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

J Bioinform Comput Biol. 2025 Mar 25:2550001. doi: 10.1142/S0219720025500015. Online ahead of print.

ABSTRACT

Drug repurposing is the process of identifying new clinical indications for an existing drug. Some of the recent studies utilized drug response prediction models to identify drugs that can be repurposed. By representing cell-line features as a pathway-pathway interaction network, we can better understand the connections between cellular processes and drug response mechanisms. Existing deep learning models for drug response prediction do not integrate known biological pathway-pathway interactions into the model. This paper presents a drug response prediction model that applies a graph convolution operation on a pathway-pathway interaction network to represent features of cancer cell-lines effectively. The model is used to identify potential drug repurposing candidates for Non-Small Cell Lung Cancer (NSCLC). Experiment results show that the inclusion of graph convolutional model applied on a pathway-pathway interaction network makes the proposed model more effective in predicting drug response than the state-of-the-art methods. Specifically, the model has shown better performance in terms of Root Mean Squared Error, Coefficient of Determination, and Pearson's Correlation Coefficient when applied to the GDSC1000 dataset. Also, most of the drugs that the model predicted as top candidates for NSCLC treatment are either undergoing clinical studies or have some evidence in the PubMed literature database.

PMID:40134346 | DOI:10.1142/S0219720025500015

Discov Oncol. 2025 Mar 26;16(1):396. doi: 10.1007/s12672-025-02067-4.

ABSTRACT

The nervous system plays a critical role in developmental biology and oncology, influencing processes from ontogeny to the complex dynamics of cancer progression. Interactions between the nervous system and cancer significantly affect oncogenesis, tumor growth, invasion, metastasis, treatment resistance, inflammation that promotes tumors, and the immune response. A comprehensive understanding of the signal transduction pathways involved in cancer biology is essential for devising effective anti-cancer strategies and overcoming resistance to existing therapies. Recent advances in cancer neuroscience promise to establish a new cornerstone of cancer therapy. Repurposing drugs originally developed for modulating nerve signal transduction represent a promising approach to target oncogenic signaling pathways in cancer treatment. This review endeavors to investigate the potential of repurposing neurological drugs, which target neurotransmitters and neural pathways, for oncological applications. In this context, it aims to bridge the interdisciplinary gap between neurology, psychiatry, internal medicine, and oncology. By leveraging already approved drugs, researchers can utilize existing extensive safety and efficacy data, thereby reducing both the time and financial resources necessary for the development of new cancer therapies. This strategy not only promises to enhance patient outcomes but also to expand the array of available treatments, thereby enriching the therapeutic landscape in oncology.

PMID:40133751 | DOI:10.1007/s12672-025-02067-4

Cell Biochem Biophys. 2025 Mar 26. doi: 10.1007/s12013-025-01725-2. Online ahead of print.

ABSTRACT

The kynurenine pathway (KP) plays a pivotal role in dampening the immune response in many types of cancer, including TNBC. The intricate involvement of tryptophan degradation via KP serves as a critical regulator in mediating immunosuppression in the tumor microenvironment. The key enzymes that facilitate this mechanism and contribute to tumor progression are indoleamine 2,3-dioxygenase (IDO1) and tryptophan 2,3-dioxygenase (TDO). Despite attempts to use navoximod as a dual-specific inhibitor, its poor bioavailability and lack of clinical efficacy have hampered its utility. To date, no FDA-approved drugs have advanced for dual targeting of these enzymes. Therefore, this study aimed to repurpose the approved drugs from the DrugBank database as novel IDO1/TDO inhibitors. Initially, 2588 FDA-approved compounds were screened by employing molecular docking and pharmacokinetic profiling. Subsequently, methods such as MM-GBSA calculations and machine learning based analysis precisely identified 20 potential lead compounds. The resultant compounds were then assessed for various toxicity endpoints and anticancer activity. The PaccMann server revealed potent anticancer activity, with sensitivities ranging from 0.203 to 24.119 μM against MDA-MB-231 TNBC cell lines. Alongside, the interaction profile with critical residues, strongly reinforced DB06292 (Dapagliflozin) as a compelling hit candidate. Finally, the reliability of the result was corroborated through a rigorous 200 ns molecular dynamics simulation, ensuring the stable binding of the hit against the target proteins. Considering the promising outcomes, we speculate that the proposed hit compound holds strong potential for the management of TNBC.

