ACS Pharmacology and Translational Science最新文献_第7页

Structural Insights into the Substrate Egress Pathways Explains Specificity and Inhibition of Human Glucose Transporters (GLUT1 and GLUT9) 底物输出通路的结构解释了人类葡萄糖转运蛋白（GLUT1和GLUT9）的特异性和抑制作用

IF 4.9

ACS Pharmacology and Translational Science Pub Date : 2025-05-15 DOI: 10.1021/acsptsci.5c0020910.1021/acsptsci.5c00209

Manming Xu, Jiwen Jiang, Lin Gao, Saleh O. Alyemni and Shozeb Haider*,

{"title":"Structural Insights into the Substrate Egress Pathways Explains Specificity and Inhibition of Human Glucose Transporters (GLUT1 and GLUT9)","authors":"Manming Xu, Jiwen Jiang, Lin Gao, Saleh O. Alyemni and Shozeb Haider*, ","doi":"10.1021/acsptsci.5c0020910.1021/acsptsci.5c00209","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00209https://doi.org/10.1021/acsptsci.5c00209","url":null,"abstract":"Glucose transporters (GLUTs) play critical roles in cellular energy homeostasis and substrate-specific transport. Dysfunctional mutations can cause GLUT1 deficiency syndrome, and excessive expression of GLUT1 is linked to cancer progression, while abnormal regulation of urate transport by GLUT9 is associated with hyperuricemia and gout. In this study, machine-learning-driven molecular dynamics simulations have been employed to investigate the mechanistic insights into the substrate egress pathways of GLUT1 and GLUT9, including the inhibition mechanism of GLUT9 by apigenin. Our findings reveal that intracellular helices play a crucial role in facilitating the transition from inward-closed to -open conformations in both transporters. Additionally, aromatic residues, F291 and W388 in GLUT1 and W336 and F435 in GLUT9, are identified as key mediators of conformational changes. Analysis of substrate exit pathways provides mechanistic insights into transport profiles and aligns with clinically observed mutations. Furthermore, the inhibitory effect of apigenin on GLUT9 is shown to arise from steric hindrance due to increased substrate size rather than stable interactions. These findings enhance our understanding of GLUT transporter dynamics and highlight the potential of targeting substrate pathways for therapeutic intervention.","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 6","pages":"1778–1790 1778–1790"},"PeriodicalIF":4.9,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsptsci.5c00209","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144269885","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

The Intersection of Psychedelics and Sleep: Exploring the Impacts on Sleep Architecture, Dream States, and Therapeutic Implications. 迷幻药与睡眠的交叉：探索对睡眠结构、梦境状态和治疗意义的影响。

IF 4.9

ACS Pharmacology and Translational Science Pub Date : 2025-05-15 eCollection Date: 2025-06-13 DOI: 10.1021/acsptsci.5c00234

Haojiang Zhai, Hongshuang Wang, Haohong Li, Xiaohui Wang

引用次数: 0

The Intersection of Psychedelics and Sleep: Exploring the Impacts on Sleep Architecture, Dream States, and Therapeutic Implications 迷幻药与睡眠的交叉：探索对睡眠结构、梦境状态和治疗意义的影响

IF 4.9

ACS Pharmacology and Translational Science Pub Date : 2025-05-15 DOI: 10.1021/acsptsci.5c0023410.1021/acsptsci.5c00234

Haojiang Zhai, Hongshuang Wang, Haohong Li* and Xiaohui Wang*,

引用次数: 0

Structural Insights into the Substrate Egress Pathways Explains Specificity and Inhibition of Human Glucose Transporters (GLUT1 and GLUT9). 底物输出通路的结构解释了人类葡萄糖转运蛋白（GLUT1和GLUT9）的特异性和抑制作用。

IF 4.9

ACS Pharmacology and Translational Science Pub Date : 2025-05-15 eCollection Date: 2025-06-13 DOI: 10.1021/acsptsci.5c00209

