ACS Pharmacology and Translational Science最新文献_第2页

Exploring End-of-Life Experiences and Consciousness through the Lens of Psychedelics

IF 4.9

ACS Pharmacology and Translational Science Pub Date : 2025-02-26 DOI: 10.1021/acsptsci.5c0011810.1021/acsptsci.5c00118

Hongyuan Li, and , Xiaohui Wang*,

引用次数: 0

Development of a Fluorescence Polarization Assay for the SARS-CoV-2 Papain-like Protease

IF 4.9

ACS Pharmacology and Translational Science Pub Date : 2025-02-26 DOI: 10.1021/acsptsci.4c0064210.1021/acsptsci.4c00642

Kan Li, Prakash Jadhav, Yu Wen, Haozhou Tan and Jun Wang*,

{"title":"Development of a Fluorescence Polarization Assay for the SARS-CoV-2 Papain-like Protease","authors":"Kan Li, Prakash Jadhav, Yu Wen, Haozhou Tan and Jun Wang*, ","doi":"10.1021/acsptsci.4c0064210.1021/acsptsci.4c00642","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00642https://doi.org/10.1021/acsptsci.4c00642","url":null,"abstract":"The COVID-19 pandemic has caused significant losses to the global community. Although effective vaccination and antiviral therapeutics provide primary defense, SARS-CoV-2 remains a public health threat, given the emerging resistant variants. The SARS-CoV-2 papain-like protease (PLpro) is essential for viral replication and is a promising drug target. We recently designed a series of biarylphenyl PLpro inhibitors with a representative lead Jun12682 showing potent antiviral efficacy in a SARS-CoV-2 infection mouse model. In this study, we designed a fluorescein-labeled biarylphenyl probe Jun12781 and used it to optimize a fluorescence polarization (FP) assay. The FP assay is suitable for high-throughput screening with a Z′ factor of 0.69. In addition, we found a positive correlation between the FP binding affinity and the enzymatic inhibitory potency of PLpro inhibitors, suggesting that the FP assay is valid in characterizing the binding affinity of PLpro inhibitors.","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 3","pages":"774–784 774–784"},"PeriodicalIF":4.9,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143608969","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

Exploring End-of-Life Experiences and Consciousness through the Lens of Psychedelics.

IF 4.9

ACS Pharmacology and Translational Science Pub Date : 2025-02-26 eCollection Date: 2025-03-14 DOI: 10.1021/acsptsci.5c00118

Hongyuan Li, Xiaohui Wang

引用次数: 0

Characterization of [3H]Propionylated Human Peptide YY-A New Probe for Neuropeptide Y Y2 Receptor Binding Studies

IF 4.9

ACS Pharmacology and Translational Science Pub Date : 2025-02-25 DOI: 10.1021/acsptsci.4c0066610.1021/acsptsci.4c00666

Franziska Schettler, Albert O. Gattor, Pierre Koch and Max Keller*,

{"title":"Characterization of [3H]Propionylated Human Peptide YY-A New Probe for Neuropeptide Y Y2 Receptor Binding Studies","authors":"Franziska Schettler, Albert O. Gattor, Pierre Koch and Max Keller*, ","doi":"10.1021/acsptsci.4c0066610.1021/acsptsci.4c00666","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00666https://doi.org/10.1021/acsptsci.4c00666","url":null,"abstract":"The neuropeptide Y (NPY) Y2 receptor (Y2R) is a G-protein-coupled receptor that is involved in the regulation of various physiological processes such as neurotransmitter release, bone metabolism, and memory. Consequently, the Y2R represents a potential drug target, e.g., for the treatment of epilepsy and mood disorders. Until now, the determination of the Y2R binding affinities of Y2R ligands has primarily been performed using 125I-labeled derivatives of the endogenous Y2R agonists NPY and peptide YY (PYY). A tritium-labeled NPY derivative has also been used; however, its suitability for binding assays in sodium-containing buffer is doubtful. We synthesized a tritium-labeled PYY derivative by [3H]propionylation at Lys4 ([3H]2). The radioligand was characterized by saturation binding, association, and dissociation kinetics and was applied in competition binding assays. Specific binding of [3H]2 at intact Chinese hamster ovary cells expressing the hY2R was saturable in both sodium-free buffer (apparent Kd = 0.016–0.067 nM) and sodium-containing buffer (175 mM Na+, apparent Kd = 0.16–0.18 nM). Competition binding experiments with Y2R reference ligands yielded Ki values, which are in good agreement with the reported Y2R binding affinities, showing that [3H]2 represents a useful tritiated tool compound for the determination of Y2R binding affinities also in buffers containing sodium at physiological concentrations.","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 3","pages":"785–799 785–799"},"PeriodicalIF":4.9,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsptsci.4c00666","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143608858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Characterization of [³H]Propionylated Human Peptide YY-A New Probe for Neuropeptide Y Y₂ Receptor Binding Studies.

