Br J Pharmacol. 2025 Mar 28. doi: 10.1111/bph.70018. Online ahead of print.

ABSTRACT

BACKGROUND AND PURPOSE: Opioid use disorder (OUD) is a pressing public health concern marked by frequent relapse during periods of abstinence, perpetuated by negative affective states. Classical antidepressants or the currently prescribed opioid pharmacotherapies have limited efficacy to reverse the negative affect or prevent relapse.

EXPERIMENTAL APPROACH: Using mouse models, we investigated the effects of ketamine's metabolite (2R,6R)-hydroxynorketamine (HNK) on reversing conditioning to sub-effective doses of morphine in stress-susceptible mice, preventing conditioned-place aversion and alleviating acute somatic abstinence symptoms in opioid-dependent mice. Additionally, we evaluated its effects on anhedonia, anxiety-like behaviours and cognitive impairment during protracted opioid abstinence, while mechanistic studies examined cortical EEG oscillations and synaptic plasticity markers.

KEY RESULTS: (2R,6R)-HNK reversed conditioning to sub-effective doses of morphine in stress-susceptible mice and prevented conditioned-place aversion and acute somatic abstinence symptoms in opioid-dependent mice. In addition, (2R,6R)-HNK reversed anhedonia, anxiety-like behaviours and cognitive impairment emerging during protracted opioid abstinence plausibly via a restoration of impaired cortical high-frequency EEG oscillations, through a GluN2A-NMDA receptor-dependent mechanism. Notably, (2R,6R)-HNK facilitated the extinction of opioid conditioning, prevented stress-induced reinstatement of opioid-seeking behaviours and reduced the propensity for enhanced morphine self-consumption in mice previously exposed to opioids.

CONCLUSIONS AND IMPLICATIONS: These findings emphasize the therapeutic potential of (2R,6R)-HNK, which is currently in Phase II clinical trials, in addressing stress-related opioid responses. Reducing the time and cost required for development of new medications for the treatment of OUDs via drug repurposing is critical due to the opioid crisis we currently face.

PMID:40155780 | DOI:10.1111/bph.70018

Cancer Lett. 2025 Mar 26:217660. doi: 10.1016/j.canlet.2025.217660. Online ahead of print.

ABSTRACT

Medulloblastoma (MB) represents the most common malignant central nervous system tumor in childhood. The nervous system plays a critical role in the progression of MB, with interactions between the nervous system and cancer significantly influencing oncogenesis, tumor growth, invasion, stemness, and metabolism. These interactions also regulate angiogenesis, metastatic dissemination, the tumor immune microenvironment, and drug resistance. Investigating the nervous system-MB axis holds promise for identifying diagnostic markers, prognostic biomarkers, and therapeutic targets. It also provides insights into the molecular mechanisms underlying MB and informs the development of novel therapeutic strategies. This review summarizes the latest advancements in understanding the interplay between the nervous system and MB, including the role of glial cells in MB and the potential of drug repurposing targeting nervous system components for MB treatment. These findings underscore promising diagnostic and therapeutic opportunities for MB management. Additionally, we outline future research directions in neurosciences that may pave the way for innovative therapeutic approaches and deepen our understanding of this complex disease.

PMID:40154912 | DOI:10.1016/j.canlet.2025.217660

Ann Pharm Fr. 2025 Mar 26:S0003-4509(25)00047-1. doi: 10.1016/j.pharma.2025.03.005. Online ahead of print.

ABSTRACT

OBJECTIVES: The key objective of present research is to effectively treat lung cancer with repurposed celecoxib while overcoming challenges such as solubility, bioavailability, non-selectivity, and negative effects by delivering celecoxib through nanostructured lipid carriers via the parenteral route.

