ACS Central Science最新文献_第7页

Identification of a Privileged Scaffold for Inhibition of Sterol Transport Proteins through the Synthesis and Ring Distortion of Diverse, Pseudo-Natural Products

IF 12.7 1区化学

ACS Central Science Pub Date : 2025-01-08 DOI: 10.1021/acscentsci.4c0165710.1021/acscentsci.4c01657

Frederik Simonsen Bro, Laura Depta, Nienke J. Dekker, Hogan P. Bryce-Rogers, Maria Lillevang Madsen, Kaia Fiil Præstegaard, Tino Petersson, Thomas Whitmarsh-Everiss, Mariusz Kubus and Luca Laraia*,

{"title":"Identification of a Privileged Scaffold for Inhibition of Sterol Transport Proteins through the Synthesis and Ring Distortion of Diverse, Pseudo-Natural Products","authors":"Frederik Simonsen Bro, Laura Depta, Nienke J. Dekker, Hogan P. Bryce-Rogers, Maria Lillevang Madsen, Kaia Fiil Præstegaard, Tino Petersson, Thomas Whitmarsh-Everiss, Mariusz Kubus and Luca Laraia*, ","doi":"10.1021/acscentsci.4c0165710.1021/acscentsci.4c01657","DOIUrl":"https://doi.org/10.1021/acscentsci.4c01657https://doi.org/10.1021/acscentsci.4c01657","url":null,"abstract":"Sterol transport proteins mediate intracellular sterol transport, organelle contact sites, and lipid metabolism. Despite their importance, the similarities in their sterol-binding domains have made the identification of selective modulators difficult. Herein we report a combination of different compound library synthesis strategies to prepare a cholic acid-inspired compound collection for the identification of potent and selective inhibitors of sterol transport proteins. The fusion of a primary sterol scaffold with a range of different fragments found in natural products followed by various ring distortions allowed the synthesis of diverse sterol-inspired compounds. This led to the identification of a complex and three-dimensional spirooxepinoindole as a privileged scaffold for sterol transport proteins. With careful optimization of the scaffold, the selectivity could be directed toward a single transporter, as showcased by the development of a potent and selective Aster-A inhibitor. We suggest that the combination of different design strategies is generally applicable for the identification of potent and selective bioactive compounds with drug-like properties.A privileged scaffold for sterol transporters was identified through fusion of a sterol scaffold and natural product fragments followed by ring distortions, leading to a selective Aster-A inhibitor.","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 1","pages":"136–146 136–146"},"PeriodicalIF":12.7,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acscentsci.4c01657","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143091565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Insights into IrtAB: Iron Transport Facilitates Ultrasensitive Detection of Mycobacteria in Both Cellular and Clinical Environments

IF 12.7 1区化学

ACS Central Science Pub Date : 2025-01-07 DOI: 10.1021/acscentsci.4c0067610.1021/acscentsci.4c00676

Dianmo Ni, Xiaoqiao Hong, Dingyi Liu, Xueyuan Li, Li Li, Wenwu Liu, Zhaogang Sun and Gang Liu*,

{"title":"Insights into IrtAB: Iron Transport Facilitates Ultrasensitive Detection of Mycobacteria in Both Cellular and Clinical Environments","authors":"Dianmo Ni, Xiaoqiao Hong, Dingyi Liu, Xueyuan Li, Li Li, Wenwu Liu, Zhaogang Sun and Gang Liu*, ","doi":"10.1021/acscentsci.4c0067610.1021/acscentsci.4c00676","DOIUrl":"https://doi.org/10.1021/acscentsci.4c00676https://doi.org/10.1021/acscentsci.4c00676","url":null,"abstract":"Mycobacterium tuberculosis (Mtb) utilizes a heterodimeric ABC transporter (IrtAB) to extract Fe3+ ions from host cells. This study demonstrates that ultrasensitive fluorescent probes, achieved through the conjugation of fluorophores with the ligand of IrtAB, N14G and N14G-Fe can detect Mycobacterium smegmatis at concentrations as low as 1–10 nM within an incubation period of less than 5 min. Furthermore, these probes effectively label Mycobacterium bovis Bacille Calmette-Guérin BCG and the wild-type Mtb strain H37Rv at a concentration of 0.1 μM after 10 min of incubation, achieving a limit of detection of 34 Colony-Forming Unit for the wild-type Mtb strain H37Rv. Both N14G and N14G-Fe successfully identified Mtb in sputum samples from patients diagnosed with tuberculosis, exhibiting exceptional fluorescence.Siderophore-based fluorescent probes, such as N14G, have been developed for the detection of mycobacteria utilizing an active heterodimeric ABC transporter (IrtAB transporter). These probes exhibit ultrasensitivity with detection concentrations as low as 1−10 nM, yield results within a rapid 5 min incubation period, and possess a limit of detection of 34 CFU for the wild-type H37Rv strain of Mycobacterium tuberculosis. N14G and N14G-Fe are ultrasensitive fluorescent probes that utilize the IrtAB transporter for the specific detection of mycobacteria and the diagnosis of clinical sputum samples at concentrations ranging from 1 to 10 nM.","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 2","pages":"261–271 261–271"},"PeriodicalIF":12.7,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acscentsci.4c00676","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143486809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Insights into IrtAB: Iron Transport Facilitates Ultrasensitive Detection of Mycobacteria in Both Cellular and Clinical Environments.