IF 4.9

ACS Pharmacology and Translational Science Pub Date : 2025-02-25 eCollection Date: 2025-03-14 DOI: 10.1021/acsptsci.4c00666

Franziska Schettler, Albert O Gattor, Pierre Koch, Max Keller

{"title":"Characterization of [3H]Propionylated Human Peptide YY-A New Probe for Neuropeptide Y Y2 Receptor Binding Studies.","authors":"Franziska Schettler, Albert O Gattor, Pierre Koch, Max Keller","doi":"10.1021/acsptsci.4c00666","DOIUrl":"10.1021/acsptsci.4c00666","url":null,"abstract":"The neuropeptide Y (NPY) Y2 receptor (Y2R) is a G-protein-coupled receptor that is involved in the regulation of various physiological processes such as neurotransmitter release, bone metabolism, and memory. Consequently, the Y2R represents a potential drug target, e.g., for the treatment of epilepsy and mood disorders. Until now, the determination of the Y2R binding affinities of Y2R ligands has primarily been performed using 125I-labeled derivatives of the endogenous Y2R agonists NPY and peptide YY (PYY). A tritium-labeled NPY derivative has also been used; however, its suitability for binding assays in sodium-containing buffer is doubtful. We synthesized a tritium-labeled PYY derivative by [3H]propionylation at Lys4 ([3H]2). The radioligand was characterized by saturation binding, association, and dissociation kinetics and was applied in competition binding assays. Specific binding of [3H]2 at intact Chinese hamster ovary cells expressing the hY2R was saturable in both sodium-free buffer (apparent K d = 0.016-0.067 nM) and sodium-containing buffer (175 mM Na+, apparent K d = 0.16-0.18 nM). Competition binding experiments with Y2R reference ligands yielded K i values, which are in good agreement with the reported Y2R binding affinities, showing that [3H]2 represents a useful tritiated tool compound for the determination of Y2R binding affinities also in buffers containing sodium at physiological concentrations.","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 3","pages":"785-799"},"PeriodicalIF":4.9,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915035/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143664897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Glycation of Proteins and Its End Products: From Initiation to Natural Product-Based Therapeutic Preventions.

IF 4.9

ACS Pharmacology and Translational Science Pub Date : 2025-02-25 eCollection Date: 2025-03-14 DOI: 10.1021/acsptsci.4c00684

Mangal Deep Burman, Sagar Bag, Souvik Ghosal, Sudipta Bhowmik

{"title":"Glycation of Proteins and Its End Products: From Initiation to Natural Product-Based Therapeutic Preventions.","authors":"Mangal Deep Burman, Sagar Bag, Souvik Ghosal, Sudipta Bhowmik","doi":"10.1021/acsptsci.4c00684","DOIUrl":"10.1021/acsptsci.4c00684","url":null,"abstract":"Diabetes is a chronic metabolic disorder characterized by elevated blood glucose levels, which lead to the glycation of proteins and the formation of advanced glycation end products (AGEs). These AGEs contribute to oxidative stress, inflammation, and the development of complications such as cardiovascular disease, nephropathy, and anemia, significantly increasing mortality rates among diabetic patients. This Review focuses on the role of glycation inhibitors as a potential strategy to prevent AGE-related pathologies. While synthetic glycation inhibitors have shown promise, their adverse effects highlight the need for safer alternatives. We specifically explore a range of natural compounds-flavonoids, curcuminoids, terpenes, stilbenes, lignans, and coumarins-that have demonstrated significant antiglycating properties. The mechanisms through which these natural products inhibit glycation, including antioxidant activity, metal ion chelation, and direct interference with the glycation process, are discussed in detail. This review underscores the potential of natural products as effective and safer glycation inhibitors, offering a promising avenue for the development of therapeutic strategies against diabetes and AGE-related disorders.","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 3","pages":"636-653"},"PeriodicalIF":4.9,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915047/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143664915","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Glycation of Proteins and Its End Products: From Initiation to Natural Product-Based Therapeutic Preventions

IF 4.9

ACS Pharmacology and Translational Science Pub Date : 2025-02-25 DOI: 10.1021/acsptsci.4c0068410.1021/acsptsci.4c00684

