ACS Pharmacology and Translational Science最新文献

{"title":"Targeting Insulin Resistance in Hepatocytes: A Novel Insulin-Mimetic Agent Delivered via an Advanced Nanocarrier System","authors":"Mihaela Turtoi*,&nbsp;Mariana Deleanu,&nbsp;Maria Anghelache,&nbsp;Geanina Voicu,&nbsp;Ruxandra Anton,&nbsp;Florentina Safciuc and Manuela Calin,&nbsp;","doi":"10.1021/acsptsci.5c00483","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00483","url":null,"abstract":"<p >Hepatic insulin resistance (IR) is a key contributor to the onset and progression of type 2 diabetes mellitus (T2DM), characterized by reduced insulin sensitivity, impaired glucose uptake, decreased glycogen synthesis, and excessive lipid accumulation in hepatocytes. Many vanadium compounds exhibit promising antidiabetic properties; however, their clinical application remains limited due to concerns about toxicity. Here, we investigate the impact of our newly developed Schiff base-binuclear oxidovanadium(V) complex (abbreviated as Van) in reversing IR and elucidate its pharmacological mechanism using an <i>in vitro</i> experimental model of hepatocarcinoma (HepG2) subjected to IR (IR-HepG2). We propose incorporating Van into liposomes as a nanotherapeutic strategy to increase its cellular uptake and maximize its therapeutic effectiveness. Our data show that Van effectively reverses IR in the IR-HepG2 cell model by increasing glucose uptake, promoting glycogen synthesis, and reducing lipid accumulation. The mechanism underlying Van’s ability to reverse IR involves the inhibition of protein tyrosine phosphatase (PTP)-1B protein expression and total PTPs’ activity, leading to the activation of the insulin receptor (InsR)/protein kinase B (AKT)/glycogen synthase kinase (GSK)3αβ pathway and a reduction in glucose-6-phosphatase (G6Pase) protein expression while maintaining unchanged phosphoenolpyruvate carboxykinase (PCK1) and glucose transporter (GLUT)2 synthesis. Moreover, we demonstrate that Van can be successfully incorporated into stable negatively charged liposomes, significantly enhancing its uptake by IR-HepG2 cells and improving therapeutic efficacy compared with free Van. This study presents a novel therapeutic approach for T2DM, specifically addressing IR and offering the first proof-of-concept that Van exhibits increased efficacy when it is precisely delivered to IR cells using nanotechnology.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 9","pages":"3334–3345"},"PeriodicalIF":3.7,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145036310","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}

{"title":"Optimized Synthetic Flavonols Support Senescence Clearance and Lung Fibrosis Resolution","authors":"Jeffrey A. Meridew,&nbsp;John A. Vu,&nbsp;Daniela Chow,&nbsp;Ana Maria Diaz Espinosa,&nbsp;Namita Saraf,&nbsp;Ashley Y. Gao,&nbsp;Jair Machado Espindola-Netto,&nbsp;Sara Dresler,&nbsp;Madison G. Whaley,&nbsp;Kyoung M. Choi,&nbsp;Yong Li,&nbsp;Helene Martini,&nbsp;Eva Carmona Porquera,&nbsp;Patrick A. Link,&nbsp;Thomas M. Kollmeyer,&nbsp;Joao F. Passos,&nbsp;Marissa J. Schafer,&nbsp;Nathan K. LeBrasseur,&nbsp;Daniel J. Tschumperlin and Andrew J. Haak*,&nbsp;","doi":"10.1021/acsptsci.5c00231","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00231","url":null,"abstract":"<p >Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease with undefined etiology and minimally effective therapies. The greatest risk factor for developing IPF is aging. The central paradigm to developing antifibrotic drugs for the last half century has focused on directly targeting proliferative lung fibroblasts. However, recent high-resolution analyses of IPF patient lungs suggests disease unique populations of resident lung cells are enriched for markers of senescence. Published work by our group and others further supports that senescent cells are key drivers of fibrosis and may provide an opportunity to develop an effective antifibrotic drug. Multiple naturally derived flavonoids can selectively induce apoptosis in senescent cells (senolytic) and improve end points in models of