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A 3D Model of the Human Lung Airway for Evaluating Permeability of Inhaled Drugs
IF 4.9
ACS Pharmacology and Translational Science Pub Date : 2024-12-29 DOI: 10.1021/acsptsci.4c0060710.1021/acsptsci.4c00607
Shekh M. Rahman*, Robert M. Geiger, Md Shadiqur Rashid Roni, Isra Tariq, Omnia Ismaiel, Murali K. Matta, Katherine Shea, Dylan Bruckner, Wenlei Jiang, Ross Walenga, Bryan Newman, Paula L. Hyland, Alexandre J.S. Ribeiro, Jeffrey Florian, Ksenia Blinova and Kevin A. Ford*, 
{"title":"A 3D Model of the Human Lung Airway for Evaluating Permeability of Inhaled Drugs","authors":"Shekh M. Rahman*,&nbsp;Robert M. Geiger,&nbsp;Md Shadiqur Rashid Roni,&nbsp;Isra Tariq,&nbsp;Omnia Ismaiel,&nbsp;Murali K. Matta,&nbsp;Katherine Shea,&nbsp;Dylan Bruckner,&nbsp;Wenlei Jiang,&nbsp;Ross Walenga,&nbsp;Bryan Newman,&nbsp;Paula L. Hyland,&nbsp;Alexandre J.S. Ribeiro,&nbsp;Jeffrey Florian,&nbsp;Ksenia Blinova and Kevin A. Ford*,&nbsp;","doi":"10.1021/acsptsci.4c0060710.1021/acsptsci.4c00607","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00607https://doi.org/10.1021/acsptsci.4c00607","url":null,"abstract":"<p >Current in vitro cell-based methods, relying on single cell types, have structural and functional limitations in determining lung drug permeability, which is a contributing factor affecting both local and systemic drug levels. To address this issue, we investigated a 3D human lung airway model generated using a cell culture insert, wherein primary human lung epithelial and endothelial cells were cocultured at an air–liquid interface (ALI). To ensure that the cell culture mimics the physiological and functional characteristics of airway tissue, the model was characterized by evaluating several parameters such as cellular confluency, ciliation, tight junctions, mucus-layer formation, transepithelial electrical resistance, and barrier function through assaying fluorescein isothiocyanate-dextran permeability. To understand how the characterized ALI quality attributes influenced the absorption of inhaled drugs through the epithelial-endothelial barrier, we measured the permeability and epithelial intracellular concentrations of albuterol sulfate (AL), formoterol fumarate (FO), and fluticasone furoate (FL). The presented characterization results overall demonstrate that this culture platform mimicked the airway-specific structure and barrier function. An apparent permeability (<i>P</i><sub>app</sub>) of 5.7 × 10<sup>–6</sup> cm/s and an intracellular concentration below 1% were quantified for AL over 3 h. The <i>P</i><sub>app</sub> of FO was 8.5 × 10<sup>–6</sup> cm/s, with an intracellular concentration of 3.8%. Due to its high lipophilicity, FL showed a higher intracellular concentration (17.4%) compared to AL and FO, but also a 73.1% loss of the compound over 3 h due to nonspecific binding, with a <i>P</i><sub>app</sub> as low as 1.3 × 10<sup>–7</sup> cm/s. While the model exhibited physiologically relevant properties, its utility in estimating the permeability of inhaled drugs may be drug-specific, warranting further optimization and study.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 1","pages":"245–255 245–255"},"PeriodicalIF":4.9,"publicationDate":"2024-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143086946","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
Safe and Orally Bioavailable Inhibitor of Serine Palmitoyltransferase Improves Age-Related Sarcopenia
IF 4.9
ACS Pharmacology and Translational Science Pub Date : 2024-12-29 DOI: 10.1021/acsptsci.4c0058710.1021/acsptsci.4c00587
Johanne Poisson, Ioanna Daskalaki, Vijay Potluri, Jean-David Morel, Sandra Rodriguez-Lopez, Alessia De Masi, Giorgia Benegiamo, Suresh Jain, Tanes Lima* and Johan Auwerx*, 