Manming Xu, Jiwen Jiang, Lin Gao, Saleh O Alyemni, Shozeb Haider

{"title":"Structural Insights into the Substrate Egress Pathways Explains Specificity and Inhibition of Human Glucose Transporters (GLUT1 and GLUT9).","authors":"Manming Xu, Jiwen Jiang, Lin Gao, Saleh O Alyemni, Shozeb Haider","doi":"10.1021/acsptsci.5c00209","DOIUrl":"10.1021/acsptsci.5c00209","url":null,"abstract":"Glucose transporters (GLUTs) play critical roles in cellular energy homeostasis and substrate-specific transport. Dysfunctional mutations can cause GLUT1 deficiency syndrome, and excessive expression of GLUT1 is linked to cancer progression, while abnormal regulation of urate transport by GLUT9 is associated with hyperuricemia and gout. In this study, machine-learning-driven molecular dynamics simulations have been employed to investigate the mechanistic insights into the substrate egress pathways of GLUT1 and GLUT9, including the inhibition mechanism of GLUT9 by apigenin. Our findings reveal that intracellular helices play a crucial role in facilitating the transition from inward-closed to -open conformations in both transporters. Additionally, aromatic residues, F291 and W388 in GLUT1 and W336 and F435 in GLUT9, are identified as key mediators of conformational changes. Analysis of substrate exit pathways provides mechanistic insights into transport profiles and aligns with clinically observed mutations. Furthermore, the inhibitory effect of apigenin on GLUT9 is shown to arise from steric hindrance due to increased substrate size rather than stable interactions. These findings enhance our understanding of GLUT transporter dynamics and highlight the potential of targeting substrate pathways for therapeutic intervention.","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 6","pages":"1778-1790"},"PeriodicalIF":4.9,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12171873/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144327099","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

Multivalent Tranexamic Acid (TXA) and Benzamidine Derivatives for Serine Protease Inhibition 多价氨甲环酸（TXA）和苯脒衍生物对丝氨酸蛋白酶的抑制作用

IF 4.9

ACS Pharmacology and Translational Science Pub Date : 2025-05-14 DOI: 10.1021/acsptsci.5c0003010.1021/acsptsci.5c00030

Tanmaye Nallan Chakravarthula, Rodrigo Santillan-Rodriguez, Ziqian Zeng, Abigail Hall, Andres Prieto Trujillo, Anushri Umesh and Nathan J. Alves*,

{"title":"Multivalent Tranexamic Acid (TXA) and Benzamidine Derivatives for Serine Protease Inhibition","authors":"Tanmaye Nallan Chakravarthula, Rodrigo Santillan-Rodriguez, Ziqian Zeng, Abigail Hall, Andres Prieto Trujillo, Anushri Umesh and Nathan J. Alves*, ","doi":"10.1021/acsptsci.5c0003010.1021/acsptsci.5c00030","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00030https://doi.org/10.1021/acsptsci.5c00030","url":null,"abstract":"Blood coagulation and fibrinolysis pathways involve many serine proteases in a careful equilibrium. Disruption of this hemostatic balance can cause life-threatening thromboembolic and bleeding disorders that require therapeutic intervention. Heterobivalent molecules synthesized with both benzamidine (active site serine protease inhibitor) and tranexamic acid (TXA, kringle/lysine-site inhibitor) of increasing dPEG linker lengths (dPEG4–dPEG36) were synthesized and analyzed for plasmin, thrombin, and tissue plasminogen activator (tPA) inhibition using soluble enzymatic substrates. Linker lengths greater than the active and lysine binding site separation achieved improved inhibition with plasmin and tPA due to multivalent subsite binding effects. Despite TXA being a weak active site inhibitor, homomultivalent TXA (PAMAM8-TXA) demonstrated strong competitive plasmin inhibition (Ki = 2.5 ± 1.8 μM) due to the statistical rebinding effect. IC50 values were also determined by assaying on physiologically relevant, fluorescently tagged, annular fibrin clots to capture the effect of kringle binding inhibition on fibrinolytic potential in the presence and absence of inhibitors.","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 6","pages":"1669–1677 1669–1677"},"PeriodicalIF":4.9,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144269698","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

