European Journal of Pharmaceutical Sciences最新文献

{"title":"Linker modifications in radiolabeled RM26-based antagonists to gastrin-releasing peptide receptor (GRPR) improved tracers’ pharmacokinetics","authors":"Ekaterina Bezverkhniaia ,&nbsp;Ayman Abouzayed ,&nbsp;Panagiotis Kanellopoulos ,&nbsp;Vladimir Tolmachev ,&nbsp;Ulrika Rosenström ,&nbsp;Anna Orlova","doi":"10.1016/j.ejps.2025.107325","DOIUrl":"10.1016/j.ejps.2025.107325","url":null,"abstract":"<div><div>Radionuclide targeting of gastrin-releasing peptide receptor (GRPR) holds significant diagnostic and therapeutic potential, particularly in PSMA-negative/low-grade prostate cancer, estrogen receptor-positive breast cancer, and other malignancies. Recently, our group reported the development and results of the Phase I clinical evaluation of [^99mTc]Tc-maSSS-PEG2-RM26, an antagonist GRPR-targeting SPECT imaging agent. This study focuses on developing the next generation of RM-26-based GRPR antagonists with enhanced metabolic stability and improved pharmacokinetics. Four new RM-26-based agents containing sarcosine (Sar) at position 11 to improve the in vivo stability and with more hydrophilic linkers were designed: Pep1 – maSSS-PEG2-[Sar¹¹]RM26, Pep2 – maSSS-PEG6-[Sar¹¹]RM26, Pep3 – maSSS-PEG2-Pip-[Sar¹¹]RM26, and Pep4 – maSSS-EEE-[Sar¹¹]RM26. These analogs were compared both in vitro and in vivo with [^99mTc]Tc-maSSS-PEG2-RM26 as a reference. In PC-3 cells, [^99mTc]Tc-Pep1, [^99mTc]Tc-Pep2 and [^99mTc]Tc-Pep3, but not [^99mTc]Tc-Pep4, specifically bound to GRPR and exhibited low nanomolar affinity. When compared in vivo, [^99mTc]Tc-Pep1, [^99mTc]Tc-Pep2, and [^99mTc]Tc-Pep3 demonstrated rapid blood clearance with different degrees of hepatobiliary excretion, particularly [^99mTc]Tc-Pep2 and [^99mTc]Tc-Pep3 had significantly lower activity uptake in the liver and gastrointestinal tract compared to [^99mTc]Tc-maSSS-PEG2-RM26. Both [^99mTc]Tc-Pep2 and [^99mTc]Tc-Pep3 showed improved metabolic stability, bound specifically to GRPR in vivo, and demonstrated a tendency (not statistically significant) for higher tumor activity uptake compared to the reference peptide. Biodistribution data were confirmed by SPECT/CT imaging. In conclusion, the analogs with an elongation of the PEG2-linker either up to PEG6 (Pep2) or with the addition of a basic piperidine-containing moiety (Pep3) demonstrated an improvement of the pharmacokinetic properties of these agents and justify further investigations.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"215 ","pages":"Article 107325"},"PeriodicalIF":4.7,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145299324","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of nonsense genetic variants on OATP1B1 expression and transport activity in vitro","authors":"Wilma Kiander ,&nbsp;Hatam Rashidpour ,&nbsp;Mikko Gynther ,&nbsp;Kati-Sisko Vellonen ,&nbsp;Mikko Neuvonen ,&nbsp;Laura Vesalainen ,&nbsp;Kristiina M. Huttunen ,&nbsp;Mikko Niemi ,&nbsp;Heidi Kidron","doi":"10.1016/j.ejps.2025.107322","DOIUrl":"10.1016/j.ejps.2025.107322","url":null,"abstract":"<div><div>Organic anion transporting polypeptide 1B1 (OATP1B1, encoded by <em>SLCO1B1</em>) is an influx transporter expressed in the basolateral membrane of hepatocytes, playing a key role in the hepatic uptake and clearance of various drugs and endogenous compounds from the plasma. Single nucleotide variants in the <em>SLCO1B1</em> gene have been shown to alter plasma drug concentration by affecting transporter activity. Furthermore, several variants leading to premature termination of translation have been observed, together with loss-of-function <em>SLCO1B3</em> variants, in patients with Rotor syndrome. In this study, we investigated whether selected nonsense variations (c.757C&gt;T, c.1738C&gt;T, c.1877T&gt;A, c.1905–1909del, c.1925–1929del, c.1929–1932del, c.1928T&gt;G, c.1968dup, c.1976C&gt;G) affect the transport activity and membrane expression of OATP1B1. HEK293 cells were transduced with baculovirus constructs carrying either a variant or reference <em>SLCO1B1</em> sequence and the uptake of 2′,7′-dichlorofluorescein or rosuvastatin was measured. Protein abundance was measured using a quantitative targeted absolute proteomics approach. Compared to reference OATP1B1, the c.1968dup and c.1976C&gt;G variants, located near the C-terminus, retained 30–40 % of transport activity. In contrast, the remaining variants, located before or in the last transmembrane helix, resulted in complete loss of OATP1B1 function. Furthermore, all variants reduced OATP1B1 expression in the cell membranes. These results suggest that most nonsense variants result in a loss of OATP1B1 activity, but those located in the C-terminal loop may retain some activity. Moreover, carriers of the studied variants may exhibit increased plasma concentrations of OATP1B1 substrates.