Protein Pept Lett. 2025 May 8. doi: 10.2174/0109298665366911250416113831. Online ahead of print.

ABSTRACT

BACKGROUND: COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a highly pathogenic human coronavirus (CoV). For the treatment of COVID-19, various drugs, ayurvedic formulations, used for other diseases, were repurposed. Ayurveda and yoga exhibited a pivotal role in the treatment of COVID-19. Various medicinal plants, including garlic, tulsi, clove, cinnamon, ginger, black pepper, and turmeric, are recommended for the prevention of COVID-19 as immunity boosters along with their antiviral property.

OBJECTIVE: In view of the drug repurposing approach, the present work has been initiated with the broader objectives of screening and identification of phytoconstituents of Indian spices against targets, namely furin, 3C-like protease (3CL-PRO), NSP-9 RNA binding protein, papain-like protease, RNA dependent RNA polymerase (RDRP), spike protein concerned with life cycle of SARS-CoV-2 using in-silico tools.

METHOD: The phytoconstituents of Indian spices were screened for interaction with several targets using a molecular docking approach with the help of Discovery Studio 4.5 software. Furthermore, the pharmacokinetic analyses of selected ligands using ADMET and Lipinski's rule of five were also performed.

RESULT: In the present study, more than 35 active phytoconstituents of Indian spices were screened for interaction with several identified targets of Covid-19 using a molecular docking approach. The ligands, namely morin, gingerol, myristic acid, quercetin, gallic acid, octacosanal, and alliin were found to be the top interacting ligands with the targets analyzed.

CONCLUSION: Based on the present in-silico finding, the active components of spices could be considered for drug-lead compounds against COVID-19.

PMID:40353411 | DOI:10.2174/0109298665366911250416113831

Anim Cells Syst (Seoul). 2025 May 8;29(1):325-338. doi: 10.1080/19768354.2025.2489389. eCollection 2025.

ABSTRACT

Yes-associated protein (YAP), a key co-transcription factor of the Hippo pathway, is a promising drug target for cancer therapy due to its critical role in promoting cell proliferation, survival, and tumor progression when dysregulated. While most Hippo pathway-targeting drugs focus on disrupting TEAD-YAP interactions or modulating the MST or LATS kinase cascade, new approaches are needed to identify small molecules that regulate YAP activity. In this study, we conducted high-throughput screening of FDA-approved drugs to discover potential YAP modulators. Using a NanoBiT-based system, which enables real-time and quantitative measurement of protein interactions, combined with phenotype-based assays in EGFP-YAP-expressing cells, we identified compounds that activate or inhibit YAP function. Among the identified YAP regulators, the microtubule destabilizer vinorelbine promoted YAP nuclear localization and transcriptional activation, while the antipsychotic drug thioridazine enhanced YAP phosphorylation at Ser127, resulting in its cytoplasmic retention and reduced transcriptional activity, effectively suppressing cancer cell growth. These findings demonstrate the potential of FDA-approved drugs in modulating YAP activity and present a novel screening strategy for developing YAP-targeting therapeutics. Furthermore, this approach can be extended to identify modulators of other signaling pathways, advancing drug discovery for a wide range of diseases.

PMID:40353256 | PMC:PMC12064127 | DOI:10.1080/19768354.2025.2489389

Narra J. 2025 Apr;5(1):e1130. doi: 10.52225/narra.v5i1.1130. Epub 2025 Jan 17.