METHODS: Celecoxib-laden nanostructured lipid carriers were manufactured by melt-emulsification ultrasonication approach and optimized through Box-Behnken Design. The celecoxib nanostructured lipid carriers were examined for particle size, % entrapment efficiency, zeta potential, in vitro release, cytotoxicity, stability, etc. Results: The optimized celecoxib nanostructured lipid carriers displayed a % entrapment efficiency of 91.69±4.9% and particle size of 132.1±6.8 nm with a polydispersity index of 0.41±0.06, and a zeta potential of -39.1 ± 3.0 mV. Notably, celecoxib nanostructured lipid carriers exhibited better and controlled celecoxib release at phosphate buffer solution pH 6.8 than pH 7.4, revealing the tumor-targeting potential of nanostructured lipid carriers. Also, the release of celecoxib from nanostructured lipid carriers was controlled for 48 h, indicating reduced chances of systemic toxicity. The in vitro cytotoxicity against A549 cells of celecoxib nanostructured lipid carriers was 1.5-fold greater than that of pure celecoxib, confirming significant anti-lung cancer effectiveness. Further, the celecoxib-loaded nanostructured lipid carriers remained stable for twelve weeks at cold and ambient temperatures.

CONCLUSION: Thus, the given research concludes that parenteral administration of nanostructured lipid carriers could be a harmless, efficient, and novel choice to treat lung cancer using repurposed celecoxib.

PMID:40154777 | DOI:10.1016/j.pharma.2025.03.005

Cell Genom. 2025 Mar 21:100820. doi: 10.1016/j.xgen.2025.100820. Online ahead of print.

ABSTRACT

Most variants identified from genome-wide association studies (GWASs) are non-coding and regulate gene expression. However, many risk loci fail to colocalize with expression quantitative trait loci (eQTLs), potentially due to limited GWAS and eQTL analysis power or cellular heterogeneity. Population-scale single-cell RNA-sequencing (scRNA-seq) datasets are emerging, enabling mapping of eQTLs in different cell types (sc-eQTLs). Compared to eQTL data from bulk tissues (bk-eQTLs), sc-eQTL datasets are smaller. We propose a joint model of bk-eQTLs as a weighted sum of sc-eQTLs (JOBS) from constituent cell types to improve power. Applying JOBS to One1K1K and eQTLGen data, we identify 586% more eQTLs, matching the power of 4× the sample sizes of OneK1K. Integrating sc-eQTLs with GWAS data creates an atlas for 14 immune-mediated disorders, colocalizing 29.9% or 32.2% more loci than using sc-eQTL or bk-eQTL alone. Extending JOBS, we develop a drug-repurposing pipeline and identify novel drugs validated by real-world data.

PMID:40154479 | DOI:10.1016/j.xgen.2025.100820

J Infect Public Health. 2025 Mar 19;18(6):102763. doi: 10.1016/j.jiph.2025.102763. Online ahead of print.

ABSTRACT

BACKGROUND: Leprosy and tuberculosis caused by Mycobacterium leprae and Mycobacterium tuberculosis, respectively, are chronic infections with significant public health implications. While leprosy affects the skin and peripheral nerves and tuberculosis primarily targets the lungs, both diseases involve systemic immune responses. This study integrates transcriptomic analysis cheminformatics and molecular dynamics simulations to identify molecular mechanisms and potential therapeutic targets.

METHODS: Transcriptomic datasets were analyzed to identify dysregulated genes and pathways. Pathway enrichment tissue-specific and bulk RNA-seq expression analyses provided biological context. System biology networks revealed regulatory hub genes and molecular docking studies evaluated CHEMBL compounds as potential therapeutics. Molecular dynamics (MD) simulations assessed the stability of top ligand-protein complexes through RMSD RMSF and MM-GBSA free energy calculations.

RESULTS: Gene expression analysis identified 13 core dysregulated genes, including HSP90AA1 MAPK8IP3 and ZMPSTE24. Tissue-specific expression localized pivotal genes to lung tissues and immune cells with HSP90AA1 highly expressed in alveolar macrophages and epithelial cells. HSP90AA1 gene emerged as a central hub gene with 96 interactions involved in stress response pathways. Docking studies identified CHEMBL3653862 and CHEMBL3653884 with strong binding affinities (-10.16 to -12.69 kcal/mol) interacting with Asp93 and Tyr139. MD simulations confirmed binding stability with RMSD fluctuations within 2.1-3.5 Å and MM-GBSA energy values supporting ligand-protein stability.