lung fibrosis; however, these natural phytochemicals are not structurally optimized to maximize their translational potential. Inspired by this opportunity we have performed hit-to-lead studies and medicinal chemistry optimization to generate a novel synthetic flavanoid (F-4N) with ∼ 50× greater senolytic potency in vitro- compared to fisetin or quercetin, two naturally derived senolytic flavonols. Furthermore, in bleomycin injury models of lung fibrosis we have shown treatment with F-4N (10 mg/kg-30 mg/kg, daily) promotes reduced senescence burden, resolution of chronic lung fibrosis, and markers of enhanced alveolar epithelial repair.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 9","pages":"3033–3046"},"PeriodicalIF":3.7,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145036683","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}

{"title":"C-X-C Motif Chemokine 10/C-X-C Motif Chemokine Receptor 3 Signaling Induces Neural Senescence and Cognitive Impairments","authors":"Monika Patel,&nbsp;Sakesh Kumar,&nbsp;Prachi Dugam,&nbsp;Aditya Singh and Prem N Yadav*,&nbsp;","doi":"10.1021/acsptsci.5c00041","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00041","url":null,"abstract":"<p >Chemokine receptors belong to the G-protein-coupled receptor family, and emerging evidence suggests that chemokines are involved in central nervous system (CNS) aging. An increased level of CXCL10 in the CNS is reported in several neurodegenerative diseases, including Alzheimer’s disease and virus-associated dementia. We also observed significantly increased expression of CXCL10 and CXCR3 in the prefrontal cortex and hippocampus of aged C57BL/6J mice (12 and 18 month old mice). This leads us to hypothesize that CXCL10, being a component of the senescence-associated secretory phenotype, may aggravate/perpetuate the brain aging process and, finally, neurodegenerative diseases. To test this hypothesis, we administered CXCL10 (intracerebroventricular: ICV, 0.5 pg/h, 28 days) in 8-month-old C57BL/6J mice. We observed increased expression of senescent marker proteins p16^INK4a, p21^Cip1, and p53 and decreased expression of pRB in the prefrontal cortex, which was blocked by CXCR3-specific antagonist AMG487. Furthermore, chronic infusion of CXCL10 induced learning and memory deficits in the Y-maze, social recognition, contextual freeze tests, and c-FOS expression in the prefrontal cortex. To further determine the specificity of CXCL10/CXCR3 signaling, we treated the primary cortical neuron (days <i>in vitro</i>: DIV-7–8) with CXCL10 and found increased senescence in a CXCR3-dependent fashion. Using RFP-EGFP-LC3-tagged transgenic mice, we also demonstrated that CXCL10/CXCR3 signaling attenuates autophagy in primary cortical neurons. Lastly, using a c-FOS-iRFP reporter, we observed that increased CXCL10/CXCR3 signaling impairs glutamate signaling in primary cortical neurons. These results support the hypothesis that increased CXCL10/CXCR3 signaling in neurons exacerbates brain aging and could be targeted for the management of aging-associated CNS disorders.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 9","pages":"2908–2921"},"PeriodicalIF":3.7,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145036306","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}

{"title":"Toward Long-Acting Psoriasis Therapy with Phloretin-Loaded Microneedle Patches: Insights from In Vitro Patient-Derived Skin Models","authors":"Yasmine Ruel,&nbsp;Fatma Moawad,&nbsp;Emmy Jean,&nbsp;Catherine Nadeau,&nbsp;Jérôme Alsarraf,&nbsp;André Pichette,&nbsp;Jean Legault,&nbsp;Davide Brambilla and Roxane Pouliot*,&nbsp;","doi":"10.1021/acsptsci.5c00361","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00361","url":null,"abstract":"<p >Plaque psoriasis is a chronic inflammatory skin disorder characterized by excessive T lymphocyte infiltration and keratinocyte hyperproliferation, resulting in epidermal thickening. Current treatments often require lifelong administration and carry risks of systemic toxicity, limiting patient adherence. Microneedle patches