ABSTRACT

Tuberculosis (TB) remains a significant and deadly infection among pulmonary diseases caused by Mycobacterium tuberculosis, a highly adaptive bacterium. The ability of M. tuberculosis to evade certain drugs has been linked to its unique structure, particularly in the cell envelope, where the Ag85 complex proteins play an essential role in this part. The aim of this study was to utilize a drug repurposing strategy targeting the Ag85 complex proteins. This study utilized a computational approach with 120 selected drugs experimentally identified to inhibit Tuberculosis. A virtual screening molecular docking with Autodock Vina was used to filter the compounds and identify the strong binders to the Ag85 Complex. Molecular dynamics simulations employed the Gromacs Packages to evaluate the stability of each complex, including root mean square deviation (RMSD), root mean square fluctuation (RMSF), and radius of gyration (RoG). Additionally, absorption, distribution, metabolism, excretion, and toxicity (ADMET) assessments were conducted to gather more information about the drug-likeness of each hit compound. Three compounds, selamectin, imatinib, and eltrombopag were selected as potential drugs repurposed to inhibit the activity of the Ag85 complex enzyme, with binding affinities ranging between -10.560 kcal/mol and -11.422 kcal/mol. The MD simulation within 100 ns (3 replicas) showed that the average RMSD of each Ag85A complex was 0.15 nm-0.16 nm, RMSF was 0.09 nm-0.10 nm, and RoG was 1.80 nm-1.81 nm. For Ag85B, the average RMSD was 1.79 nm-1.80 nm, RMSF was 0.08 nm-0.09 nm, and RoG was 1.79 nm-1.80 nm. Then, for Ag85C, the mean RMSD was 0.16 nm-0.18 nm, RMSF was 0.09, and RoG was 1.77 nm. The study highlights that these promising results demonstrate the potential of some repurposed drugs in combating the Ag85 complex.

PMID:40352212 | PMC:PMC12059857 | DOI:10.52225/narra.v5i1.1130

Antiviral Res. 2025 May 8:106172. doi: 10.1016/j.antiviral.2025.106172. Online ahead of print.

ABSTRACT

The burden of dengue on human health has dramatically increased in recent years, underscoring the urgent need for effective therapeutic interventions. Despite decades of research since the discovery of the dengue virus, no specific antiviral treatments are available and strategies to reliably prevent severe disease remain limited. Direct-acting antivirals against dengue are under active investigation but have shown limited efficacy to date. An underappreciated Achille's heal of the virus is its dependence on host factors for infection and pathogenesis, each of which presents a potential avenue for therapeutic intervention. We and others have demonstrated that dengue virus relies on multiple host kinases, some of which are already targeted by clinically approved inhibitors. These offer drug repurposing opportunities for host-directed dengue treatment. Here, we summarize findings on the role of kinases in dengue infection and disease and highlight potential kinase targets for the development of innovative host-directed therapeutics.

PMID:40348023 | DOI:10.1016/j.antiviral.2025.106172

Comput Biol Med. 2025 May 9;192(Pt B):110203. doi: 10.1016/j.compbiomed.2025.110203. Online ahead of print.

ABSTRACT

Pre-eclampsia (PE) is a severe vascular disorder during pregnancy, significantly affecting maternal and fetal health worldwide. However, the exact molecular mechanism of its pathophysiology remains unclear, highlighting the need for reliable early diagnostic methods. Our primary aim of this study was to identify key genes (KGs) that may affect the outcome of patients with PE via integrated bioinformatics analysis. We analysed a gene expression dataset from the national center for biotechnology information (NCBI) sequence read archive (SRA) database and performed standard preprocessing steps, including quality assessment, trimming, genome alignment, and feature counts. Following this, normalization and differentially expressed genes (DEGs) were performed using Deseq2, which identified 781 DEGs were identified comprising 457 upregulated and 324 downregulated genes. Identified DEGs were significantly enriched in the cytokine interaction pathway and cellular calcium ion homeostasis. PPI network analysis revealed eight KGs (CXCL8, GAPDH, MMP9, SPP1, PTGS2, LEP, FGF7, and FGF10). These KGs were further found to be regulated by ten transcription factors (TFs), among which NF-kB1 and RELA consistently interact with all the KGs, and four microRNAs (miRNAs) such as hsa-mir-335-5p, has-mir-16a-5p, has-let-7b-5p, and has-mir-204-5p. The least absolute shrinkage and selection operator (LASSO) regression with 10-fold cross-validation (CV) confirmed all eight KGs may act as potential biomarkers based on their coefficients. Among these, GAPDH, SPP1, FGF7, and FGF10 emerged as novel biomarkers. Additionally, receiver operating characteristic (ROC) curve analysis for these novel biomarkers showed an area under the curve (AUC) of 0.869, demonstrating strong discriminatory power between the healthy and EOPE groups. The drug-gene interaction was performed by DrugMap database revealed an important interaction of GAPDH and FGF7 with FDA-approved drugs, indicating their therapeutic significance in PE. This analysis also facilitates drug repurposing for PE treatment.