High-Content Microscopy Drug Screening Platform for Regulators of the Extracellular Digestion of Lipoprotein Aggregates by Macrophages 巨噬细胞细胞外消化脂蛋白聚集体调节因子的高含量显微镜药物筛选平台

IF 4.9

ACS Pharmacology and Translational Science Pub Date : 2025-05-14 DOI: 10.1021/acsptsci.4c0067510.1021/acsptsci.4c00675

Cheng-I Jonathan Ma, Noah Steinfeld, Weixiang Alvin Wang and Frederick R. Maxfield*,

{"title":"High-Content Microscopy Drug Screening Platform for Regulators of the Extracellular Digestion of Lipoprotein Aggregates by Macrophages","authors":"Cheng-I Jonathan Ma, Noah Steinfeld, Weixiang Alvin Wang and Frederick R. Maxfield*, ","doi":"10.1021/acsptsci.4c0067510.1021/acsptsci.4c00675","DOIUrl":"https://doi.org/10.1021/acsptsci.4c00675https://doi.org/10.1021/acsptsci.4c00675","url":null,"abstract":"The recruitment of macrophages to the intima of the arteries is a critical event in atherosclerotic progression. These macrophages accumulate excessive lipid droplets and become “foam cells”, a hallmark of atherosclerosis. Most studies focus on lipid accumulation through macrophage interaction with modified monomeric low-density lipoprotein (LDL). However, in the intima, macrophages predominantly encounter aggregated LDL (agLDL), an interaction that has been studied far less. Macrophages digest agLDL and generate free cholesterol in an extracellular, acidic, and hydrolytic compartment. They form a tight seal around agLDL through actin polymerization and deliver lysosomal contents into this space in a process termed digestive exophagy. There is some evidence that inhibiting digestive exophagy to slow cholesterol accumulation in macrophages protects them from becoming foam cells and slows the progression of atherosclerotic lesions. Thus, understanding the mechanisms of digestive exophagy is critical. Here, we describe a high-content microscopy screen of a library of repurposed drugs for compounds that inhibit lysosome exocytosis during digestive exophagy. We identified many hit compounds and further characterized the effects that five of these compounds have on various aspects of digestive exophagy. In addition, three of the five compounds do not inhibit oxidized LDL-induced foam cell formation, indicating that the two pathways to foam cell formation can be targeted independently. We demonstrate that this high-content screening platform has great potential as a drug discovery tool with the ability to effectively and efficiently screen for modulators of digestive exophagy.","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 6","pages":"1567–1579 1567–1579"},"PeriodicalIF":4.9,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144269687","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

IF 4.9

ACS Pharmacology and Translational Science Pub Date : 2025-05-09

Paulo Andre Bispo Machado-Junior, Andre Lass, Julia de Bortolo, Leticia Bressan Anizelli, Mateus T. Rocha, Henrique Machado Sousa Proença, Stephanie Rubianne Silva Carvalhal, Samya Hamad Mehanna, Seigo Nagashima, Luiz Claudio Fernandes, Lucia de Noronha, Thyago Proença de Moraes and Ricardo A. Pinho*,

引用次数: 0

IF 4.9

ACS Pharmacology and Translational Science Pub Date : 2025-05-09

Nicole A. Emmons, Zeki Duman, Murat Kaan Erdal, João Hespanha, Tod E. Kippin and Kevin W. Plaxco*,

引用次数: 0

IF 4.9

ACS Pharmacology and Translational Science Pub Date : 2025-05-09

引用次数: 0

IF 4.9

ACS Pharmacology and Translational Science Pub Date : 2025-05-09

Rudolph Park, and , Chengpeng Chen*,

引用次数: 0