Mangal Deep Burman, Sagar Bag, Souvik Ghosal and Sudipta Bhowmik*,

{"title":"Glycation of Proteins and Its End Products: From Initiation to Natural Product-Based Therapeutic Preventions","authors":"Mangal Deep Burman, Sagar Bag, Souvik Ghosal and Sudipta Bhowmik*, ","doi":"10.1021/acsptsci.4c0068410.1021/acsptsci.4c00684","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00684https://doi.org/10.1021/acsptsci.4c00684","url":null,"abstract":"Diabetes is a chronic metabolic disorder characterized by elevated blood glucose levels, which lead to the glycation of proteins and the formation of advanced glycation end products (AGEs). These AGEs contribute to oxidative stress, inflammation, and the development of complications such as cardiovascular disease, nephropathy, and anemia, significantly increasing mortality rates among diabetic patients. This Review focuses on the role of glycation inhibitors as a potential strategy to prevent AGE-related pathologies. While synthetic glycation inhibitors have shown promise, their adverse effects highlight the need for safer alternatives. We specifically explore a range of natural compounds─flavonoids, curcuminoids, terpenes, stilbenes, lignans, and coumarins─that have demonstrated significant antiglycating properties. The mechanisms through which these natural products inhibit glycation, including antioxidant activity, metal ion chelation, and direct interference with the glycation process, are discussed in detail. This review underscores the potential of natural products as effective and safer glycation inhibitors, offering a promising avenue for the development of therapeutic strategies against diabetes and AGE-related disorders.","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 3","pages":"636–653 636–653"},"PeriodicalIF":4.9,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143608936","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

Development of a Novel 18F-Labeled Radioligand for Imaging Cholesterol 24-Hydroxylase with Positron Emission Tomography

IF 4.9

ACS Pharmacology and Translational Science Pub Date : 2025-02-24 DOI: 10.1021/acsptsci.4c0068310.1021/acsptsci.4c00683

Jian Rong, Chunyu Zhao, Ahmad F. Chaudhary, Jiahui Chen, Xin Zhou, Kuo Zhang, Zhendong Song, Zhenkun Sun, Yabiao Gao, Zachary Zhang, Siyan Feng, Thomas Lee Collier, Hongjie Yuan, Jimmy S. Patel, Achi Haider, Yinlong Li and Steven H. Liang*,

{"title":"Development of a Novel 18F-Labeled Radioligand for Imaging Cholesterol 24-Hydroxylase with Positron Emission Tomography","authors":"Jian Rong, Chunyu Zhao, Ahmad F. Chaudhary, Jiahui Chen, Xin Zhou, Kuo Zhang, Zhendong Song, Zhenkun Sun, Yabiao Gao, Zachary Zhang, Siyan Feng, Thomas Lee Collier, Hongjie Yuan, Jimmy S. Patel, Achi Haider, Yinlong Li and Steven H. Liang*, ","doi":"10.1021/acsptsci.4c0068310.1021/acsptsci.4c00683","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00683https://doi.org/10.1021/acsptsci.4c00683","url":null,"abstract":"Cholesterol 24-hydroxylase (CYP46A1), also known as CH24H, is a brain-specific monooxygenase responsible for the elimination of cholesterol from the central nervous system (CNS). It catalyzes the conversion of cholesterol to 24(S)-hydroxycholesterol, the primary pathway for CNS cholesterol clearance. Dysregulation of cholesterol homeostasis has been implicated in neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). This study presents the synthesis and evaluation of [18F]5 ([18F]CHL2310) as a novel radioligand for imaging CYP46A1 and cholesterol metabolism in the brain by positron emission tomography (PET). CHL2310 was identified as a potent inhibitor of CYP46A1 and subsequently labeled with fluorine-18 in a radiochemical yield of 13% and a high molar activity of 93 GBq/μmol. [18F]CHL2310 was evaluated in rats using in vitro autoradiography and PET imaging, demonstrating high brain uptake, heterogeneous brain distribution, favorable binding specificity, and suitable clearance kinetic profiles within the CNS. In all, [18F]5 ([18F]CHL2310) represents a promising tool for noninvasive quantification of cholesterol metabolism by imaging CYP46A1.","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 3","pages":"800–807 800–807"},"PeriodicalIF":4.9,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsptsci.4c00683","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143608898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

d ₄-Cystamine: A Deuterated Cystamine Derivative with Improved Anti-Inflammatory and Anti-Fibrotic Activities in a Murine Model of Fibrosing Steatohepatitis.