PMID:40347801 | DOI:10.1016/j.compbiomed.2025.110203

Pharmacotherapy. 2025 May 10. doi: 10.1002/phar.70028. Online ahead of print.

ABSTRACT

BACKGROUND: Oxaliplatin-induced peripheral neuropathy (OIPN) is a major clinical challenge because it leads to discontinuation of chemotherapy. Omeprazole, a proton pump inhibitor (PPI), has been shown to prevent OIPN in a rat model. Therefore, we aimed to test whether the concomitant use of a PPI reduces oxaliplatin discontinuation due to OIPN.

METHODS: This retrospective study used data from 1015 patients who started treatment with oxaliplatin and evaluated two cohorts (PPI vs. non-PPI). The primary outcome measure was oxaliplatin discontinuation due to OIPN. A Kaplan-Meier curve was generated for cumulative doses and evaluated using the log-rank test and Cox proportional hazards analysis.

RESULTS: The log-rank test showed that the number of patients who discontinued oxaliplatin due to OIPN was significantly lower in the PPI group (p = 0.0264). Cox proportional hazards analysis incorporated and analyzed factors previously reported as potentially affecting neuropathy (sex, age, use of PPIs, calcium channel antagonists, opioids and adjuvant analgesics, and the CAPOX [capecitabine + oxaliplatin] regimen). The analysis suggested that the concomitant use of PPIs was a factor in reducing oxaliplatin discontinuation (adjusted hazard ratio [HR] = 0.568, 95% confidence interval [CI], 0.344-0.937, p = 0.0269). Since there were significant differences in some patient demographics between the two groups, propensity score matching was performed to align the patient demographics and then reanalyzed. After propensity score matching, the same analysis as above showed that oxaliplatin discontinuation due to OIPN was significantly less common in the PPI group (p = 0.0081); cox proportional hazards analysis showed that PPI use was a factor that significantly reduced oxaliplatin discontinuation due to OIPN (adjusted HR = 0.478, 95% CI, 0.273-0.836, p = 0.0096).

CONCLUSIONS: These results suggest that concomitant PPI use may reduce oxaliplatin discontinuation due to OIPN in patients receiving oxaliplatin.

PMID:40347077 | DOI:10.1002/phar.70028

Chem Biol Drug Des. 2025 May;105(5):e70122. doi: 10.1111/cbdd.70122.

ABSTRACT

Carprofen, a nonsteroidal anti-inflammatory drug (NSAID) derived from propanoic acid, is known for its analgesic and antipyretic properties. Although it has long been employed in veterinary medicine as an anti-inflammatory agent, its use in humans was discontinued shortly after its market launch due to costly raw materials, complex synthesis, and labor-intensive production processes-factors that made it less competitive compared with other NSAIDs. Despite this, the carprofen molecule remains a subject of significant scientific interest. Recent advancements in its synthesis have introduced simplified and more cost-effective methods, reigniting its potential for both novel applications and drug repurposing. Exciting new research is exploring carprofen's broader therapeutic possibilities, extending beyond its original anti-inflammatory role. Studies are investigating its efficacy in antimicrobial therapy-including antibiofilm, anticancer, antiviral, and anti-Alzheimer's applications-opening doors to a wealth of untapped possibilities. This review delves into these emerging areas, highlighting how carprofen's molecular structure and derivatives can be leveraged to expand its therapeutic reach. The literature review was conducted using four databases: Web of Science, ScienceDirect, Scopus, Embase, and Reaxys. The review focused on English-language original research and review articles, examining carprofen and its derivatives in terms of their synthesis methods as well as their use as small molecules in various therapeutic applications, both human and veterinary. With ongoing research pushing the boundaries of its potential, carprofen remains a promising candidate for innovation in drug development and treatment strategies.