{"title":"Safe and Orally Bioavailable Inhibitor of Serine Palmitoyltransferase Improves Age-Related Sarcopenia","authors":"Johanne Poisson,&nbsp;Ioanna Daskalaki,&nbsp;Vijay Potluri,&nbsp;Jean-David Morel,&nbsp;Sandra Rodriguez-Lopez,&nbsp;Alessia De Masi,&nbsp;Giorgia Benegiamo,&nbsp;Suresh Jain,&nbsp;Tanes Lima* and Johan Auwerx*,&nbsp;","doi":"10.1021/acsptsci.4c0058710.1021/acsptsci.4c00587","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00587https://doi.org/10.1021/acsptsci.4c00587","url":null,"abstract":"<p >The accumulation of ceramides and related metabolites has emerged as a pivotal mechanism contributing to the onset of age-related diseases. However, small molecule inhibitors targeting the ceramide <i>de novo</i> synthesis pathway for clinical use are currently unavailable. We synthesized a safe and orally bioavailable inhibitor, termed ALT-007, targeting the rate-limiting enzyme of ceramide <i>de novo</i> synthesis, serine palmitoyltransferase (SPT). In a mouse model of age-related sarcopenia, ALT-007, administered through the diet, effectively restored muscle mass and function compromised by aging. Mechanistic studies revealed that ALT-007 enhances protein homeostasis in <i>Caenorhabditis elegans</i> and mouse models of aging and age-related diseases, such as sarcopenia and inclusion body myositis (IBM); this effect is mediated by a specific reduction in very-long chain 1-deoxy-sphingolipid species, which accumulate in both muscle and brain tissues of aged mice and in muscle cells from IBM patients. These findings unveil a promising therapeutic avenue for developing safe ceramide inhibitors to address age-related neuromuscular diseases.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 1","pages":"203–215 203–215"},"PeriodicalIF":4.9,"publicationDate":"2024-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsptsci.4c00587","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143087418","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
Inhalable Carbonyl Sulfide Donor-Hybridized Selective Phosphodiesterase 10A Inhibitor for Treating Idiopathic Pulmonary Fibrosis by Inhibiting Tumor Growth Factor-β Signaling and Activating the cAMP/Protein Kinase A/cAMP Response Element-Binding Protein (CREB)/p53 Axis
IF 4.9
ACS Pharmacology and Translational Science Pub Date : 2024-12-28 DOI: 10.1021/acsptsci.4c0067110.1021/acsptsci.4c00671
Quan Wang, Xinyue Liu, Han Yuan, Fengcai Zhang, Jiafei Wu, Dongjing Yang, Jiang Qian, Yi-You Huang, Guihong Chai*, Hai-Bin Luo* and Lei Guo*, 
{"title":"Inhalable Carbonyl Sulfide Donor-Hybridized Selective Phosphodiesterase 10A Inhibitor for Treating Idiopathic Pulmonary Fibrosis by Inhibiting Tumor Growth Factor-β Signaling and Activating the cAMP/Protein Kinase A/cAMP Response Element-Binding Protein (CREB)/p53 Axis","authors":"Quan Wang,&nbsp;Xinyue Liu,&nbsp;Han Yuan,&nbsp;Fengcai Zhang,&nbsp;Jiafei Wu,&nbsp;Dongjing Yang,&nbsp;Jiang Qian,&nbsp;Yi-You Huang,&nbsp;Guihong Chai*,&nbsp;Hai-Bin Luo* and Lei Guo*,&nbsp;","doi":"10.1021/acsptsci.4c0067110.1021/acsptsci.4c00671","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00671https://doi.org/10.1021/acsptsci.4c00671","url":null,"abstract":"<p >Idiopathic pulmonary fibrosis (IPF) is a debilitating, incurable, and life-threatening disease that lacks effective therapy. The overexpression of phosphodiesterase 10A (PDE10A) plays a vital role in pulmonary fibrosis (PF). However, the impact of selective PDE10A inhibitors on the tumor growth factor-β (TGF-β)/small mother against decapentaplegic (Smad) signaling pathway remains unclear. Herein, we have exploited a novel carbonyl sulfide (COS)/hydrogen