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"215 ","pages":"Article 107322"},"PeriodicalIF":4.7,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145285775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety and pharmacokinetics of escalating doses of recombinant human nerve growth factor eye drops (HT006.2.2) in healthy subjects","authors":"Yuyang Dai ,&nbsp;Feng Wu ,&nbsp;Hongyan Pang ,&nbsp;Siyang Ni ,&nbsp;Xiaojun Hu ,&nbsp;Ying Jiao ,&nbsp;Huan Lu ,&nbsp;Ying Han ,&nbsp;Wei Yu ,&nbsp;Huadong Tang ,&nbsp;Ying Jie ,&nbsp;Laichun Lu","doi":"10.1016/j.ejps.2025.107314","DOIUrl":"10.1016/j.ejps.2025.107314","url":null,"abstract":"<div><h3>Background</h3><div>HT006.2.2 is a kind of recombinant human nerve growth factor (rhNGF) eye drop with the potential to treat neurotrophic keratitis.</div></div><div><h3>Objective</h3><div>To evaluate the safety, immunogenicity, and pharmacokinetic (PK) characteristics of HT006.2.2 eye drops in Chinese healthy volunteers.</div></div><div><h3>Methods</h3><div>This study was divided into three parts. In Part A (single-dose) and Part B (multi-dose), four dose groups were per-specified: 5 µg/mL, 20 µg/mL, 60 µg/mL and 120 µg/mL. Each dose group comprised eight subjects randomized in a 3:1 ratio to receive the HT006.2.2 or placebo. Serum samples were collected for systemic PK analysis and anti-drug antibody (ADA) detection. The Part C comprised two single-dose groups (20 µg/mL and 60 µg/mL), and tear samples were collected at preset time points for tear fluid PK analysis. The drug mass per gram of tears (unit: µg/g) was calculated and used as the drug concentration to recalculate the PK parameters. Safety was evaluated via vital signs monitoring, 12-lead electrocardiogram, clinical laboratory tests, and ophthalmologic assessments (ocular symptoms and signs, slit-lamp microscopy, corneal fluorescein sodium staining, intraocular pressure measurement, and best-corrected visual acuity). Adverse events were collected following the initial administration of the investigational drug and were defined as treatment-emergent adverse events (TEAEs).</div></div><div><h3>Results</h3><div>This study enrolled a total of 163 subjects, with 161 receiving the medication and completing the study as planned. HT006.2.2 showed favorable tolerance across both single-dose and multiple-dose parts. At the highest dose of 120 µg/mL, no maximum tolerated dose (MTD) was reached. No discernible dose-response relationship was identified in the incidence of TEAEs across dosage groups, with the total TEAE rate in HT006.2.2 groups remaining non-exceeding that of the placebo group. Ocular TEAEs included corneal vital dye staining, eye itching, eye pain, conjunctival hyperemia, and decreased visual acuity. In addition, no HT006.2.2 or ADA was detected in the peripheral blood of healthy subjects. Tear fluid PK analysis of HT006.2.2 (20 µg/mL) showed time to peak concentration (T_max) of 0.17 h, mean peak concentration (C_max) of 3.63 ± 2.06 µg/g, elimination half-life (t_1/2) of 4.21 h.</div></div><div><h3>Conclusions</h3><div>HT006.2.2 eye drops exhibited favorable safety in Chinese healthy subjects, with localized ocular distribution, no systemic exposure, and no detectable ADAs. These findings support the continuation of clinical development for HT006.2.2 in China.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"215 ","pages":"Article 107314"},"PeriodicalIF":4.7,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145274296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pearls of bioequivalence & biopharmaceutics award 2026 presented by EUFEPS on initiative and funding by the Frankfurt Foundation Quality of Medicines (FFQM)","authors":"","doi":"10.1016/j.ejps.2025.107261","DOIUrl":"10.1016/j.ejps.2025.107261","url":null,"abstract":"","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"214 ","pages":"Article 107261"},"PeriodicalIF":4.7,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145321200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety, tolerability, and pharmacokinetics of 4-fluoroetomidate (NH600001) in healthy subjects: a first-in-human, randomised, controlled, phase I study","authors":"Yuanyuan Sun ,&nbsp;Jie Huang ,&nbsp;Kaiming Duan ,&nbsp;Yaqi Lin ,&nbsp;Qian Wu ,&nbsp;Jinlian Xie ,&nbsp;Can Guo ,&nbsp;Yajie Cao ,&nbsp;Ling Ye ,&nbsp;Shuang Yang ,&nbsp;Saiying Wang ,&nbsp;Guo-Ping Yang","doi":"10.1016/j.ejps.2025.107317","DOIUrl":"10.1016/j.ejps.2025.107317","url":null,"abstract":"<div><h3>Background</h3><div>NH600001 (formerly EL-0052) is a novel 4-fluoroetomidate formulated as a lipid emulsion. This first-in-human, randomized, double-blind, placebo-controlled, single-ascending-dose trial aimed to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of NH600001.