PMID:40346933 | DOI:10.1111/cbdd.70122

BMC Geriatr. 2025 May 9;25(1):321. doi: 10.1186/s12877-025-05982-x.

ABSTRACT

BACKGROUND: In addition to conventional symptomatic treatment drugs, anti-amyloid beta antibody drugs are expected to benefit patients with Alzheimer's disease (AD). However, issues such as side effects and high costs persist, and new preventive and therapeutic drugs are desired. Meanwhile, information on the diagnosis and symptomatic treatment of AD accumulated during daily clinical practice is stored as real-world data and is considered a powerful means of discovering unknown factors that could provide clues for new prevention and treatment approaches for AD through comprehensive exploration.

METHODS: We used anonymized hospital information system data from a tertiary care and academic hospital in Japan, spanning from 1981 to 2016, to search for potential suppressive factors for AD onset and to verify the validity of the discovered factors. We initially conducted a comprehensive search for candidate suppressive factors for AD and verified them using the inverse probability weighting (IPW) method with propensity scores.

RESULTS: From the comprehensive search, we identified glycyrrhizic acid (GA), a component of licorice, a traditional medicine with anti-inflammatory, antioxidant, antibacterial, and antiaging properties, as a candidate suppressing factor for AD. The IPW method showed that the odds ratio of developing AD in the GA group was 0.642 (95% confidence interval: 0.566-0.727) compared with the non-GA group after adjustment.

CONCLUSIONS: This is the first human study to suggest that GA may be a factor that can suppress the onset of AD. Additionally, our method could be a promising tool for drug repositioning that applies existing drugs already used in clinical settings with well-known side effects to diseases different from their original use.

PMID:40346511 | DOI:10.1186/s12877-025-05982-x

Adv Sci (Weinh). 2025 May 8:e2415698. doi: 10.1002/advs.202415698. Online ahead of print.

ABSTRACT

Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of mature T-cell malignancies with poor prognosis. Therefore, improved therapies are urgently required to improve patient outcomes. In this study, metabolic inhibitor drug screening reveals that quinacrine elicits excellent antitumor activity both in vitro and in vivo by downregulating intracellular arginine levels in PTCL. Single-cell transcriptomic analyses reveal aberrant arginine metabolism in patients with PTCL, characterized by excessive solute carrier family 3 member 2 (SLC3A2) mediated arginine uptake preferentially in tumor cells. High SLC3A2 expression predicts poor outcomes in PTCL, as SLC3A2-mediated arginine uptake promotes the malignant behaviors of tumor cells and induces tumor immune escape, thereby fueling tumor progression. Mechanistically, high arginine levels induce global metabolic changes, including enhanced oxidative phosphorylation by promoting nascent RNA synthesis. This work identifies structure-specific recognition protein 1 (SSRP1), which upregulates SLC3A2, as a co-transcription factor with JUNB. Quinacrine disrupts SLC3A2-mediated arginine transport by targeting SSRP1. Combining quinacrine with histone deacetylase inhibitors is a promising therapeutic strategy for PTCL.

PMID:40344476 | DOI:10.1002/advs.202415698

J Cancer Res Clin Oncol. 2025 May 9;151(5):157. doi: 10.1007/s00432-025-06185-y.

ABSTRACT

PURPOSE: Drug repurposing may be an efficient strategy for identifying new cancer treatments. Tranexamic acid (TXA), an antifibrinolytic agent that affects the plasminogen-plasmin pathway, may have potential anticancer effects by influencing tumor cell proliferation, angiogenesis, inflammation, immune response, and tissue remodeling-all crucial processes contributing to tumor progression and metastasis.