sulfide (H<sub>2</sub>S)-donor hybrid PDE10A inhibitor called <b>COS-2080</b> with a well-defined mechanism of H<sub>2</sub>S-releasing action. It exhibited highly potent inhibitory activity against PDE10A and excellent PDE subfamily selectivity. Moreover, <b>COS-2080</b> demonstrated significant antifibrotic effects by inhibiting cell proliferation and mitigating fibroblast-to-myofibroblast transition (FMT). A dry powder inhalation formulation called <b>COS-2080-DPI</b> has been developed using the ultrasonic spray freeze drying (USFD) technique, demonstrating significant antifibrotic efficacy in mice with bleomycin-induced PF at a dosage approximately 600 times lower than pirfenidone. This remarkable antifibrotic efficacy of <b>COS-2080</b> on TGF-β1-induced FMT could be primarily attributed to its inhibition of the Smad2/Smad3 phosphorylation. Moreover, <b>COS-2080</b> effectively attenuated fibrosis in MRC-5 cells by activating the cAMP/protein kinase A (PKA)/CREB pathway and potentially increasing levels of p53 protein. Our findings suggest that effective inhibition of PDE10A potentially confers a protective effect on FMT in PF by impeding TGF-β signaling and activating the cAMP/PKA/CREB/p53 axis.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 1","pages":"256–269 256–269"},"PeriodicalIF":4.9,"publicationDate":"2024-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143086925","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
Inhalable Carbonyl Sulfide Donor-Hybridized Selective Phosphodiesterase 10A Inhibitor for Treating Idiopathic Pulmonary Fibrosis by Inhibiting Tumor Growth Factor-β Signaling and Activating the cAMP/Protein Kinase A/cAMP Response Element-Binding Protein (CREB)/p53 Axis. 可吸入羰基硫化物供体杂交选择性磷酸二酯酶10A抑制剂通过抑制肿瘤生长因子-β信号传导和激活cAMP/蛋白激酶A/cAMP反应元件结合蛋白(CREB)/p53轴治疗特发性肺纤维化
IF 4.9
ACS Pharmacology and Translational Science Pub Date : 2024-12-28 eCollection Date: 2025-01-10 DOI: 10.1021/acsptsci.4c00671
Quan Wang, Xinyue Liu, Han Yuan, Fengcai Zhang, Jiafei Wu, Dongjing Yang, Jiang Qian, Yi-You Huang, Guihong Chai, Hai-Bin Luo, Lei Guo
{"title":"Inhalable Carbonyl Sulfide Donor-Hybridized Selective Phosphodiesterase 10A Inhibitor for Treating Idiopathic Pulmonary Fibrosis by Inhibiting Tumor Growth Factor-β Signaling and Activating the cAMP/Protein Kinase A/cAMP Response Element-Binding Protein (CREB)/p53 Axis.","authors":"Quan Wang, Xinyue Liu, Han Yuan, Fengcai Zhang, Jiafei Wu, Dongjing Yang, Jiang Qian, Yi-You Huang, Guihong Chai, Hai-Bin Luo, Lei Guo","doi":"10.1021/acsptsci.4c00671","DOIUrl":"10.1021/acsptsci.4c00671","url":null,"abstract":"<p><p>Idiopathic pulmonary fibrosis (IPF) is a debilitating, incurable, and life-threatening disease that lacks effective therapy. The overexpression of phosphodiesterase 10A (PDE10A) plays a vital role in pulmonary fibrosis (PF). However, the impact of selective PDE10A inhibitors on the tumor growth factor-β (TGF-β)/small mother against decapentaplegic (Smad) signaling pathway remains unclear. Herein, we have exploited a novel carbonyl sulfide (COS)/hydrogen sulfide (H<sub>2</sub>S)-donor hybrid PDE10A inhibitor called <b>COS-2080</b> with a well-defined mechanism of H<sub>2</sub>S-releasing action. It exhibited highly potent inhibitory activity against PDE10A and excellent PDE subfamily selectivity. Moreover, <b>COS-2080</b> demonstrated significant antifibrotic effects by inhibiting cell proliferation and mitigating fibroblast-to-myofibroblast transition (FMT). A dry powder inhalation formulation called <b>COS-2080-DPI</b> has been developed using the ultrasonic spray freeze drying (USFD) technique, demonstrating significant antifibrotic efficacy in mice with bleomycin-induced PF at a