represent a promising alternative, offering localized, minimally invasive, and controlled drug delivery. This study evaluates the therapeutic potential of a sustained-release microneedle patch delivering phloretin or methotrexate using a tissue-engineered human psoriatic skin model. The model was developed using keratinocytes and fibroblasts isolated from lesional skin of patients with psoriasis, preserving the disease’s genetic profile. Human T lymphocytes were incorporated to replicate the inflammatory microenvironment. This study demonstrates a significant reduction in epidermal thickness while no changes were observed in healthy skin substitutes, confirming specificity for hyperproliferative tissue. The therapeutic effect was comparable to systemic methotrexate. To assess molecular diffusion, Cy5-COOH was used as a fluorescent tracer, revealing sustained dermal and longitudinal diffusion for up to 2 weeks. These results suggest that a single application could provide extended therapeutic benefit for at least 2 weeks. This is the first study to demonstrate the efficacy of microneedle patch treatment in a human psoriatic skin model, supporting their potential as a targeted, long-acting therapy for psoriasis.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 9","pages":"3221–3239"},"PeriodicalIF":3.7,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145036485","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}

{"title":"Quinolylnitrone 23 Protects from Auditory Cell Oxidative Injury and Noise-Induced Hearing Loss","authors":"Silvia Murillo-Cuesta*,&nbsp;Julio Contreras,&nbsp;Mourad Chioua,&nbsp;Carmen García-Montoya,&nbsp;Lourdes Rodríguez-de la Rosa,&nbsp;Inés Méndez-Grande,&nbsp;Dorota G. Piotrowska,&nbsp;Iwona E. Głowacka,&nbsp;Isabel Varela-Nieto* and José Marco-Contelles,&nbsp;","doi":"10.1021/acsptsci.5c00221","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00221","url":null,"abstract":"<p >Oxidative stress is a key pathogenic mechanism in noise-induced hearing loss, occurring when the production of free radicals in the cochlea overwhelms its antioxidant defenses. Thus, antioxidant molecules, including <i>N</i>-acetyl-<span>l</span>-cysteine, acetyl-L-carnitine, resveratrol, HPN-07, and 4-OHPBN nitrones, have been explored as otoprotective agents with limited success. A novel quinolylnitrone derivative QN23 has been shown to suppress oxidative stress in ischemic stroke. In this study, we show that QN23 was not ototoxic and protected from oxidative stress both <i>in vitro</i> in the cochlear HEI-OC1 cell line and <i>in vivo</i> in mice. QN23 increased HEI-OC1 cell survival after H₂O₂-induced oxidative stress, showing better effectiveness than <i>N</i>-acetyl-<span>l</span>-cysteine. Systemic administration of QN23 in mice was well-tolerated, and significantly reduced acute auditory threshold shifts 1 day postnoise exposure. The protective effects of QN23 were dose- and time-dependent, with optimal results observed when administered twice daily for 3 days, starting 1 h prior to noise exposure. This protection was associated with the duration of the treatment. QN23 normalized the expression of cochlear genes associated with oxidative stress and inflammation, such as <i>Nrf2</i>, <i>Hmox1</i>, <i>Nqo1</i>, <i>Nlrp3</i>, <i>Tnfa</i>, <i>Il1b</i>, <i>Dusp1</i>, and <i>Kim1</i>, among others, counteracting immediate noise-induced molecular alterations. These results suggest that QN23 effectively mitigates cochlear oxidative damage and that early intervention can block critical molecular changes induced by noise, thereby preserving hearing.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 9","pages":"3007–3018"},"PeriodicalIF":3.7,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsptsci.5c00221","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145036463","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}