OBJECTIVE: Evaluate TXA's anticancer effects across in vitro, animal, and clinical studies to assess its potential as a repurposed cancer drug.

METHODS: The study was designed as a PRISMA-compliant systematic review and meta-analysis. The literature search was conducted in MEDLINE, EMBASE, Web of Science, and the Cochrane Library. In vitro, animal, and clinical studies investigating the anticancer effects of TXA or epsilon-aminocaproic acid (EACA) were included. Animal and clinical studies were critically appraised, and studies with a low risk of bias were included in the meta-analysis.

RESULTS: Of 4367 identified records, 38 articles were included, collectively reporting findings from 41 in vitro studies, 34 animal studies (n = 843 animals), and seven clinical studies (n = 91 patients). The meta-analysis included nine animal studies and showed a tumor growth reduction in animals treated with TXA compared to controls with a standardized mean difference of - 1.0 (95%CI - 1.5; - 0.4) (p = 0.0002). Equivalently, the majority of in vitro studies reported reduced proliferation, viability, and invasiveness in TXA-exposed tumor cell lines. The clinical studies were considerably susceptible to bias, rendering any conclusions futile.

CONCLUSIONS: TXA shows promise as a repurposed cancer drug, revealing an overall reduction in tumor growth, viability, and invasiveness in animal and in vitro studies.

PMID:40343490 | DOI:10.1007/s00432-025-06185-y

Sci Rep. 2025 May 8;15(1):16114. doi: 10.1038/s41598-025-01303-9.

ABSTRACT

The growing prevalence of antibiotic resistance in multidrug-resistant Gram-negative bacteria (MDR-GNB), exacerbated by the misuse of antibiotics, presents a critical global health challenge. Colistin, a last-resort antibiotic for severe MDR-GNB infections, has faced diminishing efficacy due to the emergence of colistin-resistant (COL-R) strains. This study evaluates the potential of penfluridol (PF), an antipsychotic drug with notable antibacterial and antibiofilm properties, to restore colistin activity against COL-R GNB in vitro. PF alone exhibited limited antibacterial activity against COL-R GNB; however, its combination with colistin demonstrated strong synergistic effects, significantly reducing colistin's minimum inhibitory concentrations (MICs) by 4-128 times. Time-kill assays confirmed the combination's superior bactericidal activity compared to either agent alone. Membrane permeability assays revealed that PF enhanced colistin's ability to disrupt bacterial membranes, likely by facilitating colistin binding to lipopolysaccharide. Furthermore, PF significantly inhibited the development of colistin resistance over a 30-day resistance development assay. In addition to its antibacterial effects, PF exhibited notable antibiofilm activity. The combination of PF and colistin effectively inhibited biofilm formation and eradicated mature biofilms in most of the tested COL-R GNB strains. These findings mark the first report of PF's synergistic interaction with colistin against GNB biofilms, offering a promising strategy to combat biofilm-associated infections. Overall, the colistin/PF combination holds potential as an effective therapeutic strategy to enhance colistin efficacy, delay resistance development, and manage biofilm-associated infections in MDR-GNB.

PMID:40341530 | DOI:10.1038/s41598-025-01303-9

Psychol Med. 2025 May 9;55:e137. doi: 10.1017/S0033291725000819.

ABSTRACT

BACKGROUND: The Hierarchical Taxonomy of Psychopathology (HiTOP) and Research Domain Criteria (RDoC) frameworks emphasize transdiagnostic and mechanistic aspects of psychopathology. We used a multi-omics approach to examine how HiTOP's psychopathology spectra (externalizing [EXT], internalizing [INT], and shared EXT + INT) map onto RDoC's units of analysis.

