Ageing Res Rev. 2025 Feb 15:102693. doi: 10.1016/j.arr.2025.102693. Online ahead of print.

ABSTRACT

Repurposing the existing drugs for the management of both common and rare diseases is increasingly appealing due to challenges such as high attrition rates, economic, and the slow pace of discovering and improving new drugs. Drug repurposing involves the utilization of existing medications to treat diseases for which they were not originally intended. Despite encountering scientific and economic challenges, the pharmaceutical industry is intrigued by the potential to uncover new indications for medications. Medication repurposing is applicable across different stages of drug development, with the greatest potential observed when the drug has undergone prior safety testing. In this review, strategies for repurposing drugs for Parkinson's disease (PD) are outlined, a neurodegenerative disorder predominantly impacting dopaminergic neurons in the substantia nigra pars compacta region. PD is a debilitating neurodegenerative condition marked by an amalgam of motor and non-motor symptoms. Despite the availability of certain symptomatic treatments, particularly targeting motor symptoms, there remains a lack of established drugs capable of modifying the course of PD, leading to its unchecked progression. Although standard drug discovery initiatives focusing on treatments that relieve diseases have yielded valuable understanding into the underlying mechanisms of PD, none of the numerous promising candidates identified in preclinical studies have successfully transitioned into clinically effective medications. Due to the substantial expenses associated with drug discovery endeavors, it is understandable that there has been a notable shift towards reprofiling strategies. Assessing the efficacy of an existing medication offers the additional advantage of circumventing the requirement for preclinical safety assessments and formulation enhancements, consequently streamlining the process and reducing both the duration of time and financial investments involved in bringing a treatment to clinical fruition. Furthermore, repurposed drugs may benefit from lower rates of failure, presenting an additional potential advantage. various strategies for repurposing drugs are available to researchers in the field of PD. Some of these strategies have demonstrated effectiveness in identifying appropriate drugs for clinical trials, thereby providing validation for such techniques. This review provides an overview of the diverse strategies employed for drug reprofiling from approaches that emphasise on single-gene transcriptional investigations to comprehensive epidemiological correlation analysis. Additionally, instances of previous or current research endeavors employing each strategy has been discussed. For strategies not yet implemented in PD research, their efficacy is demonstrated using examples from other disorders. In this review, we assess the safety and efficacy potential of prominent candidates repurposed as potential treatments for modifying the course of PD undergoing advanced clinical trials.

PMID:39961372 | DOI:10.1016/j.arr.2025.102693

Elife. 2025 Feb 17;13:RP95952. doi: 10.7554/eLife.95952.

ABSTRACT

Despite exciting developments in cancer immunotherapy, its broad application is limited by the paucity of targetable antigens on the tumor cell surface. As an intrinsic cellular pathway, nonsense-mediated decay (NMD) conceals neoantigens through the destruction of the RNA products from genes harboring truncating mutations. We developed and conducted a high-throughput screen, based on the ratiometric analysis of transcripts, to identify critical mediators of NMD in human cells. This screen implicated disruption of kinase SMG1's phosphorylation of UPF1 as a potential disruptor of NMD. This led us to design a novel SMG1 inhibitor, KVS0001, that elevates the expression of transcripts and proteins resulting from human and murine truncating mutations in vitro and murine cells in vivo. Most importantly, KVS0001 concomitantly increased the presentation of immune-targetable human leukocyte antigens (HLA) class I-associated peptides from NMD-downregulated proteins on the surface of human cancer cells. KVS0001 provides new opportunities for studying NMD and the diseases in which NMD plays a role, including cancer and inherited diseases.

PMID:39960487 | DOI:10.7554/eLife.95952

J Clin Invest. 2025 Feb 17;135(4):e174081. doi: 10.1172/JCI174081.