</div></div><div><h3>Methods</h3><div>Eighty-eight healthy volunteers were randomized into seven dose cohorts (0.04–0.40 mg/kg). Each cohort included NH600001, placebo, and etomidate as an active comparator. The injectable emulsion was administered as a single, 10 mL intravenous dose over one minute using a syringe pump. Safety was assessed by clinical evaluations, laboratory tests, electrocardiography, and treatment-emergent adverse events (TEAEs). Plasma drug concentrations were measured for PK analysis, and bispectral index (BIS), modified observer assessment of alertness/sedation (MOAA/S), and eyelash reflex were used as PD indicators.</div></div><div><h3>Results</h3><div>Of 88 participants, 58 received NH600001, 16 received etomidate, and 14 received placebo. A total of 57 subjects (64.8 %) reported 130 TEAEs, most of which were mild; no serious adverse events were reported. TEAE incidence was 62.1 % in the NH600001 group, 81.3 % in the etomidate group, and 57.1 % in the placebo group. NH600001 did not induce adrenocortical suppression, in contrast to etomidate. Across the dose groups, the mean time to maximum plasma concentration (T_max) ranged from 2.5 ± 0.9 to 3.9 ± 3.3 min, while the mean terminal half-life (t_1/2) ranged from 4.9 to 38.6 h. A linear dose–exposure relationship was observed for area under the concentration–time curve from zero to infinity (AUC_0–∞) and to the last quantifiable concentration (AUC_0–t) across 0.04–0.40 mg/kg. At 0.26 mg/kg, NH600001 produced anesthetic onset (1.8 min) and duration (4.9 min) comparable to 0.30 mg/kg etomidate.</div></div><div><h3>Conclusions</h3><div>NH600001 demonstrated favorable safety and tolerability, with reduced adrenocortical suppression compared to etomidate. Doses of 0.20–0.30 mg/kg are supported for further clinical development. These findings suggest NH600001 may offer a promising alternative to etomidate by preserving anesthetic efficacy while minimizing endocrine adverse effects.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"215 ","pages":"Article 107317"},"PeriodicalIF":4.7,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145274239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of temperature on the aggregation of an Fc-fusion protein under agitation","authors":"Zekun Wang ,&nbsp;Arni Gambe-Gilbuena ,&nbsp;Satoru Unzai ,&nbsp;Susumu Uchiyama ,&nbsp;Tetsuo Torisu","doi":"10.1016/j.ejps.2025.107320","DOIUrl":"10.1016/j.ejps.2025.107320","url":null,"abstract":"<div><div>Mitigating protein aggregation remains a challenge in the development of biopharmaceuticals, and agitation is well known as a stress that can induce protein aggregation. However, the temperature dependence of agitation-induced aggregation is not well understood. In this study, the aggregation of an Fc-fusion protein under agitation stress was investigated at 5, 25, and 40 °C. Soluble and insoluble aggregates were quantified by size-exclusion liquid chromatography and flow imaging microscopy, respectively. Both the aggregation level and the aggregate clusters were temperature dependent. The threshold for the orbital shaking that induced protein aggregation was temperature independent. Although thermal stress at 40 °C increased the number of oligomers, it did not lead to a higher monomer loss in a subsequent agitation at 25 °C. The aggregation induced by agitation stress was suppressed by adding a surfactant or removing the vial headspace, indicating that the aggregation occurred via an interface-mediated pathway. Thus, the observed temperature dependence was attributed to the protein adsorption to the interface and the following interfacial unfolding and aggregation was affected by the temperature. The results emphasized the importance of temperature control during shipping to ensure the quality of drug products. Agitation stability studies at a controlled temperature also provide a deep understanding of the protein aggregation mechanism, which is important for formulation development.