METHODS: We conducted analyses across five RDoC units of analysis: genes, molecules, cells, circuits, and physiology. Using genome-wide association studies from the companion Part I article, we identified genes and tissue-specific expression patterns. We used drug repurposing analyses that integrate gene annotations to identify potential therapeutic targets and single-cell RNA sequencing data to implicate brain cell types. We then used magnetic resonance imaging data to examine brain regions and circuits associated with psychopathology. Finally, we tested causal relationships between each spectrum and physical health conditions.

RESULTS: Using five gene identification methods, EXT was associated with 1,759 genes, INT with 454 genes, and EXT + INT with 1,138 genes. Drug repurposing analyses identified potential therapeutic targets, including those that affect dopamine and serotonin pathways. Expression of EXT genes was enriched in GABAergic, cortical, and hippocampal neurons, while INT genes were more narrowly linked to GABAergic neurons. EXT + INT liability was associated with reduced gray matter volume in the amygdala and subcallosal cortex. INT genetic liability showed stronger causal effects on physical health - including chronic pain and cardiovascular diseases - than EXT.

CONCLUSIONS: Our findings revealed shared and distinct pathways underlying psychopathology. Integrating genomic insights with the RDoC and HiTOP frameworks advanced our understanding of mechanisms that underlie EXT and INT psychopathology.

PMID:40340892 | DOI:10.1017/S0033291725000819

J Transl Med. 2025 May 8;23(1):516. doi: 10.1186/s12967-025-06535-x.

ABSTRACT

BACKGROUND: Long COVID is a major public health burden causing a diverse array of debilitating symptoms in tens of millions of patients globally. In spite of this overwhelming disease prevalence, staggering cost, severe impact on patients' lives and intense global research efforts, study of the disease has proved challenging due to its complexity. Genome-wide association studies (GWAS) have identified only four loci potentially associated with the disease, although these results did not statistically replicate between studies. A previous combinatorial analysis study identified a total of 73 genes that were highly associated with two long COVID cohorts in the predominantly (> 91%) white European ancestry Sano GOLD population, and we sought to reproduce these findings in the independent and ancestrally more diverse All of Us (AoU) population.

METHODS: We assessed the reproducibility of the 5343 long COVID disease signatures from the original study in the AoU population. Because the very small population sizes provide very limited power to replicate findings, we initially tested whether we observed a statistically significant enrichment of the Sano GOLD disease signatures that are also positively correlated with long COVID in the AoU cohort after controlling for population substructure.

RESULTS: For the Sano GOLD disease signatures that have a case frequency greater than 5% in AoU, we consistently observed a significant enrichment (77-83%, p < 0.01) of signatures that are also positively associated with long COVID in the AoU cohort. These encompassed 92% of the genes identified in the original study. At least five of the disease signatures found in Sano GOLD were also shown to be individually significantly associated with increased long COVID prevalence in the AoU population. Rates of signature reproducibility are strongest among self-identified white patients, but we also observe significant enrichment of reproducing disease associations in self-identified black/African-American and Hispanic/Latino cohorts. Signatures associated with 11 out of the 13 drug repurposing candidates identified in the original Sano GOLD study were reproduced in this study.

CONCLUSION: These results demonstrate the reproducibility of long COVID disease signal found by combinatorial analysis, broadly validating the results of the original analysis. They provide compelling evidence for a much broader array of genetic associations with long COVID than previously identified through traditional GWAS studies. This strongly supports the hypothesis that genetic factors play a critical role in determining an individual's susceptibility to long COVID following recovery from acute SARS-CoV-2 infection. It also lends weight to the drug repurposing candidates identified in the original analysis. Together these results may help to stimulate much needed new precision medicine approaches to more effectively diagnose and treat the disease. This is also the first reproduction of long COVID genetic associations across multiple populations with substantially different ancestry distributions. Given the high reproducibility rate across diverse populations, these findings may have broader clinical application and promote better health equity. We hope that this will provide confidence to explore some of these mechanisms and drug targets and help advance research into novel ways to diagnose the disease and accelerate the discovery and selection of better therapeutic options, both in the form of newly discovered drugs and/or the immediate prioritization of coordinated investigations into the efficacy of repurposed drug candidates.