ABSTRACT

Dilated cardiomyopathy (DCM) due to genetic disorders results in decreased myocardial contractility, leading to high morbidity and mortality rates. There are several therapeutic challenges in treating DCM, including poor understanding of the underlying mechanism of impaired myocardial contractility and the difficulty of developing targeted therapies to reverse mutation-specific pathologies. In this report, we focused on K210del, a DCM-causing mutation, due to 3-nucleotide deletion of sarcomeric troponin T (TnnT), resulting in loss of Lysine210. We resolved the crystal structure of the troponin complex carrying the K210del mutation. K210del induced an allosteric shift in the troponin complex resulting in distortion of activation Ca2+-binding domain of troponin C (TnnC) at S69, resulting in calcium discoordination. Next, we adopted a structure-based drug repurposing approach to identify bisphosphonate risedronate as a potential structural corrector for the mutant troponin complex. Cocrystallization of risedronate with the mutant troponin complex restored the normal configuration of S69 and calcium coordination. Risedronate normalized force generation in K210del patient-induced pluripotent stem cell-derived (iPSC-derived) cardiomyocytes and improved calcium sensitivity in skinned papillary muscles isolated from K210del mice. Systemic administration of risedronate to K210del mice normalized left ventricular ejection fraction. Collectively, these results identify the structural basis for decreased calcium sensitivity in K210del and highlight structural and phenotypic correction as a potential therapeutic strategy in genetic cardiomyopathies.

PMID:39959972 | DOI:10.1172/JCI174081

In Silico Pharmacol. 2025 Feb 13;13(1):27. doi: 10.1007/s40203-025-00307-7. eCollection 2025.

ABSTRACT

The global spread of monkeypox, caused by the double-stranded DNA monkeypox virus (MPXV), has underscored the urgent need for effective antiviral treatments. In this study, we aim to identify a potent inhibitor for MPXV DNA polymerase (DNAP), a critical enzyme in the virus replication process. Using a computational drug repurposing approach, we performed a virtual screening of 1615 FDA-approved drugs based on drug-likeness and molecular docking against DNAP. Among these, 1430 compounds met Lipinski's rule of five for drug-likeness, with Doxycycline emerging as the most promising competitive inhibitor, binding strongly to the DNAP active site with a binding affinity of - 9.3 kcal/mol. This interaction involved significant hydrogen bonds, electrostatic interactions, and hydrophobic contacts, with Doxycycline demonstrating a stronger affinity than established antivirals for smallpox, including Cidofovir, Brincidofovir, and Tecovirimat. Stability and flexibility analyses through a 200 ns molecular dynamics simulation and normal mode analysis confirmed the robustness of Doxycycline binding to DNAP. Overall, our results suggest Doxycycline as a promising candidate for monkeypox treatment, though additional experimental and clinical studies are needed to confirm its therapeutic potential and clinical utility.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-025-00307-7.

PMID:39958784 | PMC:PMC11825436 | DOI:10.1007/s40203-025-00307-7

Mini Rev Med Chem. 2025 Feb 14. doi: 10.2174/0113895575360959250117073046. Online ahead of print.

ABSTRACT

Sleep disorders and the resultant sleep deprivation (SD) are very common nowadays, resulting in depressed mood, poor memory and concentration, and various important changes in health, performance and safety. They may provoke further impairment of the cell lining of the blood vessels, as acting as a risk factor for cardiovascular disease (CVD) onset and progression. SD may lead to low neuronal regaining and plasticity, drastically affecting brain function. Thus, SD is a known risk factor for mental, behavioral and developmental disorders. Due to the inflammatory and oxidative stressful nature of SD, immune response modulation and antioxidants could be another therapeutic approach, apart from the already known symptomatic treatment with sedatives. Additionally, many drugs approved for other indications and under investigation, have been revisited due to their wide array of pharmacological activities. This review summarizes the main aspects of SD pathology and SD interrelated comorbidities and presents direct and indirect antioxidant molecules and drugs with multi-targeting potential that could assist in the prevention or management of these factors. A number of research groups have investigated well-known antioxidant compounds with multi-targeting cores, combining structural characteristics with properties including antiinflammatory, metal chelatory, gene transcription and immune modulatory that may add towards the effective SD and its associated comorbidities treatment.

PMID:39957704 | DOI:10.2174/0113895575360959250117073046

Eur J Immunol. 2025 Feb;55(2):e202451225. doi: 10.1002/eji.202451225.