{"title":"Cannabinoid CB1 Receptor Activation Mitigates N-Methyl-d-aspartate Receptor-Mediated Neurotoxicity","authors":"Gemma Navarro*,&nbsp;Iu Raïch,&nbsp;Joan Biel Rebassa,&nbsp;Jaume Lillo,&nbsp;Catalina Pérez-Olives,&nbsp;Toni Capó,&nbsp;Erik Cubeles,&nbsp;Carlos A. Saura,&nbsp;Arnau Cordomí,&nbsp;Eddy Sotelo,&nbsp;Irene Reyes-Resina and Rafael Franco*,&nbsp;","doi":"10.1021/acsptsci.5c00230","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00230","url":null,"abstract":"<p >Alzheimer’s disease (AD) is characterized by synaptic dysfunction and excitotoxicity, yet effective therapeutic strategies remain limited. This study explores the functional and physical interplay between cannabinoid CB₁ receptors (CB₁Rs) and <i>N</i>-methyl-<span>d</span>-aspartate receptors (NMDARs), which are implicated in AD pathology. Using bioluminescence resonance energy transfer and imaging assays in HEK-293T cells, we demonstrate a direct interaction between CB₁R and the N1 subunit of NMDAR, supporting the formation of receptor complexes. Functional assays further reveal a bidirectional negative crosstalk: NMDA attenuates CB₁R-mediated cAMP inhibition, while CB₁R activation reduces NMDA-induced calcium influx and mitogen-activated protein kinase signaling pathway activation. This negative crosstalk suggests the existence of receptor–receptor interactions with functional consequences. Complexes of CB₁Rs and N₁ subunits of NMDARs are present in both neurons and microglia, and their expression is upregulated in response to Aβ_1–42 and in cells derived from the APP_Sw/Ind AD model mice. However, upregulation did not always correlate with stronger CB₁R–NMDAR cross-modulation, suggesting that cell-specific signalosome composition shapes the signaling outcome. Functionally, CB₁R activation confers neuroprotection: It rescues neurite loss induced by NMDA and Aβ_1–42, highlighting the therapeutic potential of modulating CB₁R–NMDAR interactions. These findings support a model in which CB₁R–NMDAR interactions, through dynamic functional cross-modulation, finely tune excitotoxic and inflammatory signaling pathways. This mechanism offers therapeutic prospects for addressing cannabinoid-glutamatergic interactions.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 9","pages":"3019–3032"},"PeriodicalIF":3.7,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsptsci.5c00230","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145036627","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}

{"title":"P2Y14 Receptor Antagonists: Piperidine Bioisosteres and Mutagenesis-Supported Molecular Modeling","authors":"Asmita Pramanik,&nbsp;Zhiwei Wen,&nbsp;Matteo Pavan,&nbsp;Siva Hariprasad Kurma,&nbsp;Tadeusz Karcz,&nbsp;Sarah A. Lewicki,&nbsp;Naili Liu,&nbsp;Tamar Demby,&nbsp;Oksana Gavrilova,&nbsp;Paola Oliva,&nbsp;Katharina S. Erlitz,&nbsp;Anna Junker,&nbsp;Young-Hwan Jung,&nbsp;Zhoumou Chen,&nbsp;Daniela Salvemini,&nbsp;Joseph Kousouros,&nbsp;Zhan-Guo Gao,&nbsp;Jonathan F. Fay* and Kenneth A. Jacobson*,&nbsp;","doi":"10.1021/acsptsci.5c00299","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00299","url":null,"abstract":"<p >The human P2Y₁₄ receptor (hP2Y₁₄R) has emerged as a promising target for inflammation and pain treatment, but its zwitterionic antagonists have low bioavailability. We extended the naphthalene-based antagonist series’ structure–activity relationship (SAR) by replacing an outward-facing piperidine moiety with small heteroaromatics. Notably, <i>C</i>-linked 1,2,3-triazol-4-yl (<b>10</b>, MRS4916) and pyrazol-3-yl (<b>11</b>, MRS4917) substitutions yielded antagonists with IC₅₀ values of 3.69 and 2.88 nM, respectively. In contrast, incorporation of a second triazole in the phenyl-triazolyl series (<b>16</b>) significantly reduced affinity. Charged phosphate groups were strategically placed at two positions of potent triazole derivative <b>7</b> to explore the ligand’s binding site vicinity and detect potential proximity to cationic side chains but neither increased affinity. Site-directed mutagenesis was used to probe the antagonist binding site vicinity. However, residues that were previously predicted to participate in the binding of antagonist <b>1</b> were found to be nonessential. Molecular dynamics based on SAR and