PMID:40133710 | DOI:10.1007/s12013-025-01725-2

Sci Rep. 2025 Mar 25;15(1):10298. doi: 10.1038/s41598-025-95372-5.

ABSTRACT

Drug repositioning utilizes existing drugs for new therapeutic applications, driven by the rapid increase in disease and drug-related data. However, organizing knowledge in this field and integrating the complex and scattered data from multiple systems into a cohesive knowledge network have become urgent problems to address. In this paper, we propose a drug repositioning model based on knowledge graph embedding. The model employs multivariate relational data to embed entities and relationships in a low-dimensional vector space. It also innovatively introduces the attention mechanism into translation and bilinear models, forming new models such as Attranse, Attdismult, and Attrescal. This model's feature extraction does not rely on a single approach, instead, it integrates multiple models and combines their screening results to enhance drug screening quality. The model's effectiveness was validated using COVID-19 data, yielding results consistent with 7 clinically approved drugs for COVID-19 treatment, indicating high accuracy in identifying new drug indications. The successful application of this model to COVID-19 suggests its potential for broader use in emerging infectious diseases and complex conditions, providing valuable insights for future drug development.

PMID:40133375 | DOI:10.1038/s41598-025-95372-5

Metabolites. 2025 Feb 27;15(3):159. doi: 10.3390/metabo15030159.

ABSTRACT

Background: Aging is characterized by shared cellular and molecular processes, and aging-related diseases might co-exist in a cluster of comorbidities, particularly in vulnerable individuals whose phenotype meets the criteria for frailty. Whilst the multidimensional definition of frailty is still controversial, there is an increasing understanding of the common pathways linking metabolic syndrome, cognitive decline, and sarcopenia, frequent conditions in frail elderly patients. Methods: We performed a systematic search in the electronic databases Cochrane Library and PubMed and included preclinical studies, cohort and observational studies, and trials. Discussion: Metabolic syndrome markers, such as insulin resistance and the triglyceride/HDL C ratio, correlate with early cognitive impairment. Insulin resistance is a cause of synaptic dysfunction and neurodegeneration. Conversely, fasting and fasting-mimicking agents promote neuronal resilience by enhancing mitochondrial efficiency, autophagy, and neurogenesis. Proteins acting as cellular metabolic sensors, such as SIRT1, play a pivotal role in aging, neuroprotection, and metabolic health. In AD, β-amyloid accumulation and hyperphosphorylated tau in neurofibrillary tangles can cause metabolic reprogramming in brain cells, shifting from oxidative phosphorylation to aerobic glycolysis, similar to the Warburg effect in cancer. The interrelation of metabolic syndrome, sarcopenia, and cognitive decline suggests that targeting these shared metabolic pathways could mitigate all the conditions. Pharmacological interventions, including GLP-1 receptor agonists, metformin, and SIRT 1 inducers, demonstrated neuroprotective effects in animals and some preliminary clinical models. Conclusions: These findings encourage further research on the prevention and treatment of neurodegenerative diseases as well as the drug-repurposing potential of molecules currently approved for diabetes, dyslipidemia, and metabolic syndrome.

PMID:40137124 | DOI:10.3390/metabo15030159

Metabolites. 2025 Feb 25;15(3):156. doi: 10.3390/metabo15030156.

ABSTRACT

BACKGROUND/OBJECTIVES: Neutrophil cells' lysis forms the extracellular traps (NETs) to counter the foreign body during insults to the body. Peptidyl arginine deiminase (PAD) participates in this process and is then released into the extracellular fluid with the lysed cell components. In some diseases, patients with abnormal function of PADs, especially PAD 4, tend to form autoantibodies against the abnormal citrullinated proteins that are the result of PAD activity on arginine side chains. Those antibodies, which are highly distinct in RA, are distinctly anti-citrullinated protein antibodies (ACPA). This study used an in-silico drug repurposing approach of FDA-approved medications to identify potential alternative medications that can inhibit this process and address solutions to the current limitations of existing therapies.