ABSTRACT

Regulatory T cells (Tregs) are a subset of T cells defined by the expression of Forkhead box protein P3 (FoxP3) playing a crucial role in regulating effector T cell activity. Tregs accumulate in the tumor microenvironment facilitating tumor growth. Thus, targeting FoxP3+ Tregs could improve cancer immunotherapies. Here, we conducted a high-throughput, phenotypic screening of a drug repurposing library to identify compounds downregulating FoxP3 expression in human primary T cells. We identified the tyrosine kinase inhibitor bosutinib and the STAT3 inhibitor nifuroxazide effectively downregulating FoxP3 expression. To identify more potent compounds, structural analogs of these two compounds were searched and validated. These analogs were found to reduce FoxP3 expression in a similar- or more potent manner than the original hits. All compounds inhibited Treg suppressive functions and reduced the expression of Treg activation markers. Importantly, bosutinib disrupted FAK and CaMKII signaling more potently in Tregs, whilst nifuroxazide and its analog NA16 targeted STAT3 protein levels more effectively in Tregs. Additionally, bosutinib and NA16 targeted effector Tregs more effectively than other Treg subsets. In summary, bosutinib, nifuroxazide, and their analogs inhibited FoxP3 expression, Treg suppressive abilities, and Treg activation effectively, which could serve as tools for the improvement of current cancer immunotherapies.

PMID:39955647 | DOI:10.1002/eji.202451225

Cell Rep Methods. 2025 Feb 10:100990. doi: 10.1016/j.crmeth.2025.100990. Online ahead of print.

ABSTRACT

The need for a deeper understanding of adverse drug reaction (ADR) mechanisms is vital for improving drug safety and repurposing. This study introduces Drug Adverse Reaction Mechanism Explainer (DREAMER), a network-based framework that uses a comprehensive knowledge graph to uncover molecular mechanisms underlying ADRs and disease phenotypes. By examining shared phenotypes of drugs and diseases and their effects on protein-protein interaction networks, DREAMER identifies proteins linked to ADR mechanisms. Applied to 649 ADRs, DREAMER identified molecular mechanisms for 67 ADRs, including ventricular arrhythmia and metabolic acidosis, and emphasized pathways like GABAergic signaling and coagulation proteins in personality disorders and intracranial hemorrhage. We further demonstrate the application of DREAMER in drug repurposing and propose sotalol, ranolazine, and diltiazem as candidate drugs to be repurposed for cardiac arrest. In summary, DREAMER effectively detects molecular mechanisms underlying phenotypes, emphasizing the importance of network-based analyses with integrative data for enhancing drug safety and accelerating the discovery of novel therapeutic strategies.

PMID:39954672 | DOI:10.1016/j.crmeth.2025.100990

Expert Opin Drug Discov. 2025 Feb 15. doi: 10.1080/17460441.2025.2465373. Online ahead of print.

ABSTRACT

INTRODUCTION: Bladder cancer presents a significant health problem worldwide, with environmental and genetic factors contributing to its incidence. Histologically, it can be classified as carcinoma in situ, non-muscle invasive and muscle-invasive carcinoma, each one with distinct genetic alterations impacting prognosis and response to therapy. While traditional transurethral resection is commonly performed in carcinoma in situ and non-muscle invasive carcinoma, it often fails to prevent recurrence or progression to more aggressive phenotypes, leading to the frequent need for additional treatment such as intravesical chemotherapy or immunotherapy. Despite the advances made in recent years, treatment options for bladder cancer are still lacking due to the complex nature of this disease. So, animal models may hold potential for addressing these limitations, because they not only allow the study of disease progression but also the evaluation of therapies and the investigation of drug repositioning.

AREAS COVERED: This review discusses the use of animal models over the past decade, highlighting key discoveries and discussing advantages and disadvantages for new drug discovery.

EXPERT OPINION: Over the past decade animal models have been employed to evaluate new mechanisms underlying the responses to standard therapies, aiming to optimize bladder cancer treatment. The authors propose that molecular engineering techniques and AI may hold promise for the future development of more precise and effective targeted therapies in bladder cancer.

PMID:39954010 | DOI:10.1080/17460441.2025.2465373

Virol J. 2025 Feb 15;22(1):38. doi: 10.1186/s12985-025-02647-4.

ABSTRACT

BACKGROUND: Repurposing off-label drugs during epidemics or pandemics with unknown/known pathogens, particularly when their side effects and complications are already known, can be a strategic approach, as seen during the COVID-19 pandemic. Developing surrogate in vitro experimental models (passage-to-passage), which mimic epidemic/pandemic-like transmission (human-to-human), may enhance this repurposing process. This study evaluates montelukast sodium (MLS), a US FDA-approved leukotriene receptor antagonist for asthma, to explore its potential repurposing antiviral effects against bovine respiratory syncytial virus (BRSV), which has basic similarities to human respiratory syncytial virus (HRSV) as both belong to the Pneumoviridae family.