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"215 ","pages":"Article 107320"},"PeriodicalIF":4.7,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145279306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High-fidelity prediction of drug solubility in supercritical CO₂ for pharmaceutical applications using advanced computational modeling","authors":"Hashem O. Alsaab ,&nbsp;Saeed Shirazian","doi":"10.1016/j.ejps.2025.107321","DOIUrl":"10.1016/j.ejps.2025.107321","url":null,"abstract":"<div><div>Accurately estimating the solubility of drugs in supercritical carbon dioxide (SC<img>CO₂) still represents a major difficulty in drug formulation, separation processes, and green technologies. Traditional empirical and semi-empirical methods usually have a hard time representing the complex non-linear interactions that determine solubility under different thermodynamic conditions (e.g., T and P), which, in turn, restricts their applicability and predictive consistency. This study presents an ensemble framework that combines three machine learning regressors, namely, Extreme Gradient Boosting Regression (XGBR), Light Gradient Boosting Regression (LGBR), and CatBoost Regression (CATr), facilitated by two bio-inspired optimization algorithms, the Artificial Protozoa Optimizer (APO) and the Hippopotamus Optimization Algorithm (HOA) for estimation of pharmaceutical solubility in supercritical CO₂. A dataset of 110 experimental samples reflecting the temperature, pressure, molecular weight (MW), and melting point (MP) of four drugs (Rifampin, Sirolimus, Tacrolimus, and Teriflunomide) was used to model their solubility. Model robustness was ensured through k-fold cross-validation, and interpretability was assessed via SHAP and FAST sensitivity analysis. Additionally, prediction intervals were generated using bootstrapping, enhancing reliability for real-world applications. The ensemble (XGBR + LGBR + CATr optimized by HOA) achieved predictive accuracy (R² = 0.9920, RMSE = 0.08878). The results highlight the potential of optimized ensemble learning in capturing non-linear solubility behaviors, offering a reliable computational framework for pharmaceutical engineering and green drug processing.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"215 ","pages":"Article 107321"},"PeriodicalIF":4.7,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145279243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The impact of cyclodextrin architecture and charge for optimized nucleic acid delivery: A comparison of monomers, dimers, and polymers","authors":"Ayse Kont ,&nbsp;Monique C.P. Mendonça ,&nbsp;Milo Malanga ,&nbsp;Kristof Felegyi ,&nbsp;Andrew J. Lindsay ,&nbsp;Michael F. Cronin ,&nbsp;Mary R. Cahill ,&nbsp;Caitriona M. O’Driscoll","doi":"10.1016/j.ejps.2025.107316","DOIUrl":"10.1016/j.ejps.2025.107316","url":null,"abstract":"<div><div>Cyclodextrins (CDs) are cyclic oligosaccharides that offer a highly tuneable platform for drug delivery applications, owing to their unique toroidal architecture and modifiable primary and secondary hydroxyl groups. Due to these distinctive features, CDs have emerged as promising non-viral vectors for the delivery of nucleic acid therapeutics, including antisense oligonucleotides (ASOs) and small interfering RNA (siRNA). In this study, we evaluate and compare the physicochemical and biological performance of β-cyclodextrin (β-CD)-based monomer, dimers and cationic polymers engineered for siRNA delivery. The constructs include a head-to-head β-CD dimer linked via a triazole moiety, as well as two β-CD-based polymers functionalized with either quaternary ammonium (QA-polymer) or primary amine (PA-polymer) groups, with degrees of substitution of 3.5 and 7, respectively, for the cationic functionalities. Although the monomer and dimer did not show siRNA complexation under the tested conditions, both QA- and PA-polymers efficiently complexed siRNA, as confirmed by agarose gel, forming stable nanoparticles (NPs) in the 150–200 nm size range at polymer:siRNA mass ratios (MR) of 5:1, 7.5:1, and 10:1. Dynamic light scattering (DLS) revealed narrow size distributions (150 – 200 nm, PDI 0.2 for QA-polymer-NP and 0.4 for PA-polymer-NP) and zeta potentials in the range of 26–37 mV, indicating favourable colloidal stability. Long-term storage at 4 °C and freeze-drying (without the use of cryoprotectants) followed by resuspension demonstrated superior stability of PA-polymer NPs compared to their QA-polymer counterparts. <em>In vitro</em> evaluation, using A549-luciferase (A549luc) lung carcinoma cells showed that both polymeric carriers were non-toxic at working concentrations (20 pmol siRNA/well), maintaining ≥80 % cell viability as demonstrated by CellTiter-Fluor™ Cell Viability Assay. Cellular uptake studies with flow cytometry indicated minimal internalization for the QA-polymer, whereas the PA-polymer achieved up to 40 % uptake, resulting in approximately 40 % gene knockdown, as assessed by ONE-Glo™ EX Luciferase Assay. These findings underscore the influence of polymer architecture and surface charge chemistry on cellular interaction and gene silencing efficiency, with the enhanced performance of the PA-polymer potentially attributable to its protonatable amines and their capacity to promote endosomal escape.