dosage approximately 600 times lower than pirfenidone. This remarkable antifibrotic efficacy of <b>COS-2080</b> on TGF-β1-induced FMT could be primarily attributed to its inhibition of the Smad2/Smad3 phosphorylation. Moreover, <b>COS-2080</b> effectively attenuated fibrosis in MRC-5 cells by activating the cAMP/protein kinase A (PKA)/CREB pathway and potentially increasing levels of p53 protein. Our findings suggest that effective inhibition of PDE10A potentially confers a protective effect on FMT in PF by impeding TGF-β signaling and activating the cAMP/PKA/CREB/p53 axis.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 1","pages":"256-269"},"PeriodicalIF":4.9,"publicationDate":"2024-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11729434/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143013411","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
Lipopolysaccharide-Neutralizing Peptide Modulates P2X7 Receptor-Mediated Interleukin-1β Release
IF 4.9
ACS Pharmacology and Translational Science Pub Date : 2024-12-23 DOI: 10.1021/acsptsci.4c0049610.1021/acsptsci.4c00496
Jonas Engelhardt, Anna Klawonn, Ann-Kathrin Dobbelstein, Aliaa Abdelrahman, Johannes Oldenburg, Klaus Brandenburg, Christa E. Müller and Günther Weindl*, 
{"title":"Lipopolysaccharide-Neutralizing Peptide Modulates P2X7 Receptor-Mediated Interleukin-1β Release","authors":"Jonas Engelhardt,&nbsp;Anna Klawonn,&nbsp;Ann-Kathrin Dobbelstein,&nbsp;Aliaa Abdelrahman,&nbsp;Johannes Oldenburg,&nbsp;Klaus Brandenburg,&nbsp;Christa E. Müller and Günther Weindl*,&nbsp;","doi":"10.1021/acsptsci.4c0049610.1021/acsptsci.4c00496","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00496https://doi.org/10.1021/acsptsci.4c00496","url":null,"abstract":"<p >Lipopolysaccharide (LPS)-neutralizing peptides are emerging as new potential therapeutic modalities to treat sepsis and skin infections. Purinergic ligand-gated ion channels (P2X receptors) play a critical role in various biological processes, including inflammation. Recent drug development efforts have significantly focused on the modulation of P2X receptors. Here, we investigated the effects of the synthetic LPS-neutralizing peptide Pep19–2.5 on human P2X receptors in cells of the innate immune system. Pep19–2.5 concentration-dependently triggered Ca<sup>2+</sup> influx, interleukin (IL)-1β, and lactate dehydrogenase (LDH) release in Toll-like receptor-stimulated human macrophages and monocytes. Ca<sup>2+</sup> influx was mediated at least partially by P2X7 receptors, and IL-1β and LDH release by P2X7 receptors, respectively. Confocal microscopy confirmed the colocalization of Pep19–2.5 with P2X7 receptors. Pep19–2.5-induced IL-1β release in primed cells was dependent on K<sup>+</sup> efflux, caspase-1, and the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein 3 inflammasome. In the presence of the P2X7 receptor agonist 2′(3′)-<i>O</i>-(4-benzoylbenzoyl)adenosine-5′-triphosphate, Pep19–2.5 reduced IL-1β and LDH release. In 1321N1, astrocytoma cells stably transfected with human P2X receptors, Pep19–2.5 potently modulated P2X7 and P2X4 receptors (IC<sub>50</sub> values of 0.346 and 0.146 μM, respectively) but showed less (P2X1, P2X3) or no activity (P2X2) at other P2X receptor subtypes. Our findings underline the potential of LPS-neutralizing peptides as modulators of P2X receptors, thus expanding their applicability beyond the treatment of sepsis to the treatment of inflammatory diseases.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 1","pages":"136–145 136–145"},"PeriodicalIF":4.9,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143086011","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