METHODS: An in vitro serial passage model was developed using MDBK cells infected with a local wild-type strain of BRSV (43TR2018). The cytotoxicity of MLS was assessed via the trypan blue exclusion method, identifying non-toxic concentrations. The impact of MLS on viral spread and infectivity was measured through TCID50 values over 10 passages. Viral loads were confirmed by nested RT-PCR and quantified using qPCR, while apoptosis, necrosis, and nitric oxide production were evaluated through staining and nitrite assays. Data were analyzed using ANOVA and Tukey's test (p < 0.05).

RESULTS: Control cells exhibited 97.16% viability, with 10 µM and 20 µM MLS concentrations maintaining viabilities of 89.2% and 87.3%, respectively. Viral titers significantly decreased at higher concentrations of MLS (up to 99.94% inhibition). Apoptosis rates decreased in MLS-treated cells, and live cell percentages improved, especially at 20 µM. Nitric oxide levels showed no significant differences across groups.

CONCLUSION: MLS demonstrated a dose-dependent antiviral effect against BRSV, achieving 99% viral inhibition properties in MDBK cells. These promising results warrant further investigation into the antiviral mechanisms of MLS.

PMID:39953515 | DOI:10.1186/s12985-025-02647-4

J Biomed Inform. 2025 Feb 12:104786. doi: 10.1016/j.jbi.2025.104786. Online ahead of print.

ABSTRACT

OBJECTIVE: Drug repurposing accelerates therapeutic development by finding new indications for approved drugs. However, accounting for individual patient differences is challenging. This study introduces a Precision Drug Repurposing (PDR) framework at single-patient resolution, integrating individual-level data with a foundational biomedical knowledge graph to enable personalized drug discovery.

METHODS: We developed a framework integrating patient-specific data from the UK Biobank (Polygenic Risk Scores, biomarker expressions, and medical history) with a comprehensive biomedical knowledge graph (61,146 entities, 1,246,726 relations). Using Alzheimer's Disease as a case study, we compared three diverse patient-specific models with a foundational model through standard link prediction metrics. We evaluated top predicted candidate drugs using patient medication history and literature review.

RESULTS: Our framework maintained the robust prediction capabilities of the foundational model. The integration of patient data, particularly Polygenic Risk Scores (PRS), significantly influenced drug prioritization (Cohen's d = 1.05 for scoring differences). Ablation studies demonstrated PRS's crucial role, with effect size decreasing to 0.77 upon removal. Each patient model identified novel drug candidates that were missed by the foundational model but showed therapeutic relevance when evaluated using patient's own medication history. These candidates were further supported by aligned literature evidence with the patient-level genetic risk profiles based on PRS.

CONCLUSION: This exploratory study demonstrates a promising approach to precision drug repurposing by integrating patient-specific data with a foundational knowledge graph.

PMID:39952626 | DOI:10.1016/j.jbi.2025.104786

Front Microbiol. 2025 Jan 30;16:1554339. doi: 10.3389/fmicb.2025.1554339. eCollection 2025.

NO ABSTRACT

PMID:39949624 | PMC:PMC11822564 | DOI:10.3389/fmicb.2025.1554339

Cell Mol Bioeng. 2025 Jan 23;18(1):71-82. doi: 10.1007/s12195-024-00841-y. eCollection 2025 Feb.

ABSTRACT

PURPOSE: Cervical and endometrial cancers pose significant challenges in women's healthcare due to their high mortality rates and limited treatment options. High throughput screening (HTS) of cervical and endometrial cancer in vitro models offers a promising avenue for drug repurposing and broadening patient treatment options. Traditional two-dimensional (2D) cell-based screenings have limited capabilities to capture crucial multicellular interactions, that are improved upon in three dimensional (3D) multicellular tissue engineered models. However, manual fabrication of the 3D platforms is both time consuming and subject to variability. Thus, the goal of this study was to utilize automated cell dispensing to fabricate 3D cell-based HTS platforms using the HP D100 Single Cell Dispenser to dispense cervical and endometrial cancer cells.

METHODS: We evaluated the effects of automated dispensing of the cancer cell lines by tuning the dispensing protocol to align with cell size measured in solution and the minimum cell number for acceptable cell viability and proliferation. We modified our previously reported coculture models of cervical and endometrial cancer to be in a 384 well plate format and measured microvessel length and cancer cell invasion.