CONCLUSION: This study identifies HSP90AA1 as a potential drug target in leprosy and tuberculosis. Findings support host-directed therapy approaches and highlight the importance of computational modeling in accelerating drug discovery. The study provides a foundation for future experimental validation, including in vitro and in vivo testing to advance drug repurposing strategies for these chronic infections.

PMID:40153981 | DOI:10.1016/j.jiph.2025.102763

Biomedicines. 2025 Mar 13;13(3):706. doi: 10.3390/biomedicines13030706.

ABSTRACT

After it has metastasized, bladder cancer, the malignant transformation of the bladder urothelium, continues to be a common cause of death after maximal use of all currently available standard treatments. To address this problem in 2025, the drug repurposing movement within oncology aims to identify medicines in common general medical care use that have data indicating that they can interfere or inhibit a growth driving element that has been identified in bladder cancer. This paper now outlines extensive preclinical data showing that four drugs from general medical practice meet these criteria-the melatonergic drug ramelteon, the antidepressant fluoxetine, the antibiotic dapsone, and the analgesic drug celecoxib. This is the UBC4 regimen, meant as a possible adjunct added to standard treatments of metastatic bladder cancer. Three factors justify a clinical pilot trial of UBC4: (1) the UBC4 drugs are usually well tolerated and carry a low risk of harm, (2) the commonly fatal outcome of bladder cancer once it has widely metastasized, plus (3) the strong preclinical database showing UBC growth inhibition by each of the individual UBC4 drugs as outlined in this paper.

PMID:40149682 | DOI:10.3390/biomedicines13030706

Antibiotics (Basel). 2025 Mar 18;14(3):315. doi: 10.3390/antibiotics14030315.

ABSTRACT

Background: Phosphoinositide 3-kinase is a potent target for cancer therapy due to its significant role in the regulation of cellular growth and proliferation. Dysregulation of the PI3k signaling cascade can constitutively activate growth pathways to trigger the progression of cancer, resulting in the development of multiple inhibitors as cancer therapeutics. Objectives: The wide array of cells expressing PI3k also include immune cells, and the inhibition of these receptors has shown promise in combating inflammation and infectious disease, a relationship we sought to examine further. Methods: We infected wild-type and PI3kγ knockout murine macrophages as well as PI3kγ inhibitor-treated THP-1 human macrophage-like cells with Staphylococcus aureus and quantified inflammation through gene expression analysis, protein secretion assays, and immunofluorescence imaging. Results: We observed that knockout of PI3kγ in murine macrophages alongside pharmacological inhibition through IPI549 treatment in THP-1 cells led to an NF-κB-driven suppression in transcription and release of inflammatory cytokines upon infection with methicillin-resistant Staphylococcus aureus. We were also able to confirm that this suppression of NF-κB translocation and subsequent decrease in inflammatory cytokine release did not compromise and even slightly boosted the bacterial killing ability. Conclusion: PI3k is primarily targeted for cancer therapies, but further exploration can also be carried out on its potential roles in treating bacterial infection.

PMID:40149125 | DOI:10.3390/antibiotics14030315

Antibiotics (Basel). 2025 Feb 25;14(3):231. doi: 10.3390/antibiotics14030231.