IF 4.9

ACS Pharmacology and Translational Science Pub Date : 2025-02-24 eCollection Date: 2025-03-14 DOI: 10.1021/acsptsci.4c00738

Aleksandra Leszczynska, Thibault Alle, Benedikt Kaufmann, Hana Sung, Christian Stoess, Agustina Reca, Andrea Kim, Sun Kim, Chelsea Tran, Killian Oukoloff, Ludovica Monti, Bobby Lucero, Ilya Gertsman, Jeremiah D Momper, Phillipp Hartmann, Ariel E Feldstein, Ranjan Dohil, Carlo Ballatore

{"title":"d 4-Cystamine: A Deuterated Cystamine Derivative with Improved Anti-Inflammatory and Anti-Fibrotic Activities in a Murine Model of Fibrosing Steatohepatitis.","authors":"Aleksandra Leszczynska, Thibault Alle, Benedikt Kaufmann, Hana Sung, Christian Stoess, Agustina Reca, Andrea Kim, Sun Kim, Chelsea Tran, Killian Oukoloff, Ludovica Monti, Bobby Lucero, Ilya Gertsman, Jeremiah D Momper, Phillipp Hartmann, Ariel E Feldstein, Ranjan Dohil, Carlo Ballatore","doi":"10.1021/acsptsci.4c00738","DOIUrl":"10.1021/acsptsci.4c00738","url":null,"abstract":"Metabolic dysfunction-associated steatotic liver disease (MASLD) is a multifactorial chronic disease that can progress to metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis, ultimately leading to liver cirrhosis and hepatocellular carcinoma. Oxidative stress is believed to play an important role in the development of MASH. Small aminothiol compounds such as cysteamine and its oxidized precursor, cystamine, are known pleiotropic compounds that exhibit relatively potent antioxidant and other effects. Herein, we evaluate the efficacy of cystamine, as well as two deuterated derivatives, in a choline-deficient, L-amino acid-defined, high-fat-diet (CDAA-HFD) mouse model of rapidly progressing liver fibrosis. Compared to control mice, daily oral administration of isotopically reinforced cystamine derivatives (200 mg/kg) led to a significant reduction of liver fibrosis and inflammation as well as oxidative stress. Moreover, the efficacy of treatment appeared to increase with the deuteration state of cystamine, with the tetradeuterated derivative, d 4 -cystamine, being the most effective. These results indicate that deuterated cystamine derivatives hold promise as potential candidates for the treatment of MASH.","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 3","pages":"885-898"},"PeriodicalIF":4.9,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915185/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143664877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Development of a Novel ¹⁸F-Labeled Radioligand for Imaging Cholesterol 24-Hydroxylase with Positron Emission Tomography.

IF 4.9

ACS Pharmacology and Translational Science Pub Date : 2025-02-24 eCollection Date: 2025-03-14 DOI: 10.1021/acsptsci.4c00683

Jian Rong, Chunyu Zhao, Ahmad F Chaudhary, Jiahui Chen, Xin Zhou, Kuo Zhang, Zhendong Song, Zhenkun Sun, Yabiao Gao, Zachary Zhang, Siyan Feng, Thomas Lee Collier, Hongjie Yuan, Jimmy S Patel, Achi Haider, Yinlong Li, Steven H Liang

{"title":"Development of a Novel 18F-Labeled Radioligand for Imaging Cholesterol 24-Hydroxylase with Positron Emission Tomography.","authors":"Jian Rong, Chunyu Zhao, Ahmad F Chaudhary, Jiahui Chen, Xin Zhou, Kuo Zhang, Zhendong Song, Zhenkun Sun, Yabiao Gao, Zachary Zhang, Siyan Feng, Thomas Lee Collier, Hongjie Yuan, Jimmy S Patel, Achi Haider, Yinlong Li, Steven H Liang","doi":"10.1021/acsptsci.4c00683","DOIUrl":"10.1021/acsptsci.4c00683","url":null,"abstract":"Cholesterol 24-hydroxylase (CYP46A1), also known as CH24H, is a brain-specific monooxygenase responsible for the elimination of cholesterol from the central nervous system (CNS). It catalyzes the conversion of cholesterol to 24(S)-hydroxycholesterol, the primary pathway for CNS cholesterol clearance. Dysregulation of cholesterol homeostasis has been implicated in neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). This study presents the synthesis and evaluation of [18F]5 ([18F]CHL2310) as a novel radioligand for imaging CYP46A1 and cholesterol metabolism in the brain by positron emission tomography (PET). CHL2310 was identified as a potent inhibitor of CYP46A1 and subsequently labeled with fluorine-18 in a radiochemical yield of 13% and a high molar activity of 93 GBq/μmol. [18F]CHL2310 was evaluated in rats using in vitro autoradiography and PET imaging, demonstrating high brain uptake, heterogeneous brain distribution, favorable binding specificity, and suitable clearance kinetic profiles within the CNS. In all, [18F]5 ([18F]CHL2310) represents a promising tool for noninvasive quantification of cholesterol metabolism by imaging CYP46A1.","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 3","pages":"800-807"},"PeriodicalIF":4.9,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11915032/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143664907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0