ACS Pharmacology and Translational Science最新文献

Amaryllidaceae Alkaloids Screen Unveils Potent Anticoronaviral Compounds and Associated Structural Determinants. 金盏花科生物碱筛选出强效抗oronaviral 化合物及相关结构决定因素。

IF 4.9

ACS Pharmacology and Translational Science Pub Date : 2024-10-30 eCollection Date: 2024-11-08 DOI: 10.1021/acsptsci.4c00424

Natacha Merindol, Luan Letieri Belem Martins, Ghada Elfayres, Alexandre Custeau, Lionel Berthoux, Antonio Evidente, Isabel Desgagné-Penix

{"title":"Amaryllidaceae Alkaloids Screen Unveils Potent Anticoronaviral Compounds and Associated Structural Determinants.","authors":"Natacha Merindol, Luan Letieri Belem Martins, Ghada Elfayres, Alexandre Custeau, Lionel Berthoux, Antonio Evidente, Isabel Desgagné-Penix","doi":"10.1021/acsptsci.4c00424","DOIUrl":"10.1021/acsptsci.4c00424","url":null,"abstract":"Betacoronaviruses encompass a spectrum of respiratory diseases, from common cold caused by the human coronavirus (HCoV)-OC43 to life-threatening severe acute respiratory syndrome (SARS)-CoV-2. Addressing the constant need for novel antiviral compounds, we turned to the exploration of 40 plant-specialized metabolites produced by the medicinal plant family Amaryllidaceae, known to produce lycorine, a strong antiviral alkaloid. The present screen included 35 alkaloids with representatives of 8 ring-type structures. Pancracine, crinamine, hemanthamine, and hemanthidine exhibited potency comparable to lycorine in blocking HCoV-OC43 replication, while amarbellisine demonstrated superior efficacy (SI = 60, EC50 = 0.2 μM). Their anticoronaviral activity was confirmed using a SARS-CoV-2 replicon system. Time-of-drug-addition experiments established that a postentry step consistent with ribonucleic acid (RNA) replication or translation was targeted. Most antiviral Amaryllidaceae alkaloids selectively induced the expression of transcripts associated with the integrated stress response. Structure-activity relationship analyses elucidated key functional groups contributing to antiviral properties in the crinine- and lycorine-type. This study reveals that Amaryllidaceae produce a diverse repertoire of promising antiviral compounds in addition to lycorine, offering insights for developing new antiviral agents.","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"7 11","pages":"3527-3539"},"PeriodicalIF":4.9,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555508/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142628484","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 "Schisandrin B Suppresses Colon Cancer Growth by Inducing Cell Cycle Arrest and Apoptosis: Molecular Mechanism and Therapeutic Potential". 更正 "五味子素 B 通过诱导细胞周期停滞和凋亡抑制结肠癌生长：分子机制和治疗潜力"。

IF 4.9

ACS Pharmacology and Translational Science Pub Date : 2024-10-28 eCollection Date: 2024-11-08 DOI: 10.1021/acsptsci.4c00580

Vanessa Anna Co, Hani El-Nezami, Yawen Liu, Bonsra Twum, Priyanka Dey, Paul A Cox, Shalu Joseph, Roland Agbodjan-Dossou, Mehdi Sabzichi, Roger Draheim, Murphy Lam Yim Wan

引用次数: 0

Understanding Comorbidities of Respiratory Models as Novel Platforms for Drug Discovery. 了解作为药物发现新平台的呼吸模型的合并症。

IF 4.9

ACS Pharmacology and Translational Science Pub Date : 2024-10-25 eCollection Date: 2024-11-08 DOI: 10.1021/acsptsci.4c00484

Simone N De Luca, Avanka Gunatilaka, Madison Coward-Smith, Henry M Gomez, Richard Y Kim, Aimee Stenekes, Stanley M H Chan, Wei Wang, Daniel Tan, Ross Vlahos, Alastair G Stewart, Chantal Donovan