PMID:40340717 | DOI:10.1186/s12967-025-06535-x

J Med Chem. 2025 May 9. doi: 10.1021/acs.jmedchem.5c00021. Online ahead of print.

ABSTRACT

Aging induces dysfunction and increases the risk of chronic diseases in the elderly, positioning the development of antiaging drugs to the forefront of research. Drug repurposing offers an efficient strategy for identifying antiaging lead compounds. In this study, we employed phenotypic screening and discovered that enrofloxacin could extend the lifespan in Caenorhabditis elegans. Based on these findings, we conducted rational drug design to eliminate its antibacterial activity while maintaining the lifespan-extending effect, with the goal of developing safe and novel antiaging compounds. Consequently, JX10 exhibited minimal antibacterial activity and competent antiaging effects in C. elegans, senescent cells, and aged mice. In terms of its mechanism, JX10 acted as a senomorphic agent by suppressing the expression of p38 MAPK and NF-κB. Furthermore, JX10 demonstrated favorable safety and pharmacokinetic properties, supporting the feasibility of JX10 as a promising candidate with the potential for therapeutic interventions in aging and aging-related diseases.

PMID:40340340 | DOI:10.1021/acs.jmedchem.5c00021

J Clin Endocrinol Metab. 2025 May 8:dgaf276. doi: 10.1210/clinem/dgaf276. Online ahead of print.

ABSTRACT

BACKGROUND: Observational studies have shown association between polycystic ovary syndrome (PCOS) and asthma-related traits. However, whether this association is genetically driven or arises from observational biases remains unclear.

METHODS: This study integrated data from 10,074 PCOS cases and asthma-related traits obtained from UK Biobank and FinnGen cohorts. Global and local genetic architectures were examined using pleiotropic analysis under the composite null hypothesis, Functional Mapping and Annotation of Genetic Associations, and fine-mapping credible set analysis. Drug database mining was employed to identify pleiotropic genes as potential therapeutic targets. Tissue and cell enrichment analyses were conducted to uncover shared biological mechanisms.

RESULTS: We identified 3 novel significant genetic loci for asthma subtypes (2 for allergic asthma and 1 for childhood asthma). A positive overall genetic correlation between PCOS and asthma-related traits was observed. We discovered 5 pleiotropic causal regions encompassing 13 genes, with ERBB3 emerging as a potential central gene contributing to the shared pathophysiology of PCOS and asthma-related traits. Additionally, drug repositioning analysis suggested anakinra and artenimol as potential therapeutic candidates for PCOS and asthma comorbidity. Linkage disequilibrium score for the specific expression of genes analysis, along with transcriptome-wide association study, further identified gene expression patterns at the tissue/cell level in hypothalamo-pituitary, exocrine/endocrine, respiratory, and urogenital systems.

CONCLUSIONS: Our findings provide novel insights into the genetic basis and biological processes underlying the association between PCOS and asthma-related traits, warranting evaluation of whether PCOS-specific asthma risk assessment could improve clinical outcomes.

PMID:40339110 | DOI:10.1210/clinem/dgaf276

J Clin Invest. 2025 May 8:e181394. doi: 10.1172/JCI181394. Online ahead of print.

ABSTRACT

The activated JAK2/STAT pathway is characteristic of myeloproliferative neoplasms (MPNs). Pleckstrin-2 (PLEK2) signalosome is downstream of the JAK2/STAT5 pathway and plays an important role in MPN development. The detailed molecular composition of this signalosome is unclear. Here, we revealed peptidylprolyl isomerase-like 2 (PPIL2) as a critical component of the complex in regulating human and murine erythropoiesis. PPIL2 was a direct target of STAT5 and was upregulated in MPN patients and a Jak2V617F MPN mouse model. Mechanistically, PPIL2 interacted with and catalyzed p53 polyubiquitination and proteasome-mediated degradation to promote cell growth. Ppil2 deficiency, or inhibition by cyclosporin A, led to a marked upregulation of p53 in vivo and ameliorated myeloproliferative phenotypes in Jak2V617F mice. Cyclosporin A also markedly reduced JAK2 mutated erythroid and myeloid proliferation in an induced pluripotent stem cell-derived human bone marrow organoid model. Our findings revealed PPIL2 as a critical component of the PLEK2 signalosome in driving MPN pathogenesis through negatively regulating p53, thus providing a target and an opportunity for drug repurposing by using cyclosporin A to treat MPNs.