mutagenesis identified a critical interaction between the ligand’s carboxylate and R253, defining a binding pose where the aromatic core inserts into a hydrophobic cleft between TM6 and TM7. This interaction supports a minimally orthosteric antagonist mechanism. Compound <b>11</b> demonstrated oral efficacy in reversing mechanoallodynia in mice. Additionally, a selective P2Y₁₄R agonist, 2-thiouridine-5′-<i>O</i>-(α,β-methylene)diphosphate (MRS2905), caused acute hypothermia in mice, likely via mast cell activation, while antagonists <b>1</b> and <b>11</b> had no such effect. Our study refines the P2Y₁₄R antagonist binding model and introduces new drug-like scaffolds with improved solubility and CNS penetration. This work provides a platform for future SAR optimization and virtual screening campaigns targeting P2Y₁₄R.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 9","pages":"3126–3148"},"PeriodicalIF":3.7,"publicationDate":"2025-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145036619","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}

{"title":"Comprehensive Analysis of Clinically Discontinued Compounds Using an In Vitro Secondary Pharmacology Panel to Predict Potential Safety Risks during Drug Development","authors":"Verena Albert,&nbsp;Danielle E. Skinner,&nbsp;Saloni Karnwal,&nbsp;Lauren N. Guili,&nbsp;Miguel Vazquez,&nbsp;Omar Ledezma,&nbsp;Rebecca Shaffer,&nbsp;Aura Celniker,&nbsp;Alexander De La Cruz,&nbsp;Matthew Caliendo,&nbsp;Andrew M. Hanna,&nbsp;Luciano Galdieri,&nbsp;Alastair J. King,&nbsp;Nicole B. Servant and Mirza Jahic*,&nbsp;","doi":"10.1021/acsptsci.5c00452","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00452","url":null,"abstract":"<p >In vitro secondary pharmacology remains a critical tool in pharmaceutical drug discovery for evaluating potential off-target interactions before lead candidates advance into clinical development. Its primary aim is to reduce clinical attrition caused by adverse drug reactions and enhance patient safety. A widely adopted approach involves safety pharmacological profiling across a broad panel of targets, typically focusing on a chemical series with an identified therapeutic target. Utilizing a robust high-throughput screening platform, such as SAFETY<i>scan</i>47 from Eurofins Discovery, enables the rapid identification and mitigation of potential liabilities within discovery compounds. This article highlights the utility of in vitro pharmacological profiling by comparing clinically failed drug candidates against a broader compound modality data set. By more thoroughly evaluating the data generated through SAFETY<i>scan</i>47, we aim to demonstrate how in vitro profiling can offer valuable insights during preclinical discovery, ultimately supporting patient safety and reducing clinical attrition.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 9","pages":"3314–3333"},"PeriodicalIF":3.7,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsptsci.5c00452","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145036458","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}

{"title":"Next-Generation Lipid Prodrugs Orally Deliver Tenofovir via Enhanced Chylomicron Incorporation","authors":"Hannah Beth Gold,&nbsp;Nicole Pribut,&nbsp;Esther L. Outtrim,&nbsp;Priscilla Davidson,&nbsp;Christopher M. Monaco,&nbsp;August Myers,&nbsp;Carrie Qi Sun,&nbsp;Goknil Pelin Coskun,&nbsp;Andrea Mancia,&nbsp;Yanli Yang,&nbsp;Samantha Burton,&nbsp;Areeb Aftab,&nbsp;Cindy A. Derdeyn,&nbsp;Rebecca S. Arnold,&nbsp;John A. Petros,&nbsp;Ken Liu,&nbsp;Eric J. Miller* and Dennis C. Liotta*,&nbsp;","doi":"10.1021/acsptsci.5c00237","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00237","url":null,"abstract":"<p >Lipid-derived prodrugs can enhance the oral bioavailability of therapeutic agents by promoting uptake into the lymphatic system. Chylomicrons (CMs) are lipoproteins that transport dietary lipids into the lymphatics. However, their role in the systemic distribution of orally administered lipid prodrugs remains understudied. We developed an <i>in vitro</i> assay demonstrating