Lipopolysaccharide-Neutralizing Peptide Modulates P2X7 Receptor-Mediated Interleukin-1β Release. 脂多糖中和肽调节P2X7受体介导的白介素-1β释放。
IF 4.9
ACS Pharmacology and Translational Science Pub Date : 2024-12-23 eCollection Date: 2025-01-10 DOI: 10.1021/acsptsci.4c00496
Jonas Engelhardt, Anna Klawonn, Ann-Kathrin Dobbelstein, Aliaa Abdelrahman, Johannes Oldenburg, Klaus Brandenburg, Christa E Müller, Günther Weindl
{"title":"Lipopolysaccharide-Neutralizing Peptide Modulates P2X7 Receptor-Mediated Interleukin-1β Release.","authors":"Jonas Engelhardt, Anna Klawonn, Ann-Kathrin Dobbelstein, Aliaa Abdelrahman, Johannes Oldenburg, Klaus Brandenburg, Christa E Müller, Günther Weindl","doi":"10.1021/acsptsci.4c00496","DOIUrl":"10.1021/acsptsci.4c00496","url":null,"abstract":"<p><p>Lipopolysaccharide (LPS)-neutralizing peptides are emerging as new potential therapeutic modalities to treat sepsis and skin infections. Purinergic ligand-gated ion channels (P2X receptors) play a critical role in various biological processes, including inflammation. Recent drug development efforts have significantly focused on the modulation of P2X receptors. Here, we investigated the effects of the synthetic LPS-neutralizing peptide Pep19-2.5 on human P2X receptors in cells of the innate immune system. Pep19-2.5 concentration-dependently triggered Ca<sup>2+</sup> influx, interleukin (IL)-1β, and lactate dehydrogenase (LDH) release in Toll-like receptor-stimulated human macrophages and monocytes. Ca<sup>2+</sup> influx was mediated at least partially by P2X7 receptors, and IL-1β and LDH release by P2X7 receptors, respectively. Confocal microscopy confirmed the colocalization of Pep19-2.5 with P2X7 receptors. Pep19-2.5-induced IL-1β release in primed cells was dependent on K<sup>+</sup> efflux, caspase-1, and the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein 3 inflammasome. In the presence of the P2X7 receptor agonist 2'(3')-<i>O</i>-(4-benzoylbenzoyl)adenosine-5'-triphosphate, Pep19-2.5 reduced IL-1β and LDH release. In 1321N1, astrocytoma cells stably transfected with human P2X receptors, Pep19-2.5 potently modulated P2X7 and P2X4 receptors (IC<sub>50</sub> values of 0.346 and 0.146 μM, respectively) but showed less (P2X1, P2X3) or no activity (P2X2) at other P2X receptor subtypes. Our findings underline the potential of LPS-neutralizing peptides as modulators of P2X receptors, thus expanding their applicability beyond the treatment of sepsis to the treatment of inflammatory diseases.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 1","pages":"136-145"},"PeriodicalIF":4.9,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11729421/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143013432","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
Molecular Targets and Small Molecules Modulating Acetyl Coenzyme A in Physiology and Diseases. 生理与疾病中调节乙酰辅酶A的分子靶点和小分子。
IF 4.9
ACS Pharmacology and Translational Science Pub Date : 2024-12-18 eCollection Date: 2025-01-10 DOI: 10.1021/acsptsci.4c00476
Heba Ewida, Harrison Benson, Syed Tareq, Mahmoud Salama Ahmed
{"title":"Molecular Targets and Small Molecules Modulating Acetyl Coenzyme A in Physiology and Diseases.","authors":"Heba Ewida, Harrison Benson, Syed Tareq, Mahmoud Salama Ahmed","doi":"10.1021/acsptsci.4c00476","DOIUrl":"10.1021/acsptsci.4c00476","url":null,"abstract":"<p><p>Acetyl coenzyme A (acetyl-CoA), a pivotal regulatory metabolite, is a product of numerous catabolic reactions and a substrate for various anabolic responses. Its role extends to crucial physiological processes, such as glucose homeostasis and free fatty acid utilization. Moreover, acetyl-CoA plays a significant part in reshaping the metabolic microenvironment and influencing the progression of