIUrl":"https://doi.org/10.1021/jacsau.4c00220","url":null,"abstract":"Around two-thirds of chronic human disease can not be explained by genetics alone. The Lancet Commission on Pollution and Health estimates that 16% of global premature deaths are linked to pollution. Additionally, it is now thought that humankind has surpassed the safe planetary operating space for introducing human-made chemicals into the Earth System. Direct and indirect exposure to a myriad of chemicals, known and unknown, poses a significant threat to biodiversity and human health, from vaccine efficacy to the rise of antimicrobial resistance as well as autoimmune diseases and mental health disorders. The exposome chemical space remains largely uncharted due to the sheer number of possible chemical structures, estimated at over 1060 unique forms. Conventional methods have cataloged only a fraction of the exposome, overlooking transformation products and often yielding uncertain results. In this Perspective, we have reviewed the latest efforts in mapping the exposome chemical space and its subspaces. We also provide our view on how the integration of data-driven approaches might be able to bridge the identified gaps.","PeriodicalId":14799,"journal":{"name":"JACS Au","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141520616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Engineering Bifunctional Galactokinase/Uridyltransferase Chimera for Enhanced UDP-d-Xylose Production 设计双功能半乳糖激酶/胞苷酸转移酶嵌合体，提高 UDP-d-木糖产量

JACS Au Pub Date : 2024-06-20 DOI: 10.1021/jacsau.4c00288

Jin-Da Zhuang, Jin-Min Shi, Chen-Cheng Hong, Ting-Ting Wu, Li Liu, Josef Voglmeir

{"title":"Engineering Bifunctional Galactokinase/Uridyltransferase Chimera for Enhanced UDP-d-Xylose Production","authors":"Jin-Da Zhuang, Jin-Min Shi, Chen-Cheng Hong, Ting-Ting Wu, Li Liu, Josef Voglmeir","doi":"10.1021/jacsau.4c00288","DOIUrl":"https://doi.org/10.1021/jacsau.4c00288","url":null,"abstract":"The biotechnological production of uridine diphosphate-d-xylose (UDP-d-xylose), the glycosyl donor in enzymatic for d-xylose, is an important precursor for advancing glycoengineering research on biopharmaceuticals such as heparin and glycosaminoglycans. Leveraging a recently discovered UDP-xylose salvage pathway, we have engineered a series of bifunctional chimeric biocatalysts derived from Solitalea canadensis galactokinase/uridyltransferase, facilitating the conversion of d-xylose to UDP-d-xylose. This study elucidates the novel assembly of eight fusion protein constructs, differing in domain orientations and linker peptide lengths, to investigate their functional expression in Escherichia coli, resulting in the synthesis of the first bifunctional enzyme that orchestrates a direct transformation from d-xylose to UDP-d-xylose. Fusion constructs with a NH2-GSGGGSGHM-COOH peptide linker demonstrated the highest expression and catalytic tenacity. For the highest catalytic conversion from d-xylose to UDP-d-xylose, we established an optimum pH of 7.0 and a temperature optimum of 30 °C, with an optimal fusion enzyme concentration of 3.3 mg/mL for large-scale UDP-d-xylose production. Insights into ATP and ADP inhibition further helped to optimize the reaction conditions. Testing various ratios of unfused galactokinase and uridyltransferase biocatalysts for UDP-xylose synthesis from d-xylose revealed that a 1:1 ratio was optimal. The Kcat/Km value for the NH2-GSGGGSGHM-COOH peptide linker showed a 10% improvement compared with the unfused counterparts. The strategic design of these fusion enzymes efficiently routes for the convenient and efficient biocatalytic synthesis of xylosides in biotechnological and pharmaceutical applications.","PeriodicalId":14799,"journal":{"name":"JACS Au","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141520672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cyclic Peptides KS-133 and KS-487 Multifunctionalized Nanoparticles Enable Efficient Brain Targeting for Treating Schizophrenia 环肽 KS-133 和 KS-487 多功能纳米粒子可实现高效脑靶向治疗精神分裂症

JACS Au Pub Date : 2024-06-20 DOI: 10.1021/jacsau.4c00311

Kotaro Sakamoto, Seigo Iwata, Zihao Jin, Lu Chen, Tatsunori Miyaoka, Mei Yamada, Kaiga Katahira, Rei Yokoyama, Ami Ono, Satoshi Asano, Kotaro Tanimoto, Rika Ishimura, Shinsaku Nakagawa, Takatsugu Hirokawa, Yukio Ago, Eijiro Miyako