{"title":"Understanding Comorbidities of Respiratory Models as Novel Platforms for Drug Discovery.","authors":"Simone N De Luca, Avanka Gunatilaka, Madison Coward-Smith, Henry M Gomez, Richard Y Kim, Aimee Stenekes, Stanley M H Chan, Wei Wang, Daniel Tan, Ross Vlahos, Alastair G Stewart, Chantal Donovan","doi":"10.1021/acsptsci.4c00484","DOIUrl":"10.1021/acsptsci.4c00484","url":null,"abstract":"Chronic respiratory diseases affect over 450 million people worldwide and result in 4 million deaths per year. The majority of lung diseases are treated with drugs delivered directly to the lungs. However, there is bidirectional crosstalk between the lung and other organs/tissues in health and disease. This crosstalk supports targeting of extrapulmonary sites in addition to the lung to improve the comorbidities associated with lung disease. However, new preclinical in vivo and in vitro assays that model the human pathophysiology are required. In this review, we showcase the latest knowledge of the bidirectional relationship between the respiratory system and organs affected by comorbidities such as obesity and atherosclerosis. We also discuss the impact of new cell culture systems, including complex 3D culture models that may be used as platforms to generate disease insights and for drug discovery. This review highlights work presented by Respiratory and Inflammation Special Interest Group researchers as part of the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists (ASCEPT) annual scientific meeting in 2023.","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"7 11","pages":"3385-3393"},"PeriodicalIF":4.9,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555503/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142629237","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

Baculovirus Expressing Tumor Growth Factor-β1 (TGFβ1) Nanoshuttle Augments Therapeutic Effects for Vascular Wound Healing: Design and In Vitro Analysis. 表达肿瘤生长因子-β1（TGFβ1）的纳米树突状芽孢杆菌病毒增强了血管伤口愈合的治疗效果：设计与体外分析。

IF 4.9

ACS Pharmacology and Translational Science Pub Date : 2024-10-25 eCollection Date: 2024-11-08 DOI: 10.1021/acsptsci.4c00509

Paromita Islam, Ahmed Abosalha, Sabrina Schaly, Jacqueline L Boyajian, Madison Santos, Stephanie Makhlouf, Editha Renesteen, Amal Kassab, Cedrique Shum-Tim, Dominique Shum-Tim, Satya Prakash

{"title":"Baculovirus Expressing Tumor Growth Factor-β1 (TGFβ1) Nanoshuttle Augments Therapeutic Effects for Vascular Wound Healing: Design and In Vitro Analysis.","authors":"Paromita Islam, Ahmed Abosalha, Sabrina Schaly, Jacqueline L Boyajian, Madison Santos, Stephanie Makhlouf, Editha Renesteen, Amal Kassab, Cedrique Shum-Tim, Dominique Shum-Tim, Satya Prakash","doi":"10.1021/acsptsci.4c00509","DOIUrl":"10.1021/acsptsci.4c00509","url":null,"abstract":"One of the major challenges in vascular tissue regeneration is effective wound healing that can be resolved by an innovative targeted nanoshuttle that delivers growth factors to blood vessels. This study investigates the production and efficacy of transforming growth factor-β1 (TGFβ1) gene delivery using poly(lactic-co-glycolic acid) (PLGA) baculovirus (BV) nanoshuttles (NSs). They exhibited an encapsulation efficiency of 86.23% ± 0.65% and a negative zeta potential of -29.57 ± 1.27 mV. In vitro studies in human umbilical vein endothelial cells (HUVECs) revealed that a 12 h incubation period optimized virus transduction. The safety and superior intracellular uptake of NSs and BVs in HUVECs were observed. The NSs carrying 100 and 400 MOI exhibited the highest cell proliferation rates in HUVECs. These sustained-release NSs significantly improved vascular cell migration and wound closure compared to free TGFβ1 carrying BV and can be a groundbreaking find in regenerative medicine, cardiovascular diseases, and chronic ulcer conditions.","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"7 11","pages":"3419-3428"},"PeriodicalIF":4.9,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555499/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142628623","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

Complex Inhibitory Activity of Pentacyclic Triterpenoids against Cutaneous Melanoma In Vitro and In Vivo: A Literature Review and Reconstruction of Their Melanoma-Related Protein Interactome. 五环三萜类化合物对体外和体内皮肤黑色素瘤的复合抑制活性：文献综述及其与黑色素瘤相关蛋白质相互作用组的重建

IF 4.9

ACS Pharmacology and Translational Science Pub Date : 2024-10-23 eCollection Date: 2024-11-08 DOI: 10.1021/acsptsci.4c00422