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"214 ","pages":"Article 107316"},"PeriodicalIF":4.7,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145268283","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An integrated deep learning model accelerates luciferase based high throughput drug screening.","authors":"Xiaonan Zhang, Xinxin Zhang, Shuang Wang, Qiaoling Song, Hang Xu, Minghui Zhang, Xudong Zhang, Hao Xie, Jing Xu, Ying Zhang, Jiayi Yin, Qingyu Tian, Xiaochun Liu, Yue Zhong, Wei He, Changming Dong, Mingming Zhou, Wenting Wang, Xiaohan Xu, Lewei Wang, Meng Zhang, Xiaoyu Li, Jinbo Yang, Tao Song, Chunhua Lin","doi":"10.1016/j.ejps.2025.107315","DOIUrl":"https://doi.org/10.1016/j.ejps.2025.107315","url":null,"abstract":"<p><p>High-throughput screening presents clear advantages in accelerating drug development efficiency, but also faces challenges such as high costs, time-consuming processes, and labor-intensive procedures. To address these issues, we developed an integrated deep learning model to find patterns between the structural and molecular characteristics of compounds and our well-established luciferase based HTS values. We utilized about 100,000 HTS values from 18,840 compounds in five luciferase assays including STAT&NFκB system, PPAR system, P53 system, WNT system, and HIF system. Following AI-prediction for putative targeted hit compounds from 8,713 compounds, the in vitro and in vivo experimental validation was performed, and drug candidates (inhibitors or activators) with anti-inflammatory, anti-tumor or anti-metabolic syndrome were identified. T4230 exerts its anti-inflammatory effects by inhibiting the expression of inflammatory factors. The classification performance of the compounds after the joint screening exceeded the performance of the respective sub-models when screened independently and the screening accuracy and efficiency improved 7.08 to 32.04-fold across these five systems compared to our conventional HTS. The integrated AI-conducted HTS model we have developed could reduce R&D costs and accelerate the drug development process, making it a valuable referential pipeline for the artificial intelligence accelerated specific signaling pathway-luciferase HTS.</p>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":" ","pages":"107315"},"PeriodicalIF":4.7,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145257652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SARS-CoV-2 N7-methyltransferase inhibitors: Towards selective and potent antivirals","authors":"Katarina Sujova,&nbsp;Vladimir Frecer","doi":"10.1016/j.ejps.2025.107312","DOIUrl":"10.1016/j.ejps.2025.107312","url":null,"abstract":"<div><div>Recent studies have identified nsp14 <em>N7</em>-methyltransferase (<em>N7</em>-MTase) as a promising therapeutic target for the development of new antiviral agents against SARS-CoV-2. Utilising <em>S</em>-adenosyl-L-methionine (SAM) as a methyl donor, <em>N7</em>-MTase mediates the first methylation step in viral RNA capping, which is necessary for the replication of SARS-CoV-2 and its immune evasion. To design selective and potent inhibitors of CoV nsp14 <em>N7</em>-MTase, various research groups have focused on targeting the nsp14 binding site for SAM. In this paper, promising CoV <em>N7</em>-MTase inhibitors designed to date are analysed with a particular focus on SAM/<em>S</em>-adenosyl-L-homocysteine (SAH) analogues, which can be further extended to occupy the RNA binding site and/or the adjacent lateral cavity. The structure-activity relationship (SAR) data and binding modes of the inhibitors are also investigated. This study highlights limitations that currently hinder the development of effective antiviral agents, notably limited selectivity and cellular activity, and discusses potential strategies to address them. In particular, the design of <em>C</em>-nucleosides has shown promising results, although no inhibitor has reached clinical trials yet. Thus, further efforts are necessary to identify viable drug candidates.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"214 ","pages":"Article 107312"},"PeriodicalIF":4.7,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145250524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}