RESULTS: Automatically and manually dispensed cells were directly compared revealing minimal differences between the dispensing methods. These findings suggest that automated dispensing of cancer cells minimally affects cell behavior and can be deployed to decrease in vitro model fabrication time.

CONCLUSIONS: By streamlining the manufacturing process, automated dispensing holds promise for enhancing efficiency and scalability of 3D in vitro HTS platforms, ultimately contributing to advancement in cancer research and treatment.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12195-024-00841-y.

PMID:39949489 | PMC:PMC11813830 | DOI:10.1007/s12195-024-00841-y

Sci Rep. 2025 Feb 13;15(1):5365. doi: 10.1038/s41598-025-89128-4.

ABSTRACT

Ulcerative colitis (UC), a chronic inflammatory bowel disease, significantly increases the risk of colon adenocarcinoma (COAD). Disulfidptosis, a novel form of programmed cell death, has been implicated in various diseases, including UC. This study investigates the expression of disulfidptosis-related genes, particularly CD2AP and MYH10, in UC and COAD. Through analysis of public datasets, we found MYH10 significantly upregulated and CD2AP downregulated in UC compared to healthy controls, with consistent patterns in COAD. Immune infiltration analysis revealed correlations between these genes and specific immune cell types, suggesting their roles in immune modulation. Molecular docking showed strong binding affinities of UC drugs such as budesonide and sulfasalazine with CD2AP and MYH10. Connectivity Map analysis identified additional drug candidates, including simvastatin and mephenytoin, which may be repurposed for UC and COAD therapy. These findings suggest disulfidptosis-related genes as potential biomarkers and therapeutic targets, linking chronic inflammation to cancer progression.

PMID:39948102 | DOI:10.1038/s41598-025-89128-4

Parasitol Int. 2025 Feb 11:103041. doi: 10.1016/j.parint.2025.103041. Online ahead of print.

ABSTRACT

The malarial parasite Plasmodium falciparum has evolved resistance to several antimalarial drugs, posing a significant challenge to the effective management and treatment of malaria in endemic areas. Drug repurposing has emerged as a potential alternative strategy for addressing this issue. This study aimed to identify an FDA-approved microbicidal agent, zinc pyrithione (ZPT), against mixed blood-stage parasites of P. falciparum chloroquine-sensitive (Pf3D7) and resistant strains (PfINDO). Based on the time-inhibition kinetics assay, the parasite viability was significantly inhibited by ZPT treatment for 96 (0.77 μM and 0.37 μM) and 72 h (0.63 μM and 0.61 μM), followed by 48 h (0.76 μM and 1.32 μM) and moderate inhibitory effects for 12 and 24 h in both Pf3D7 and PfINDO culture. Stage-specific treatment revealed that trophozoites and schizonts exposed to ZPT were more susceptible than ring-stage parasites. Phenotypic assays revealed that trophozoites and schizonts failed to mature and exhibited aberrant morphologies such as condensed nuclei, as determined by Giemsa staining. Furthermore, ZPT in combination with dihydroartemisinin and chloroquine demonstrated additive interactions in both Pf3D7 and PfINDO parasites. At therapeutic dosages, ZPT failed to cause hemolysis in human erythrocytes. Overall, this study demonstrated a time-dependent effect of ZPT on the blood stages of human P. falciparum in culture, suggesting its utility in clinical settings.

PMID:39947389 | DOI:10.1016/j.parint.2025.103041

Int J Mol Sci. 2025 Feb 2;26(3):1287. doi: 10.3390/ijms26031287.

ABSTRACT

Space exploration has progressed from contemporary discoveries to current endeavors, such as space tourism and Mars missions. As human activity in space accelerates, understanding the physiological effects of microgravity on the human body is becoming increasingly critical. This study analyzes transcriptomic data from human cell lines exposed to microgravity, investigates its effects on gene expression, and identifies potential therapeutic interventions for health challenges posed by spaceflight. Our analysis identified five under-expressed genes (DNPH1, EXOSC5, L3MBTL2, LGALS3BP, SPRYD4) and six over-expressed genes (CSGALNACT2, CSNK2A2, HIPK1, MBNL2, PHF21A, RAP1A), all of which exhibited distinct expression patterns in response to microgravity. Enrichment analysis highlighted significant biological functions influenced by these conditions, while in silico drug repurposing identified potential modulators that could counteract these changes. This study introduces a novel approach to addressing health challenges during space missions by repurposing existing drugs and identifies specific genes and pathways as potential biomarkers for microgravity effects on human health. Our findings represent the first systematic effort to repurpose drugs for spaceflight, establishing a foundation for the development of targeted therapies for astronauts. Future research should aim to validate these findings in authentic space environments and explore broader biological impacts.