several diseases and conditions, including cancer, insulin resistance, diabetes, heart failure, fear, and neuropathic pain. This Review delves into the role of acetyl-CoA in both physiological and pathological conditions, shedding light on the key players in its formation within the cytosol. We specifically focus on the physiological impact of malonyl-CoA decarboxylase (MCD), acetyl-CoA synthetase2 (ACSS2), and ATP-citrate lyase (ACLY) on metabolism, glucose homeostasis, free fatty acid utilization, and post-translational modification cellular processes. Additionally, we present the pathological implications of MCD, ACSS2, and ACLY in various clinical manifestations. This Review also explores the potential and limitations of targeting MCD, ACSS2, and ACLY using small molecules in different clinical settings.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 1","pages":"36-46"},"PeriodicalIF":4.9,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11729435/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143013376","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
Molecular Targets and Small Molecules Modulating Acetyl Coenzyme A in Physiology and Diseases
IF 4.9
ACS Pharmacology and Translational Science Pub Date : 2024-12-18 DOI: 10.1021/acsptsci.4c0047610.1021/acsptsci.4c00476
Heba Ewida, Harrison Benson, Syed Tareq and Mahmoud Salama Ahmed*, 
{"title":"Molecular Targets and Small Molecules Modulating Acetyl Coenzyme A in Physiology and Diseases","authors":"Heba Ewida,&nbsp;Harrison Benson,&nbsp;Syed Tareq and Mahmoud Salama Ahmed*,&nbsp;","doi":"10.1021/acsptsci.4c0047610.1021/acsptsci.4c00476","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00476https://doi.org/10.1021/acsptsci.4c00476","url":null,"abstract":"<p >Acetyl coenzyme A (acetyl-CoA), a pivotal regulatory metabolite, is a product of numerous catabolic reactions and a substrate for various anabolic responses. Its role extends to crucial physiological processes, such as glucose homeostasis and free fatty acid utilization. Moreover, acetyl-CoA plays a significant part in reshaping the metabolic microenvironment and influencing the progression of several diseases and conditions, including cancer, insulin resistance, diabetes, heart failure, fear, and neuropathic pain. This Review delves into the role of acetyl-CoA in both physiological and pathological conditions, shedding light on the key players in its formation within the cytosol. We specifically focus on the physiological impact of malonyl-CoA decarboxylase (MCD), acetyl-CoA synthetase2 (ACSS2), and ATP-citrate lyase (ACLY) on metabolism, glucose homeostasis, free fatty acid utilization, and post-translational modification cellular processes. Additionally, we present the pathological implications of MCD, ACSS2, and ACLY in various clinical manifestations. This Review also explores the potential and limitations of targeting MCD, ACSS2, and ACLY using small molecules in different clinical settings.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 1","pages":"36–46 36–46"},"PeriodicalIF":4.9,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143085389","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
Detailed Structural Elucidation of Antibody-Drug Conjugate Biotransformation Species Using High Resolution Multiple Reaction Monitoring Mass Spectrometry with Orthogonal Dissociation Methods
IF 4.9
ACS Pharmacology and Translational Science Pub Date : 2024-12-17 DOI: 10.1021/acsptsci.4c0044510.1021/acsptsci.4c00445
Junyan Yang, Hui Yin Tan, Jiaqi Yuan, Yue Huang and Anton I. Rosenbaum*, 