IF 12.7 1区化学

ACS Central Science Pub Date : 2025-01-07 eCollection Date: 2025-02-26 DOI: 10.1021/acscentsci.4c00676

Dianmo Ni, Xiaoqiao Hong, Dingyi Liu, Xueyuan Li, Li Li, Wenwu Liu, Zhaogang Sun, Gang Liu

引用次数: 0

Wash-free Imaging in Live Cells. 活细胞免洗成像

IF 12.7 1区化学

ACS Central Science Pub Date : 2025-01-06 eCollection Date: 2025-01-22 DOI: 10.1021/acscentsci.4c02083

Mahdi Hasan, Ashraf Brik

引用次数: 0

Wash-free Imaging in Live Cells

IF 12.7 1区化学

ACS Central Science Pub Date : 2025-01-06 DOI: 10.1021/acscentsci.4c0208310.1021/acscentsci.4c02083

Mahdi Hasan, and , Ashraf Brik*,

引用次数: 0

NSF NeXUS: A New Model for Accessing the Frontiers of Ultrafast Science.

IF 12.7 1区化学

ACS Central Science Pub Date : 2025-01-06 eCollection Date: 2025-01-22 DOI: 10.1021/acscentsci.4c01682

L Robert Baker, Louis F DiMauro, Claudia Turro, Jay A Gupta, Roland K Kawakami, Thomas K Allison, Theodore J Ronningen, Timothy D Scarborough, Vyacheslav Leshchenko, Seth S Shields, John E Beetar

引用次数: 0

NSF NeXUS: A New Model for Accessing the Frontiers of Ultrafast Science

IF 12.7 1区化学

ACS Central Science Pub Date : 2025-01-06 DOI: 10.1021/acscentsci.4c0168210.1021/acscentsci.4c01682

L. Robert Baker*, Louis F. DiMauro, Claudia Turro, Jay A. Gupta, Roland K. Kawakami, Thomas K. Allison, Theodore J. Ronningen, Timothy D. Scarborough, Vyacheslav Leshchenko, Seth S. Shields and John E. Beetar,

引用次数: 0

Identifying Opportunity Targets in Gram-Negative Pathogens for Infectious Disease Mitigation

IF 12.7 1区化学

ACS Central Science Pub Date : 2025-01-03 DOI: 10.1021/acscentsci.4c0143710.1021/acscentsci.4c01437

Isaac A. Paddy, and , Laura M. K. Dassama*,

{"title":"Identifying Opportunity Targets in Gram-Negative Pathogens for Infectious Disease Mitigation","authors":"Isaac A. Paddy,  and , Laura M. K. Dassama*, ","doi":"10.1021/acscentsci.4c0143710.1021/acscentsci.4c01437","DOIUrl":"https://doi.org/10.1021/acscentsci.4c01437https://doi.org/10.1021/acscentsci.4c01437","url":null,"abstract":"Antimicrobial drug resistance (AMR) is a pressing global human health challenge. Humans face one of their grandest challenges as climate change expands the habitat of vectors that bear human pathogens, incidences of nosocomial infections rise, and new antibiotics discovery lags. AMR is a multifaceted problem that requires a multidisciplinary and an “all-hands-on-deck” approach. As chemical microbiologists, we are well positioned to understand the complexities of AMR while seeing opportunities for tackling the challenge. In this Outlook, we focus on vulnerabilities of human pathogens and posit that they represent “opportunity targets” for which few modulatory ligands exist. We center our attention on proteins in Gram-negative organisms, which are recalcitrant to many antibiotics because of their external membrane barrier. Our hope is to highlight such targets and explore their potential as “druggable” proteins for infectious disease mitigation. We posit that success in this endeavor will introduce new classes of antibiotics that might alleviate some of the current pressing AMR concerns.Antibiotic resistance is rapidly increasing while discovery of new drugs lags. Uncovering of new druggable targets could increase the number of antibiotics and temporarily abate the AMR crisis.","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 1","pages":"25–35 25–35"},"PeriodicalIF":12.7,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acscentsci.4c01437","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143090607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Identifying Opportunity Targets in Gram-Negative Pathogens for Infectious Disease Mitigation. 识别革兰氏阴性病原体中的机会目标，缓解传染病。