Arseny D Moralev, Marina A Zenkova, Andrey V Markov

{"title":"Complex Inhibitory Activity of Pentacyclic Triterpenoids against Cutaneous Melanoma In Vitro and In Vivo: A Literature Review and Reconstruction of Their Melanoma-Related Protein Interactome.","authors":"Arseny D Moralev, Marina A Zenkova, Andrey V Markov","doi":"10.1021/acsptsci.4c00422","DOIUrl":"10.1021/acsptsci.4c00422","url":null,"abstract":"Pentacyclic triterpenoids (PTs) are a class of plant metabolites with a wide range of pharmacological activities, including strong antitumor potential against skin malignancies. By acting on multiple signaling pathways that control key cellular processes, PTs are able to exert complex effects on melanoma progression in vitro and in vivo. In this review, we have analyzed the works published in the past decade and devoted to the effects of PTs, both natural and semisynthetic, on cutaneous melanoma pathogenesis, including not only their direct action on melanoma cells but also their influence on the tumor microenvironment and abberant melanogenesis, often associated with melanoma aggressiveness. Special attention will be paid to the molecular basis of the pronounced antimelanoma potency of PTs, including a detailed consideration of the pathways sensitive to PTs in melanoma cells, as well as the reconstruction of the melanoma-related protein interactome of PTs using a network pharmacology approach based on previously published experimentally verified protein targets of PTs. The information collected on the primary targets of PTs was compiled in the Protein Interactome of PTs (PIPTs) database, freely available at http://www.pipts-db.ru/, which can be used to further optimize the mechanistic studies of PTs in the context of melanoma and other malignancies. By summarizing recent research findings, this review provides valuable information to scientists working in the fields related to the evaluation of melanoma pathogenesis and development of PTs-based drug candidates.","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"7 11","pages":"3358-3384"},"PeriodicalIF":4.9,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555519/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142628804","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

Turn-Adopting Peptidomimetic as a Formyl Peptide Receptor-1 Antagonist. 作为甲酰肽受体-1 拮抗剂的转折肽类似物

IF 4.9

ACS Pharmacology and Translational Science Pub Date : 2024-10-23 eCollection Date: 2024-11-08 DOI: 10.1021/acsptsci.4c00366

Maria De Fenza, Filippo Locri, Flavia Plastino, Marco Chino, Ornella Maglio, Linda Leone, Giorgia Gazzaroli, Mirella Belleri, Arianna Giacomini, Anders Kvanta, Helder André, Vincenzo Pavone, Daniele D'Alonzo

引用次数: 0

Tat-Beclin-1 Ameliorates Memory by Improving Neuronal Cytoarchitecture and Mitigating Mitochondrial Dysfunction in Scopolamine-Induced Amnesic Male Mice. Tat-Beclin-1通过改善东莨菪碱诱导的失忆雄性小鼠的神经元细胞结构和线粒体功能障碍来改善其记忆。

IF 4.9

ACS Pharmacology and Translational Science Pub Date : 2024-10-22 eCollection Date: 2024-11-08 DOI: 10.1021/acsptsci.4c00283

Ela Mishra, Mahendra Kumar Thakur

{"title":"Tat-Beclin-1 Ameliorates Memory by Improving Neuronal Cytoarchitecture and Mitigating Mitochondrial Dysfunction in Scopolamine-Induced Amnesic Male Mice.","authors":"Ela Mishra, Mahendra Kumar Thakur","doi":"10.1021/acsptsci.4c00283","DOIUrl":"10.1021/acsptsci.4c00283","url":null,"abstract":"Mitophagy, the targeted breakdown of damaged mitochondria, plays a vital role in maintaining cellular homeostasis. As impairment of mitophagy leads to neurodegeneration and memory decline, the current study explores the therapeutic potential of an autophagy inducer Tat-Beclin-1 during scopolamine-induced amnesia. Tat-Beclin-1 improved contextual and recognition memory and also mitochondrial ultrastructure by restoring mitochondrial length and area and reducing the number of fragmented mitochondria. Tat-Beclin-1 upregulated the expression of genes associated with mitophagy (PTEN-induced kinase 1, Parkin, Lamp2, and LC3), mitochondrial fusion (Mfn1, Mfn2, and optic atrophy1), and fission (dynamin-related protein 1 and Fis1) in amnesic mice. Subsequently, these results were supported by a decreased level of p-Drp1 (S616) and Drp 1 ratios and an increased level of Mfn2, LC3BI, and BII in Tat-Beclin-1-treated mice. Moreover, Tat-Beclin-1 maintained mitochondrial membrane potential and complex I/V activity in amnesic mice. Tat-Beclin-1 enhanced myelination and diminished the activity of acetylcholinesterase and caspase-3 activity. Sholl analysis revealed augmented dendritic branching and length, elevated dendritic spine density, and upregulated the expression of synaptophysin and PSD95 proteins, indicating neuronal plasticity enhancement by Tat-Beclin-1. Thus, these findings provide valuable insights into the therapeutic potential of Tat-Beclin-1, addressing mitochondrial dysfunction to mitigate cognitive impairment associated with amnesic conditions.","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"7 11","pages":"3462-3475"},"PeriodicalIF":4.9,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555511/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142629213","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