PMID:39941055 | DOI:10.3390/ijms26031287

Cancers (Basel). 2025 Jan 27;17(3):439. doi: 10.3390/cancers17030439.

ABSTRACT

Central nervous system (CNS) tumors are the leading cause of cancer-related mortality in children, with prognosis remaining dismal for some of these malignancies. Though the past two decades have seen advancements in surgery, radiation, and targeted therapy, major unresolved hurdles continue to undermine the therapeutic efficacy. These include challenges in suboptimal drug delivery through the blood-brain barrier (BBB), marked intra-tumoral molecular heterogeneity, and the elusive tumor microenvironment. Drug repurposing or re-tasking FDA-approved drugs with evidence of penetration into the CNS, using newer methods of intracranial drug delivery facilitating optimal drug exposure, has been an area of intense research. This could be a valuable tool, as most of these agents have already gone through the lengthy process of drug development and the evaluation of safety risks and the optimal pharmacokinetic profile. They can now be used and tested in clinics with an accelerated and different approach. Conclusions: The next-generation therapeutic strategy should prioritize repurposing oncologic and non-oncologic drugs that have been used for other indication, and have demonstrated robust preclinical activity against pediatric brain tumors. In combination with novel drug delivery techniques, these drugs could hold significant therapeutic promise in pediatric neurooncology.

PMID:39941807 | DOI:10.3390/cancers17030439

Int J Mol Sci. 2025 Feb 6;26(3):1389. doi: 10.3390/ijms26031389.

ABSTRACT

Multiple signaling pathways are dysregulated in melanoma, notably the Ras/RAF/MAPK/ERK and PI3K/AKT/mTOR pathways, which can be targeted therapeutically. The high immunogenicity of melanoma has been exploited using checkpoint inhibitors. Whilst targeted therapies and immune checkpoint inhibitors have improved the survival of patients with advanced melanoma, treatment resistance, their side effect profiles, and the prohibitive cost remain a challenge, and the survival outcomes remain suboptimal. Treatment resistance has been attributed to the presence of cancer stem cells (CSCs), a small subpopulation of pluripotent, highly tumorigenic cells proposed to drive cancer progression, recurrence, metastasis, and treatment resistance. CSCs reside within the tumor microenvironment (TME) regulated by the immune system, and the paracrine renin-angiotensin system, which is expressed in many cancer types, including melanoma. This narrative review discusses the role of CSCs and the paracrine renin-angiotensin system in the melanoma TME, and its implications on the current treatment of advanced melanoma with targeted therapy and immune checkpoint blockers. It also highlights the regulation of the Ras/RAF/MAPK/ERK and PI3K/AKT/mTOR pathways by the renin-angiotensin system via pro-renin receptors, and how this may relate to CSCs and treatment resistance, underscoring the potential for improving the efficacy of targeted therapy and immunotherapy by concurrently modulating the renin-angiotensin system.

PMID:39941158 | DOI:10.3390/ijms26031389

Int J Mol Sci. 2025 Jan 23;26(3):925. doi: 10.3390/ijms26030925.