ABSTRACT

Background/Objectives:Streptococcus pneumoniae (S. pneumoniae) is a major pathogen causing severe infectious diseases, with an escalating issue of antimicrobial resistance that threatens the efficacy of existing antibiotics. Given the challenges in developing traditional antibiotics, drug repurposing strategies offer a novel approach to address the resistance crisis. This study aims to evaluate the antibacterial and anti-biofilm activities of the approved non-antibiotic anticancer drug carmofur against multidrug-resistant S. pneumoniae, and investigate the mechanism of action, and assess therapeutic potential in vivo. Methods/Results: Antimicrobial tests revealed that carmofur exhibited strong antibacterial activity against multidrug-resistant S. pneumoniae strains, with minimum inhibitory concentrations (MICs) ranging from 0.25 to 1 µg/mL. In the biofilm detection experiments, carmofur not only inhibited the formation of biofilms, but also effectively removed biofilms under high concentration conditions. Mechanistic studies showed that carmofur disrupted bacterial membrane permeability and decreased intracellular ATP levels. Molecular docking and dynamics simulation assays indicated that carmofur could stably bind to thymidylate synthase through hydrogen bonding and hydrophobic interactions, thereby exerting antibacterial effects. Meanwhile, carmofur was able to repress the expression of the thyA gene at the mRNA level. In a mouse infection model, the carmofur treatment group showed a reduction of approximately two log levels in bacterial load in lung tissue and blood, a significant decrease in the levels of inflammatory cytokines TNF-α and IL-6, and an improvement in survival rate to 60%. Conclusions: In summary, carmofur demonstrated significant antibacterial and anti-biofilm activities against multidrug-resistant S. pneumoniae and showed good anti-infective effects in vivo, suggesting its potential clinical application as a therapeutic agent against drug-resistant bacteria.

PMID:40149043 | DOI:10.3390/antibiotics14030231

Biol Direct. 2025 Mar 27;20(1):38. doi: 10.1186/s13062-025-00631-0.

ABSTRACT

BACKGROUND: Acute kidney injury (AKI) remains a critical condition with limited therapeutic options, predominantly managed by renal replacement therapy. The challenge of developing targeted treatments persists.

METHODS: We integrated genetic data related to druggable proteins and gene expression with AKI genome-wide association study (GWAS) findings. Based on multi-omics Mendelian randomization (MR), we identified the potential causal influence of 5,883 unique proteins and genes on AKI. We also performed using reverse MR and external cohort-based analysis to verify the robustness of this causal relationship. Expression patterns of these targets were examined using bulk transcriptome and single-cell transcriptome data. In addition, drug repurposing analyses were conducted to explore the potential of existing medications. We also constructed a molecular interaction network to explore the interplay between identified targets and known drugs.

RESULTS: Genetically predicted levels of seven proteins and twelve genes were associated with an increased risk of AKI. Of these, six targets (NCF1, TNFRSF1B, APEH, ACADSB, ADD1, and FAM3B) were prioritized based on robust evidence and validated in independent cohorts. Reverse MR showed a one-way causal relationship of targets. These targets are predominantly expressed in proximal tubular cells, endothelial cells, collecting duct-principal cells, and immune cells within both AKI-affected and normal tissues. Several promising drug repurposing opportunities were identified, such as telmisartan-NCF1, calcitriol-ACADSB, and ethinyl estradiol-ACADSB. The molecular interaction mapping and pathway integration analysis provided further insights, suggesting potential strategies for combinatorial therapies.

CONCLUSIONS: This extensive investigation identified several promising therapeutic targets for AKI and highlighted opportunities for drug repurposing. These findings offer valuable insights that could shape future research and the development of targeted treatments.

PMID:40148878 | DOI:10.1186/s13062-025-00631-0

Sci Rep. 2025 Mar 27;15(1):10606. doi: 10.1038/s41598-025-94283-9.