{"title":"Detailed Structural Elucidation of Antibody-Drug Conjugate Biotransformation Species Using High Resolution Multiple Reaction Monitoring Mass Spectrometry with Orthogonal Dissociation Methods","authors":"Junyan Yang,&nbsp;Hui Yin Tan,&nbsp;Jiaqi Yuan,&nbsp;Yue Huang and Anton I. Rosenbaum*,&nbsp;","doi":"10.1021/acsptsci.4c0044510.1021/acsptsci.4c00445","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00445https://doi.org/10.1021/acsptsci.4c00445","url":null,"abstract":"<p >Antibody-drug conjugates (ADCs) are a promising drug modality substantially expanding in both the discovery space and clinical development. Assessing the biotransformation of ADCs <i>in vitro</i> and <i>in vivo</i> is important in understanding their stability and pharmacokinetic properties. We previously reported biotransformation pathways for the anti-B7H4 topoisomerase I inhibitor ADC, AZD8205, puxitatug samrotecan, that underpin its structural stability <i>in vivo</i> using an intact protein liquid chromatography-high resolution mass spectrometry (LC-HRMS) approach. Herein, we employed a LC-high resolution multiple reaction monitoring (LC-MRM<sup>HR</sup>) approach using both collision-induced dissociation (CID) and electron-activated dissociation (EAD) methods, confirming our earlier findings. Furthermore, we were able to obtain additional detailed structural information on the biotransformation products expanding on earlier intact analyses. We also highlight the high sensitivity of LC-MRM<sup>HR</sup> for successfully identifying minor biotransformation products at low concentrations that were not detectable using the intact protein LC-HRMS workflow. Especially, EAD aided in the confirmation of biotransformation species that contain newly formed disulfide bonds due to the preferential dissociation of disulfide bonds using this method. We observed biotransformation reactions that vary between linker-payload (PL) conjugation sites on the antibody. For example, the trend toward constitutional isomerism in thio-succinimide linker hydrolysis, and the resulting positional isomers from thiol adduct formation following linker-PL deconjugation. The reported orthogonal analytical approaches highly complement and fortify the intact protein LC-HRMS data. This study sheds further light on detailed structural characterization of various ADC species and validates the proposed biotransformation pathways explaining the stability of AZD8205 <i>in vivo</i>.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 1","pages":"113–123 113–123"},"PeriodicalIF":4.9,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsptsci.4c00445","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143085153","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
Correction to "Optochemical Control of mTOR Signaling and mTOR-Dependent Autophagy". 更正“mTOR信号传导和mTOR依赖性自噬的光化学控制”。
IF 4.9
ACS Pharmacology and Translational Science Pub Date : 2024-12-17 eCollection Date: 2025-01-10 DOI: 10.1021/acsptsci.4c00714
Tianyi Wang, Kaiqi Long, Yang Zhou, Xiaoding Jiang, Jinzhao Liu, John H C Fong, Alan S L Wong, Wai-Lung Ng, Weiping Wang
{"title":"Correction to \"Optochemical Control of mTOR Signaling and mTOR-Dependent Autophagy\".","authors":"Tianyi Wang, Kaiqi Long, Yang Zhou, Xiaoding Jiang, Jinzhao Liu, John H C Fong, Alan S L Wong, Wai-Lung Ng, Weiping Wang","doi":"10.1021/acsptsci.4c00714","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00714","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.1021/acsptsci.1c00230.].</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 1","pages":"270"},"PeriodicalIF":4.9,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11729420/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143013363","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
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