ABSTRACT

Human immunodeficiency virus (HIV) and hepatitis B virus (HBV) continue to be global public health issues. Globally, about 39.9 million persons live with HIV in 2023, according to the Joint United Nations Programme on HIV/AIDS (UNAIDS) 2024 Fact Sheet. Consequently, the World Health Organisation (WHO) reported that about 1.5 million new cases of HBV occur, with approximately 820 thousand mortalities yearly. Conversely, the lower percentage of HBV (30%) cases that receive a diagnosis is a setback in achieving the WHO 2030 target for zero HBV globally. This has necessitated a public health concern to repurpose antiretroviral (ARV) drugs for the treatment of HBV diseases. This review provides an introductory background, including the pros and cons of repurposing antiretrovirals (ARVs) for HBV treatment. We examine the similarities in replication mechanisms between HIV and HBV. We further investigate some clinical studies and trials of co-infected and mono-infected patients with HIV-HBV. The topical keywords including repurposing ARV drugs, repurposing antiretroviral therapy, Hepatitis B drugs, HBV therapy, title, and abstracts are searched in PubMed, Web of Science, and Google Scholar. The advanced search includes the search period 2014-2024, full text, clinical trials, randomized control trials, and review. The search results filtered from 361 to 51 relevant articles. The investigations revealed that HIV and HBV replicate via a common route known as 'reverse transcription'. Clinical trial results indicate that an early initiation of ARVs, particularly with tenofovir disoproxil fumarate (TDF) as part of a regimen, significantly reduced the HBV viral load in co-infected patients. In mono-infected HBV, timely and correct precise medication is essential for HBV viral load reduction. Therefore, genetic profiling is pivotal for successful ARV drug repurposing in HBV treatment. Pharmacogenetics enables the prediction of the right dosages, specific individual responses, and reactions. This study uniquely explores the intersection of pharmacogenetics and drug repurposing for optimized HBV therapy. Additional in vivo, clinical trials, and in silico research are important for validation of the potency, optimum dosage, and safety of repurposed antiretrovirals in HBV therapy. Furthermore, a prioritization of research collaborations comprising of regulators and funders to foster clinically adopting and incorporating repurposed ARVs for HBV therapy is recommended.

PMID:39940695 | DOI:10.3390/ijms26030925

Int J Mol Sci. 2025 Jan 21;26(3):888. doi: 10.3390/ijms26030888.

ABSTRACT

Classic galactosemia is a rare disease with long-term consequences that seriously affect the quality of life of patients. To date, various therapeutic approaches are being developed, but treatments that target the molecular defects in the mutant galactose-1-phosphate uridylyltransferase (GALT) gene are lacking. We conducted a computational search for putative pharmacochaperones by applying a drug repurposing strategy, and we found that one compound, already active as a pharmacochaperone in another pathology, doubled the enzymatic activity of the purified mutant enzyme in an in vitro test. Furthermore, an extensive computational search in a database of known active molecules found another compound able in its turn to improve in vitro enzymatic activity. Both compounds are predicted to interact with a cavity at the enzyme interface previously supposed to be an allosteric site for the GALT enzyme. In vitro tests confirmed also the reduced accumulation of galactose-1-phosphate (G1P) in fibroblasts of patients. Although these results must be considered preliminary, our findings pave the way for future research lines focused on the search for promising pharmacochaperones that can directly rescue the activity of the enzyme.

PMID:39940658 | DOI:10.3390/ijms26030888

Pharmacol Res Perspect. 2025 Feb;13(1):e70076. doi: 10.1002/prp2.70076.

ABSTRACT

Drug repurposing provides a cost-effective and time-saving approach to cancer therapy. Aripiprazole (ARI), a third-generation antipsychotic, has shown potential anticancer properties by modulating pathways central to tumor progression and resistance. This scoping review systematically examines evidence on ARI's anticancer effects, mechanisms of action, and translational potential. A systematic search of PubMed, EMBASE, SCOPUS, and Web of Science was conducted following PRISMA-ScR guidelines. Eligible studies included in vitro, in vivo, and clinical investigations. Data on cancer types, pathways, assays, and outcomes were extracted and synthesized to identify trends and gaps. Of 588 screened studies, 23 met inclusion criteria, spanning cancer types such as breast, colorectal, lung, and brain cancers. ARI modulates key pathways like PI3K/AKT/mTOR and Wnt/β-catenin, induces apoptosis through mitochondrial dysfunction and ER stress, and overcomes drug resistance by inhibiting P-glycoprotein activity and expression. It exhibits tumor-suppressive effects in vivo and synergizes with chemotherapy and radiotherapy. Retrospective population studies suggest ARI's prolactin-sparing properties may reduce the risk of hormone-sensitive cancers such as breast and endometrial cancer compared to antipsychotics with stronger dopamine receptor blockade. Additionally, ARI's ability to target multiple Hallmarks of Cancer highlights its promise as a repurposed anticancer agent. However, current evidence is primarily preclinical and observational, with limited clinical validation. Large-scale cohort studies and prospective trials are essential to confirm its efficacy and address translational challenges. By bridging these gaps, ARI could emerge as a valuable adjunctive therapy in oncology, leveraging its safety profile and versatility to address unmet needs in cancer treatment.

PMID:39939172 | DOI:10.1002/prp2.70076