ABSTRACT

The 2019 pandemic of coronavirus disease (COVID-19) caused by SARS-CoV-2 led to millions of deaths worldwide since its emergence. The viral genomic material can code structural and non-structural proteins including the main protease or 3CLpro, a cysteine protease that cleavages the viral polyprotein generating 11 proteins that participate in viral pre-replication. Thus, 3CLpro is a promising therapeutic target for SARS-CoV-2 inhibition by new drugs or drug repositioning because 3CLpro is dissimilar to human proteases. We conducted in vitro assays demonstrating the modulation activity of ambenonium, a drug already used in Myasthenia gravis that acts by inhibiting the action of acetylcholinesterase, and had its potential inhibitory activity against viral replication pointed out in a previous in silico study. In concentrations of 100 µM, 50 µM, 25 µM, 10 µM, and 1 µM there was no inhibition in the formation of lysis plates, with a slight increase in the genome copy number at the higher concentrations evaluated. However, in the concentrations of 0,1 µM and 0,01 µM, there was a reduction in the number of lysis plates. This behavior suggests that the ambenonium acts as a modulator of viral activity in vitro. To investigate potential conformational changes in the protein between dimeric and monomeric forms in the presence of the compound, a local docking analysis was performed. Results indicated this conformational shift is possible, though further studies are needed to confirm these findings.

PMID:40148508 | DOI:10.1038/s41598-025-94283-9

Sci Rep. 2025 Mar 27;15(1):10563. doi: 10.1038/s41598-024-83178-w.

ABSTRACT

Despite the abundance of large-scale molecular and drug-response data, current research on early-onset Parkinson's disease (EOPD) markers often lacks mechanistic interpretations of drug-gene relationships, limiting our understanding of how drugs exert their therapeutic effects. While existing studies provide valuable EOPD markers, the mechanisms by which targeted drugs act remain poorly understood. We propose DTI-Prox, a novel workflow that identifies potentially overlooked EOPD markers and suggests relevant drug targets. DTI-Prox employs network proximity to measure how closely connected a drug and gene are within a biological network. Additionally, node similarity, which assesses the functional resemblance between network nodes, reveals meaningful drug-gene connections. DTI-Prox identifies 417 novel drug-target pairs and four previously unreported EOPD markers (PTK2B, APOA1, A2M, and BDNF), demonstrating significant pathway enrichment in neurodegenerative processes. Notably, shared pathway analysis shows that prioritized drugs such as Amantadine, Apomorphine, Atropine, Benztropine, Biperiden, Bromocriptine, Cabergoline, Carbidopa, and Citalopram, currently used for other conditions, interact with key EOPD-associated diagnostic markers, suggesting their potential for drug repurposing. The constructed functional network's validity is reinforced by statistically significant drug-target pairs. The findings provide new insights into EOPD drug mechanisms and identify promising therapeutic candidates, potentially leading to more effective, personalized treatment approaches for EOPD patients.

PMID:40148390 | DOI:10.1038/s41598-024-83178-w

Pharmacol Rev. 2025 Mar;77(2):100033. doi: 10.1016/j.pharmr.2024.100033. Epub 2024 Dec 24.

ABSTRACT

Cancer and cardiovascular disease (CVD) are the 2 biggest killers worldwide. Specific treatments have been developed for the 2 diseases. However, mutual therapeutic targets should be considered because of the overlap of cellular and molecular mechanisms. Cancer research has grown at a fast pace, leading to an increasing number of new mechanistic treatments. Some of these drugs could prove useful for treating CVD, which realizes the concept of cancer drug repurposing. This review provides a comprehensive outline of the shared hallmarks of cancer and CVD, primarily ischemic heart disease and heart failure. We focus on chronic inflammation, altered immune response, stromal and vascular cell activation, and underlying signaling pathways causing pathological tissue remodeling. There is an obvious scope for targeting those shared mechanisms, thereby achieving reciprocal preventive and therapeutic benefits. Major attention is devoted to illustrating the logic, advantages, challenges, and viable examples of drug repurposing and discussing the potential influence of sex, gender, age, and ethnicity in realizing this approach. Artificial intelligence will help to refine the personalized application of drug repurposing for patients with CVD. SIGNIFICANCE STATEMENT: Cancer and cardiovascular disease (CVD), the 2 biggest killers worldwide, share several underlying cellular and molecular mechanisms. So far, specific therapies have been developed to tackle the 2 diseases. However, the development of new cardiovascular drugs has been slow compared with cancer drugs. Understanding the intersection between pathological mechanisms of the 2 diseases provides the basis for repurposing cancer therapeutics for CVD treatment. This approach could allow the rapid development of new drugs for patients with CVDs.