{"title":"Cyclic Peptides KS-133 and KS-487 Multifunctionalized Nanoparticles Enable Efficient Brain Targeting for Treating Schizophrenia","authors":"Kotaro Sakamoto, Seigo Iwata, Zihao Jin, Lu Chen, Tatsunori Miyaoka, Mei Yamada, Kaiga Katahira, Rei Yokoyama, Ami Ono, Satoshi Asano, Kotaro Tanimoto, Rika Ishimura, Shinsaku Nakagawa, Takatsugu Hirokawa, Yukio Ago, Eijiro Miyako","doi":"10.1021/jacsau.4c00311","DOIUrl":"https://doi.org/10.1021/jacsau.4c00311","url":null,"abstract":"Establishing drug delivery systems (DDSs) for transporting drugs from peripheral tissues to the brain is crucial for treating central nervous system diseases. We previously reported the interactions of (1) KS-133, a selective antagonist peptide, with vasoactive intestinal peptide receptor 2 (VIPR2), a drug target for schizophrenia, and (2) KS-487, a selective binding peptide, with the cluster IV domain of low-density lipoprotein receptor-related protein 1 (LRP1), which is involved in crossing the blood–brain barrier. We developed a novel DDS-based strategy for treating schizophrenia using KS-487 as a brain-targeting peptide and KS-133 as a drug. Dibenzocyclooctyne-KS-487 was conjugated with N3-indocyanine green (ICG) using a click reaction and administered intravenously into mice. Fluorescence was clearly observed from ICG in the brains of the mice. Nanoparticles (NPs) encapsulating ICG and displaying KS-487 were prepared and subcutaneously administered to mice, resulting in a significant accumulation of ICG in the brain. Pharmacokinetic analysis of NPs containing KS-133 and displaying KS-487 (KS-133/KS-487 NPs) revealed the time-dependent transport of KS-133 into the brain. KS-133/KS-487 NPs were subcutaneously administered to mouse models of schizophrenia, which significantly improved cognitive dysfunction. This is the first study to demonstrate the potential therapeutic efficacy of a multifunctionalized multipeptide NP in inhibiting VIPR2.","PeriodicalId":14799,"journal":{"name":"JACS Au","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141506601","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Covalent Inhibition of a Host–Pathogen Protein–Protein Interaction Reduces the Infectivity of Streptococcus pneumoniae 共价抑制宿主-病原体蛋白质-蛋白质相互作用可降低肺炎链球菌的感染性

JACS Au Pub Date : 2024-06-20 DOI: 10.1021/jacsau.4c00195

Yuhan Lyu, Fan Yang, Bharathi Sundaresh, Federico Rosconi, Tim van Opijnen, Jianmin Gao

{"title":"Covalent Inhibition of a Host–Pathogen Protein–Protein Interaction Reduces the Infectivity of Streptococcus pneumoniae","authors":"Yuhan Lyu, Fan Yang, Bharathi Sundaresh, Federico Rosconi, Tim van Opijnen, Jianmin Gao","doi":"10.1021/jacsau.4c00195","DOIUrl":"https://doi.org/10.1021/jacsau.4c00195","url":null,"abstract":"The ever-expanding antibiotic resistance urgently calls for novel antibacterial therapeutics, especially those with a new mode of action. We report herein our exploration of protein–protein interaction (PPI) inhibition as a new mechanism to thwart bacterial pathogenesis. Specifically, we describe potent and specific inhibitors of the pneumococcal surface protein PspC, an important virulence factor that facilitates the infection of Streptococcus pneumoniae. Specifically, PspC has been documented to recruit human complement factor H (hFH) to suppress host complement activation and/or promote the bacterial attachment to host tissues. The CCP9 domain of hFH was recombinantly expressed to inhibit the PspC–hFH interaction as demonstrated on live pneumococcal cells. The inhibitor allowed for the first pharmacological intervention of the PspC–hFH interaction. This PPI inhibition reduced pneumococci’s attachment to epithelial cells and also resensitized the D39 strain of S. pneumoniae for opsonization. Importantly, we have further devised covalent versions of CCP9, which afforded long-lasting PspC inhibition with low nanomolar potency. Overall, our results showcase the promise of PPI inhibition for combating bacterial infections as well as the power of covalent inhibitors.","PeriodicalId":14799,"journal":{"name":"JACS Au","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141520615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Tetraborylation of p-Benzynes Generated by the Masamune–Bergman Cyclization through Reaction Design Based on the Reaction Path Network 通过基于反应路径网络的反应设计对 Masamune-Bergman 环化反应生成的对苄基进行四乙酰化反应

JACS Au Pub Date : 2024-06-20 DOI: 10.1021/jacsau.4c00302

Soichiro Nakatsuka, Seiji Akiyama, Yu Harabuchi, Satoshi Maeda, Yuuya Nagata

引用次数: 0