that human intestinal enterocyte-like cell-derived CMs incorporate lipid prodrugs, and that the efficiency of this incorporation varies as a function of the lipid promoiety. We synthesized a series of lipid prodrugs of tenofovir (TFV), an important but poorly bioavailable anti-HIV agent. These lipid prodrugs, featuring a benzyloxyglycerol (BOG) motif and/or an ω-CF₃ group, demonstrated improved metabolic stability and favorable antiviral activity <i>in vitro</i>, relative to unfunctionalized lipid conjugate TFV exalidex (TXL). Additionally, the ω-CF₃ and BOG modifications significantly increased prodrug uptake into CMs <i>in vitro</i>. Subsequent mouse pharmacokinetic (PK) studies revealed higher systemic drug levels of orally dosed ω-CF₃ BOG prodrugs relative to TXL, as well as substantially enhanced lung distribution. This study is the first to quantify drug incorporation into human intestinal enterocyte-like cell-derived CMs using LC-MS/MS. In conclusion, highly lipophilic TFV prodrugs efficiently incorporate into CMs <i>in vitro</i>, and mouse PK data is consistent with lymphatic absorption <i>in vivo</i>, providing a framework for the rational design and screening of lipid-based prodrugs for optimization of drug distribution.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 9","pages":"3047–3073"},"PeriodicalIF":3.7,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsptsci.5c00237","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145036390","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}

{"title":"Visualization of KCa3.1 Channels in Tumor Cells by Optimized Senicapoc-Bodipy Conjugates","authors":"Insa Thale,&nbsp;Joana Massa,&nbsp;Elke Naß,&nbsp;Laura Vinnenberg,&nbsp;Luca Matteo Todesca,&nbsp;Thomas Budde,&nbsp;Iván Maisuls,&nbsp;Cristian A. Strassert,&nbsp;Oliver Koch,&nbsp;Albrecht Schwab and Bernhard Wünsch*,&nbsp;","doi":"10.1021/acsptsci.5c00510","DOIUrl":"https://doi.org/10.1021/acsptsci.5c00510","url":null,"abstract":"<p >Upregulation of K_Ca3.1 channels was observed in highly aggressive tumor cells, such as non small cell lung cancer cells of the A549 line. In order to visualize K_Ca3.1 channels in these cells, novel fluorescent probes with increased polarity were designed. Key step of the synthesis was a 1,3-dipolar cycloaddition of senicapoc propargyl ether <b>4</b> with various azide substituted bodipy dyes. Due to their reduced lipophilicity and promising photophysical properties, the senicapoc-bodipy conjugates <b>7a</b> (log<i>P</i> = 4.3) and <b>16</b> (log<i>P</i> = 4.4) were able to stain K_Ca3.1 ion channels in fixed, living, and permeabilized A549–3R tumor cells. The apparent size of the observed fluorescent dots indicates labeling of single K_Ca3.1 channels. The recorded density is in good accordance with literature values. The specificity of K_Ca3.1 labeling by the senicapoc-bodipy conjugates <b>7a</b> and <b>16</b> was shown with HEK293 cells, blocking experiments and azide precursors. Subsequent staining of K_Ca3.1 ion channels with hydroxyphenyl derivative <b>16</b> and antibodies did not lead to overlapping (yellow) dots, as different states of the ion channel were stained by <b>16</b> (open state) and antibody (closed state). In patch clamp experiments, both senicapoc-bodipy conjugates <b>7a</b> and <b>16</b> reduced the current density, although less efficiently than senicapoc. MD simulations showed weaker interactions of the amide moiety of <b>16</b> with Thr250, explaining the lower channel inhibition of the open-pore blocker <b>16</b> compared to senicapoc (<b>1</b>). Due to their optimal imaging properties, high specificity, balanced lipophilicity/hydrophilicity, and sufficient water solubility, senicapoc-bodipy conjugates <b>7a</b> and <b>16</b> represent innovative diagnostic tools to image K_Ca3.1 channels.</p>","PeriodicalId":36426,"journal":{"name":"ACS Pharmacology and Translational Science","volume":"8 9","pages":"3371–3388"},"PeriodicalIF":3.7,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145036460","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}