PMID:40148035 | DOI:10.1016/j.pharmr.2024.100033

Eur J Pharmacol. 2025 Mar 25:177537. doi: 10.1016/j.ejphar.2025.177537. Online ahead of print.

ABSTRACT

In severe COVID-19 patients, excessive inflammation can lead to multiorgan dysfunction. Current anti-inflammatory treatments like glucocorticoids partially improve the outcomes, while immune systems are compromised. We have identified that SARS-CoV-2-infected obese mice were a good model of the cytokine storm seen in COVID-19. Here, we revealed that iguratimod (IGU), an approved agent for rheumatoid arthritis, improved survival by attenuating inflammation with minimal immune suppression. In this study, C57BL/6 mice were fed a high-fat diet (HFD) or a normal-fat diet (NFD) for ten weeks before being infected with a mouse-adapted SARS-CoV-2. IGU significantly improved survival rates and reduced lung inflammation in HFD-fed mice, with minimal impact on interferon-induced genes and viral load. Meanwhile, dexamethasone (DEX) did not improve survival, while it suppressed various immune reactions with different mechanisms to IGU. Interestingly, IGU-treated mice had fewer SARS-CoV-2 positive cells in the lung, although viral replication was comparable to the control mice. Neither IGU nor DEX inhibited the SARS-CoV-2 infection in Vero-E6 cells, unlike the antiviral agent, remdesivir. Of note, IGU was effective prophylactically and therapeutically in HFD mice, and showed beneficial effects in NFD-fed mice with a lethal dose exposure of SARS-CoV-2. We demonstrated that IGU could be a promising treatment for severe COVID-19, especially in obese patients, by fine-tuning inflammation without compromising antiviral immunity. This study supports the possibility of drug repositioning for IGU COVID-19 beyond autoimmune diseases.

PMID:40147575 | DOI:10.1016/j.ejphar.2025.177537

JMIR Form Res. 2025 Mar 27;9:e50536. doi: 10.2196/50536.

ABSTRACT

A sentiment analysis of 5051 Twitter posts from January 2022 found that 53.4% of them expressed positive views on ivermectin as a COVID-19 treatment, 35.6% of them were neutral, and 11% of them were negative, highlighting the polarized public perception and the need for careful interpretation of social media data in health communication.

PMID:40146987 | DOI:10.2196/50536

Front Microbiol. 2025 Mar 12;16:1539629. doi: 10.3389/fmicb.2025.1539629. eCollection 2025.

ABSTRACT

Chagas disease, caused by the parasite Trypanosoma cruzi, affects 6 million people worldwide. Although the drugs benznidazole (BZN) and nifurtimox are available to treat Chagas, they are not effective in the chronic phase when most patients are diagnosed. Moreover, long-term regimen and severe side effects often lead to poor adherence and treatment abandonment. These problems highlight the urgent need to develop new therapies to treat this neglected disease. Given that the antifungal drug nystatin (NYS) affects arginine uptake in yeasts, and fluctuations on arginine availability through transport processes in T. cruzi can negatively affect its viability, in this work we evaluated the potential of NYS for drug repurposing against T. cruzi. NYS inhibited arginine uptake and presented trypanocidal effect in both epimastigotes (IC50 0.17 μM) and trypomastigotes (IC50 4.90 μM). In addition, treatment of infected cells with NYS decreased the release of trypomastigotes with better efficacy than BZN (IC50s 4.83 μM and 8.60 μM, respectively) suggesting that NYS affects the progression of the intracellular life cycle. Furthermore, we observed a synergistic effect both in isolated trypomastigotes and infected cells when NYS was combined with BZN, which could enhance efficacy while improving treatment safety and adherence. As in yeasts, the mechanism of action of NYS in T. cruzi involved the plasma membrane disruption, and membrane transport processes, like amino acids and thymidine uptake, were affected prior to the disruption probably due to NYS interaction with the membrane. Drug repurposing is a recommended strategy by the World Health Organization to develop new therapeutic alternatives for neglected diseases. Our results indicate that NYS presents great potential to be repurposed as a trypanocidal drug to fight T. cruzi.