METHODS: We utilized Maestro Schrödinger as a computational tool for preparing and docking simulations on the PAD 4 enzyme crystal structure that is retrieved from RCSB Protein Data Bank (PDB ID: 4X8G) while the docked FDA-approved medications are obtained from the Zinc 15 database. The protein was bound to GSK 199-an investigational compound-as a positive control for the docked molecules. Preparation of the protein was performed by Schrödinger Protein Preparation Wizard tool. Binding pocket determination was performed by Glide software (Schrödinger Release 2021-3:Schrödinger, LLC., New York, NY, USA, 2021). and validation of molecular docking was carried out through the redocking of GSK 199 and superimposition. After that, standard and induced fit docking were performed.

RESULTS/CONCLUSIONS: Among the four obtained hits Pemetrexed, Leucovorin, Chlordiazepoxide, and Ioversol, which showed the highest XP scores providing favorable binding interactions. The induced-fit docking (IFD) results displayed the strong binding affinities of Ioversol, Pemetrexed, Leucovorin, Chlordiazepoxide in the order IFD values -11.617, -10.599, -10.521, -9.988, respectively. This research investigates Pemetrexed, Leucovorin, Chlordiazepoxide, and Ioversol as potential repurposing agents in the treatment of rheumatoid arthritis (RA) as they are identified as PAD4 inhibitors.

PMID:40137121 | DOI:10.3390/metabo15030156

Curr Issues Mol Biol. 2025 Feb 26;47(3):153. doi: 10.3390/cimb47030153.

ABSTRACT

Metastatic endometrial cancer continues to be a common cause of death as of 2024, even after maximal use of all currently available standard treatments. To address this problem of metastatic cancer generally in 2025, the drug repurposing movement within oncology identifies medicines in common general medical use that have clinical or preclinical experimental data indicating that they interfere with or inhibit a specific growth driving element identified in a given cancer. The drug repurposing movement within oncology also uses data from large scale in vitro screens of thousands of drugs, looking for simple empirical growth inhibition in a given cancer type. This paper outlines the data showing that five drugs from general medical practice meet these evidence criteria for inhibition of endometrial cancer growth, the EC5 regimen. The EC5 regimen uses the osteoporosis treatment drug, alendronate; the analgesic drug, celecoxib; the antifungal drug, itraconazole; the sleep aid, ramelteon; and the cholesterol lowering drug, simvastatin. Side effects seen with these drugs are usually minimal and easily tolerated by patients.

PMID:40136407 | DOI:10.3390/cimb47030153

mBio. 2025 Mar 26:e0020525. doi: 10.1128/mbio.00205-25. Online ahead of print.

ABSTRACT

Coccidioidomycosis or valley fever is a treatment-limited fungal infection endemic to the alkaline deserts of North and South America for which two classes of antifungals are typically used: the polyenes and the triazoles. In light of the limited usefulness of the echinocandins and a growing trend of azole resistance, it is essential that we identify novel antifungals. In this study, we have developed and optimized a screening methodology for identifying potential antifungals effective against Coccidioides spherule initials using a metabolic assay, used it to screen four diverse drug libraries with limited drug overlap, and established safety and efficacy data for a majority of the compounds, including the Broad Repurposing Hub, Prestwick Chemicals 1520, Selleck L8200 Anti-parasitic, and MedChemExpress CNS Penetrants libraries. Hits were defined as compounds with strong metabolic inhibition (≥70%), which were significantly different compared to the median plate readout (B-scores ≤ -3). We identified 30 promising hits and found 12 compounds exhibiting half-maximal inhibitory concentrations below 6 µM. Among these, oxethazaine, niclosamide ethanolamine, 10058-F4, niclosamide (NIC), and pentamidine isethionate showed synergy with amphotericin B, suggesting their potential use in combination therapy. Further assessment of lead compounds' effects on spherules was conducted by image flow cytometry. Additionally, we explored the potential to use an attenuated, Biosafety Level 2 containment mutant, C. posadasii ∆cts2/∆ard1/∆cts3 (∆T), as a surrogate model for drug screening. Overall, our findings provide a foundation for future research focused on screening and developing novel coccidioidomycosis treatments.IMPORTANCEThe antifungal treatment arsenal is especially limited against Coccidioides. Due to toxicity concerns, amphotericin B is generally reserved for triazole-recalcitrant infections. Recent laboratory susceptibility tests show an increase in fluconazole resistance, highlighting a need for new treatments. We have developed a large-scale metabolic screening assay under Biosafety Level 3 containment to identify existing drugs with novel activity against Coccidioides spherules. This drug-repurposing approach represents a convenient and cost-effective strategy to increase the available antifungals effective against these infections.