Eugenol-Loaded Lipid Nanoparticles-Derived Hydrogels Ameliorate Psoriasis-like Skin Lesions by Lowering Oxidative Stress and Modulating Inflammation. 丁香酚负载脂质纳米颗粒衍生水凝胶通过降低氧化应激和调节炎症改善牛皮癣样皮肤病变

IF 4.9

ACS Pharmacology and Translational Science Pub Date : 2024-10-22 eCollection Date: 2024-11-08 DOI: 10.1021/acsptsci.4c00493

Roshan Keshari, Abhay Tharmatt, Mamatha M Pillai, Deepak Chitkara, Prakriti Tayalia, Rinti Banerjee, Shamik Sen, Rohit Srivastava

{"title":"Eugenol-Loaded Lipid Nanoparticles-Derived Hydrogels Ameliorate Psoriasis-like Skin Lesions by Lowering Oxidative Stress and Modulating Inflammation.","authors":"Roshan Keshari, Abhay Tharmatt, Mamatha M Pillai, Deepak Chitkara, Prakriti Tayalia, Rinti Banerjee, Shamik Sen, Rohit Srivastava","doi":"10.1021/acsptsci.4c00493","DOIUrl":"10.1021/acsptsci.4c00493","url":null,"abstract":"Psoriasis is a chronic T-cell-mediated autoimmune skin disorder characterized by excessive epidermal thickening, overproliferation of keratinocyte, disruption of epidermal cell differentiation, and increased blood vessel growth in the dermal layer. Despite the common use of corticosteroids in psoriasis treatment, their limited efficacy and numerous side effects pose significant challenges. This research introduces a promising alternative approach by encapsulating eugenol (EU) in soya phosphatidylcholine (SPC) nanoparticles (EUNPs) which showed spherical shape nanoparticles with a hydrodynamic size of approximately 200 nm, polydispersity index 0.23, encapsulation efficiency of 85% having good colloidal stability indicated by ζ-potential of -27 mV. Later on, these EUNPs were formulated into a topical hydrogel system by using Carbopol 974P (EUNPGel), which exhibited superior drug loading, enhanced release kinetics for 48 h, long-term stability, and the ability to scavenge reactive oxygen species (ROS). Furthermore, EUNPs inhibited keratinocyte proliferation, induced apoptosis, and augmented the uptake of IL-6-mediated inflammation in human keratinocyte cells. Application of EUNPs-loaded gels (EUNPGel) to imiquimod-induced psoriatic lesions demonstrated effective dermal penetration, suppressed keratinocyte hyperplasia and restored epidermal growth. This led to a remarkable reduction in the Psoriasis Area and Severity Index (PASI) score from 3.75 to 0.5 within 5 days. This novel approach enhances ROS scavenging capacity, improves cellular uptake, facilitates skin penetration and retention, reduces the activity of hyperactive immune cells, and suggests potential applications for treating other immune-related disorders such as acne and atopic dermatitis.","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"7 11","pages":"3592-3606"},"PeriodicalIF":4.9,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555504/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142629091","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 2-Aminoadenine-Based Proteolysis-Targeting Chimeras (PROTACs) as Novel Potent Degraders of Monopolar Spindle 1 and Aurora Kinases. 开发基于 2-氨基腺嘌呤的蛋白水解靶向嵌合体 (PROTAC)，作为单极纺锤体 1 和极光激酶的新型强效降解剂。

IF 4.9

ACS Pharmacology and Translational Science Pub Date : 2024-10-19 eCollection Date: 2024-11-08 DOI: 10.1021/acsptsci.4c00405