PMID:40143876 | PMC:PMC11937040 | DOI:10.3389/fmicb.2025.1539629

Front Microbiol. 2025 Mar 12;16:1539778. doi: 10.3389/fmicb.2025.1539778. eCollection 2025.

ABSTRACT

Trypanosomatids are parasites of health importance that cause neglected diseases in humans and animals. Chagas' disease, caused by Trypanosoma cruzi, affects 6-7 millions of people worldwide, mostly in Latin America, most of whom do not have access to diagnosis or treatment. Currently, there are no available vaccines, and the antiparasitic drugs used for treatment are often toxic and ineffective for the chronic stage of infection. Therefore, exploration of new therapeutic targets is necessary and highlights the importance of identifying new therapeutic options for the treatment of this disease. Trypanosomatid genes are organized and expressed in a species-specific fashion and many of their regulatory factors remain to be explored, so proteins involved in the regulation of gene expression are interesting candidates as drug targets. Previously, we demonstrated that the TbRRM1 protein from T. brucei is an essential nuclear factor involved in Pol-II transcriptional regulation. TcSR62 is a TbRRM1 orthologous protein in T. cruzi, but little is known about its function. In this study, we used molecular modeling of the RNA-binding domains of the TcSR62 protein and computational molecular docking to identify TcSR62-specific drug candidates. We identified sorafenib tosylate (ST) as a compound with trypanocidal activity. Sorafenib tosylate showed promising half-maximal inhibitory concentration (IC50) for all parasite stages in vitro. Furthermore, overexpression of TcSR62 protein led to ST-resistant parasites, suggesting that the trypanocidal effect might be due to the inhibition of TcSR62 function. These results demonstrate that ST could be repurposed as a novel drug to treat Chagas' disease.

PMID:40143855 | PMC:PMC11936972 | DOI:10.3389/fmicb.2025.1539778

Viruses. 2025 Mar 7;17(3):385. doi: 10.3390/v17030385.

ABSTRACT

The pandemic threat from newly emerging viral diseases constitutes a major unsolved issue for global health. Antiviral therapy can play an important role in treating and preventing the spread of unprecedented viral infections. A repository of compounds exhibiting broad-spectrum antiviral activity against a series of different viral families would be an invaluable asset to be prepared for future pandemic threats. Utilizing an open innovation crowd-sourcing paradigm, we were able to identify a compound class of diphenylureas that exhibits in vitro antiviral activity against multiple viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), adenovirus, dengue virus, herpes, and influenza viruses. Compound 4 among the series exhibits strong activity against dengue virus, a growing global health problem with high medical need and no approved antiviral drug. The compounds are active against SARS-CoV-2 in a primary human stem cell-based mucociliary airway epithelium model and also active in vivo, as shown in a murine SARS-CoV-2 infection model. These results demonstrate the potential of the chemical class as antivirals on the one hand and the power of open innovation, crowd-sourcing, and repurposing on the other hand.

PMID:40143313 | DOI:10.3390/v17030385

Pharmaceuticals (Basel). 2025 Mar 16;18(3):419. doi: 10.3390/ph18030419.