IF 12.7 1区化学

ACS Central Science Pub Date : 2025-01-03 eCollection Date: 2025-01-22 DOI: 10.1021/acscentsci.4c01437

Isaac A Paddy, Laura M K Dassama

{"title":"Identifying Opportunity Targets in Gram-Negative Pathogens for Infectious Disease Mitigation.","authors":"Isaac A Paddy, Laura M K Dassama","doi":"10.1021/acscentsci.4c01437","DOIUrl":"10.1021/acscentsci.4c01437","url":null,"abstract":"Antimicrobial drug resistance (AMR) is a pressing global human health challenge. Humans face one of their grandest challenges as climate change expands the habitat of vectors that bear human pathogens, incidences of nosocomial infections rise, and new antibiotics discovery lags. AMR is a multifaceted problem that requires a multidisciplinary and an \"all-hands-on-deck\" approach. As chemical microbiologists, we are well positioned to understand the complexities of AMR while seeing opportunities for tackling the challenge. In this Outlook, we focus on vulnerabilities of human pathogens and posit that they represent \"opportunity targets\" for which few modulatory ligands exist. We center our attention on proteins in Gram-negative organisms, which are recalcitrant to many antibiotics because of their external membrane barrier. Our hope is to highlight such targets and explore their potential as \"druggable\" proteins for infectious disease mitigation. We posit that success in this endeavor will introduce new classes of antibiotics that might alleviate some of the current pressing AMR concerns.","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 1","pages":"25-35"},"PeriodicalIF":12.7,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11758222/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143044846","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Enhancing the Optically Detected Magnetic Resonance Signal of Organic Molecular Qubits.

IF 12.7 1区化学

ACS Central Science Pub Date : 2025-01-03 eCollection Date: 2025-01-22 DOI: 10.1021/acscentsci.4c01632

Yong Rui Poh, Joel Yuen-Zhou

{"title":"Enhancing the Optically Detected Magnetic Resonance Signal of Organic Molecular Qubits.","authors":"Yong Rui Poh, Joel Yuen-Zhou","doi":"10.1021/acscentsci.4c01632","DOIUrl":"10.1021/acscentsci.4c01632","url":null,"abstract":"In quantum information science and sensing, electron spins are often purified into a specific polarization through an optical-spin interface, a process known as optically detected magnetic resonance (ODMR). Diamond-NV centers and transition metals are both excellent platforms for these so-called color centers, while metal-free molecular analogues are also gaining popularity for their extended polarization lifetimes, milder environmental impacts, and reduced costs. In our earlier attempt at designing such organic high-spin π-diradicals, we proposed to spin-polarize by shelving triplet M S = ±1 populations as singlets. This was recently verified by experiments albeit with low ODMR contrasts of <1% at temperatures above 5 K. In this work, we propose to improve the ODMR signal by moving singlet populations back into the triplet M S = 0 sublevel, designing a true carbon-based molecular analogue to the NV center. Our proposal is based upon transition-orbital and group-theoretical analyses of beyond-nearest-neighbor spin-orbit couplings, which are further confirmed by ab initio calculations of a realistic trityl-based radical dimer. Microkinetic analyses point toward high ODMR contrasts of around 30% under experimentally feasible conditions, a stark improvement from previous works. Finally, in our quest toward ground-state optically addressable molecular spin qubits, we exemplify how our symmetry-based design avoids Zeeman-induced singlet-triplet mixings, setting the scene for realizing electron spin qubit gates.","PeriodicalId":10,"journal":{"name":"ACS Central Science","volume":"11 1","pages":"116-126"},"PeriodicalIF":12.7,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11758272/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143044843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0