PMID:40135873 | DOI:10.1128/mbio.00205-25

J Biomol Struct Dyn. 2025 Mar 26:1-12. doi: 10.1080/07391102.2025.2483963. Online ahead of print.

ABSTRACT

Poly (ADP-ribose) polymerase 1 (PARP1) is a nuclear protein that plays a pivotal role in DNA repair and has emerged as a promising target for cancer therapy. Repurposing existing FDA-approved drugs for PARP1 inhibition offers an accelerated route to drug discovery. Here, we present an integrated approach to drug repurposing for PARP1 inhibition while utilizing an integrated approach involving structure-based virtual screening and molecular dynamics (MD) simulations. First, a curated library of 3648 FDA-approved drugs from DrugBank was screened to identify potential candidates capable of binding to the PARP1. Our study reveals a subset of drug molecules with favorable binding profiles and stable interactions within the PARP1 active site. The standout candidate, Nilotinib, was selected based on its drug profile and subjected to a detailed analysis, including interaction studies and 500 ns all-atom MD simulations. By integrating multiple computational approaches, we provide a rational framework for the selection of Nilotinib, demonstrating its PARP1 binding features and potential for therapeutic development after further experimentation. This study highlights the power of computational methods in accelerating drug repurposing efforts, offering an efficient strategy for identifying novel therapeutic options for PARP1-associated diseases.

PMID:40135853 | DOI:10.1080/07391102.2025.2483963

Int J Pharm. 2025 Mar 23:125499. doi: 10.1016/j.ijpharm.2025.125499. Online ahead of print.

ABSTRACT

Bio-inspired nanotopographical carriers have emerged as innovative cancer therapy strategies, mimicking natural processes to enhance targeted delivery and reduce systemic toxicity. This study presents the development of virus-like mesoporous silica nanoparticles (MSN) as a delivery platform for repurposed metformin (MTF) in a topical multi-stimuli responsive system for melanoma treatment. Metformin-loaded virus-like MSN (MTF-MSN) were fabricated and incorporated into a thermo-responsive gelling system. The particles were evaluated for morphology, zeta potential (ZP), particle size (PS), entrapment efficiency (EE%), Fourier-transform infrared (FT-IR) spectroscopy, MTT cytotoxicity assay, in vitro release, and in a melanoma in vivo model. The particles exhibited a spherical morphology, a zeta potential of +31.9 ± 1.45 mV, and a particle size of 197 ± 3.47 nm, ideal for skin penetration. MTF-MSN demonstrated significant antiproliferative activity against melanoma A375 cells, with lower IC50 values (192 μg/mL) compared to free MTF (>300 μg/mL). Sustained, pH-sensitive MTF release was observed over 48 h at pH 7.4 and 6 h at pH 5.5. In vivo studies showed enhanced anti-cancer efficacy of MTF-MSN, evidenced by elevated caspase-3 and Neurofibromin Type-1 (NF-1) levels, along with suppressed angiogenesis markers VEGF and NRAS. The MTF-MSN-treated group exhibited superior outcomes compared to free MTF and controls (p < 0.05). This innovative bio-inspired MTF-MSN hydrogel system optimizes MTF delivery for melanoma therapy, pioneering advancements in drug repurposing and nano-oncology.

PMID:40132769 | DOI:10.1016/j.ijpharm.2025.125499