Eleni Sflakidou, Bikash Adhikari, Christos Siokatas, Elmar Wolf, Vasiliki Sarli

{"title":"Development of 2-Aminoadenine-Based Proteolysis-Targeting Chimeras (PROTACs) as Novel Potent Degraders of Monopolar Spindle 1 and Aurora Kinases.","authors":"Eleni Sflakidou, Bikash Adhikari, Christos Siokatas, Elmar Wolf, Vasiliki Sarli","doi":"10.1021/acsptsci.4c00405","DOIUrl":"10.1021/acsptsci.4c00405","url":null,"abstract":"Monopolar spindle 1 (Mps1, also known as TTK) and Aurora kinase (AURK) A and B are critical regulators of mitosis and have been linked to the progression of various cancers. Here, we report the design, synthesis, and biological evaluation of a series of PROTACs (proteolysis-targeting chimeras) targeting TTK and AURKs. We synthesized various degrader molecules based on four different 2-aminoadenine-based ligands, recruiting either cereblon or VHL as the E3-ligase. Our research showed that the nature of the linker and modification of the ligand significantly influence the target specificity and degradation efficacy. Notably, compound 19, among the most potent degraders, demonstrated robust proteasome-mediated degradation of TTK with D max of 66.5% and DC50 value (6 h) of 17.7 nM as compared to its structurally akin inhibitor control, 23. The cytotoxicity of most of the synthesized chimeras against acute myeloid leukemia cell line MV4-11 was lower than that of the corresponding parent inhibitors. However, we could also identify degraders such as 15 and 26 that induce potent AURKA degradation and display comparable antiproliferative activities to their parent compound SF1. Compound 15 degrades AURKA with low DC50 value of 2.05 nM, which is 77-fold and 21-fold more selective toward AURKB and TTK and has an EC50 value of 39 nM against cancer MV4-11 cells. Overall, the observations we made with the degrader molecules we developed can further aid in the design and development of optimized TTK or AURK degraders for cancer therapy.","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"7 11","pages":"3488-3501"},"PeriodicalIF":4.9,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555526/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142629087","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

All Blood Brain Barrier Cell Types Demonstrate Capability to Influence Differential Tenofovir and Emtricitabine Metabolism and Transport in the Brain. 所有血脑屏障细胞类型都能影响特诺福韦和恩曲他滨在大脑中的代谢和转运。

IF 4.9

ACS Pharmacology and Translational Science Pub Date : 2024-10-18 eCollection Date: 2024-11-08 DOI: 10.1021/acsptsci.4c00510

Hannah N Wilkins, Stephen A Knerler, Ahmed Warshanna, Rodnie Colón Ortiz, Kate Haas, Benjamin C Orsburn, Dionna W Williams

{"title":"All Blood Brain Barrier Cell Types Demonstrate Capability to Influence Differential Tenofovir and Emtricitabine Metabolism and Transport in the Brain.","authors":"Hannah N Wilkins, Stephen A Knerler, Ahmed Warshanna, Rodnie Colón Ortiz, Kate Haas, Benjamin C Orsburn, Dionna W Williams","doi":"10.1021/acsptsci.4c00510","DOIUrl":"10.1021/acsptsci.4c00510","url":null,"abstract":"The blood brain barrier (BBB) represents a significant obstacle in brain drug penetration that challenges efforts in the treatment of neurological disorders. Therapeutically targeting the brain requires interactions with each BBB cell type, including endothelial cells, pericytes, and astrocytes. Yet, the relative contribution of these BBB cell types to the mechanisms that facilitate brain drug disposition is not well characterized. Here, we use first-line antiretroviral therapies, tenofovir (TFV) and emtricitabine (FTC), as models to investigate the mechanisms of drug transport and metabolism at the BBB that may influence access of the drug to the brain. We evaluated regional and cell-type-specific drug metabolism and transport mechanisms using rhesus macaques and in vitro treatment of primary human cells. We report heterogeneous distribution of TFV, FTC, and their active metabolites, which cerebrospinal fluid measures could not reflect. We found that all BBB cell types possessed functional drug-metabolizing enzymes and transporters that promoted TFV and FTC uptake and pharmacologic activation. Pericytes and astrocytes emerged as pharmacologically dynamic cells that rival hepatocytes and were uniquely susceptible to modulation by disease and treatment. Together, our findings demonstrate the importance of considering the BBB as a unique pharmacologic entity rather than viewing it as an extension of the liver, as each cell type possesses distinct drug metabolism and transport capacities that contribute to differential brain drug disposition. Further, our work highlights pharmacologically active pathways at the BBB that may regulate brain drug disposition and impact therapeutic efforts to alleviate neurologic disease.","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"7 11","pages":"3626-3640"},"PeriodicalIF":4.9,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555524/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142628083","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