ABSTRACT

Hepatitis B virus (HBV) is an important global public health issue. The World Health Organization (WHO) 2024 Global Hepatitis Report estimated that the global prevalence of people living with HBV infection is 254 million, with an estimated prevalence incidence of 1.2 million new HBV infections yearly. Previous studies have shown that natural compounds have antiviral inhibition potentials. In silico methods such as molecular docking, virtual screening, pharmacophore modeling, quantitative structure-activity relationship (QSAR), and molecular dynamic simulations have been successfully applied in identifying bioactive compounds with strong binding energies in HBV treatment targets. The COVID-19 pandemic necessitated the importance of repurposing already approved drugs using in silico methods. This study is aimed at unveiling the benefits of in silico techniques as a potential alternative in natural compounds' drug discovery and repurposing for HBV therapy. Relevant articles from PubMed, Google Scholar, and Web of Science were retrieved and analyzed. Furthermore, this study comprehensively reviewed the literature containing identified bioactive compounds with strong inhibition of essential HBV proteins. Notably, hesperidin, quercetin, kaempferol, myricetin, and flavonoids have shown strong binding energies for hepatitis B surface antigen (HBsAg). The investigation reveals that in silico drug discovery methods offer an understanding of the mechanisms of action, reveal previously overlooked viral targets (including PreS1 Domain of HBsAg and cccDNA (Covalently Closed Circular DNA) regulators, and facilitate the creation of specific inhibitors. The integration of in silico, in vitro, and in vivo techniques is essential for the discovery of new drugs for HBV therapy. The insights further highlight the importance of natural compounds and in silico methods as targets in drug discovery for HBV therapy. Moreover, the combination of natural compounds, an in silico approach, and drug repurposing improves the chances of personalized and precision medicine in HBV treatment. Therefore, we recommend drug repurposing strategies that combine in vitro, in vivo, and in silico approaches to facilitate the discovery of effective HBV drugs.

PMID:40143195 | DOI:10.3390/ph18030419

Pharmaceuticals (Basel). 2025 Mar 4;18(3):364. doi: 10.3390/ph18030364.

ABSTRACT

The rising burden of fungal infections presents a significant challenge to global healthcare, particularly with increasing antifungal resistance limiting treatment efficacy. Early detection and timely intervention remain critical, yet fungal pathogens employ diverse mechanisms to evade host immunity and develop resistance, undermining existing therapeutic options. Limited antifungal options and rising resistance necessitate novel treatment strategies. This review provides a comprehensive overview of conventional antifungal agents, their mechanisms of action, and emerging resistance pathways. Furthermore, it highlights recently approved and investigational antifungal compounds while evaluating innovative approaches such as nanotechnology, drug repurposing, and immunotherapy. Addressing antifungal resistance requires a multifaceted strategy that integrates novel therapeutics, enhanced diagnostic tools, and future research efforts to develop sustainable and effective treatment solutions.

PMID:40143141 | DOI:10.3390/ph18030364

Pharmacol Res. 2025 Mar 24:107710. doi: 10.1016/j.phrs.2025.107710. Online ahead of print.

ABSTRACT

Drug-target interaction prediction is critical for drug development. Through the integration of structural and transcriptional signature information, molecules both binding to the target and inducing therapeutic activities could be found out to improve targeted drug prediction. Therefore, the approaches that integrate the two types of data are worth exploring. Here, we present an integrated method named Data Integration Oriented Repurposing Strategy (DIORS) combining molecular docking and gene-signature matching to enhance the prediction of protein-targeted drugs. The StandardScaler algorithm was selected after evaluation of five algorithms and was used in DIORS. Surface Plasmon Resonance (SPR) was used to verify the molecular affinities and cell-based assays were used to verify the activities of DIORS predicted molecules. In Piezo1-targeted molecule prediction, among the top ten predicted molecules by DIORS, four of them, namely gefitinib, rifaximin, bosutinib and vandetanib, exhibited binding affinities. In the prediction of TLR4/MD2-targeted anti-inflammatory molecules, among the top ten predicted molecules, three of them, namely enoxolone, dabrafenib and ponatinib, exhibit both high binding affinities and anti-inflammatory activities. The results demonstrated that DIORS can serve as a better approach with high performance to predict and find new targeted drugs by combining structural and signature information.

PMID:40139454 | DOI:10.1016/j.phrs.2025.107710