PMID:40338661 | DOI:10.1172/JCI181394

Curr Med Chem. 2025 May 7. doi: 10.2174/0109298673367163250417065816. Online ahead of print.

ABSTRACT

BACKGROUND: Developing new COVID-19 antivirals requires understanding viral proteins, oxidative stress, and drug repositioning. Safety assessments of organochalcogen molecules derived from AZT in Caenorhabditis elegans offer promising prospects for new treatments.

OBJECTIVE: In this work, we evaluated the safety and antioxidant effect of eight organochalcogen AZT-derivatives using the free-living nematode C. elegans through chronic exposure [48h]. In addition, we used in silico computational modelling analyses to predict protein targets for these compounds.

METHODS: This study used survival, litter size, brood size as toxicological and safety parameters, subcellular localization of DAF-16, expression of SOD-3 and GST-4, and ROS levels to evaluate the antioxidant effects and target prediction by similarity set approach [SEA], protein-protein interaction [PPI] network analysis, and comparative phylogenetic analysis to predict protein targets for these compounds.

RESULTS: The molecules were safe at concentrations of 1-500 μM. AZT, R3a, and R3f promoted DAF-16 nuclear translocation without affecting SOD-3 levels. R3f reduced GST-4 levels, while R3a increased ROS levels. In silico analyses identified 16 human protein targets of AZT and its derivatives, linked to nucleotide metabolism, DNA replication, and anti-inflammatory pathways, showing high homology to C. elegans.

CONCLUSION: We hypothesize that Se and Te atom insertion may alter pharmacological properties by modulating DAF-16, GST-4, and ROS-related pathways. in silico data suggest these derivatives are promising for antiviral activity, targeting nucleotide metabolism and DNA replication while also potentially modulating the anti-inflammatory response, an appealing feature for COVID-19 treatment.

PMID:40337965 | DOI:10.2174/0109298673367163250417065816

Nucleic Acids Res. 2025 May 8:gkaf399. doi: 10.1093/nar/gkaf399. Online ahead of print.

ABSTRACT

Enzymes with buried active sites utilize molecular tunnels to exchange substrates, products, and solvent molecules with the surface. These transport mechanisms are crucial for protein function and influence various properties. As proteins are inherently dynamic, their tunnels also vary structurally. Understanding these dynamics is essential for elucidating structure-function relationships, drug discovery, and bioengineering. Caver Web 2.0 is a user-friendly web server that retains all Caver Web 1.0 functionalities while introducing key improvements: (i) generation of dynamic ensembles via automated molecular dynamics with YASARA, (ii) analysis of dynamic tunnels with CAVER 3.0, (iii) prediction of ligand trajectories in multiple snapshots with CaverDock 1.2, and (iv) customizable ligand libraries for virtual screening. Users can assess protein flexibility, identify and characterize tunnels, and predict ligand trajectories and energy profiles in both static and dynamic structures. Additionally, the platform supports virtual screening with FDA/EMA-approved drugs and user-defined datasets. Caver Web 2.0 is a versatile tool for biological research, protein engineering, and drug discovery, aiding the identification of strong inhibitors or new substrates to bind to the active sites or tunnels, and supporting drug repurposing efforts. The server is freely accessible at https://loschmidt.chemi.muni.cz/caverweb.

PMID:40337920 | DOI:10.1093/nar/gkaf399

Int J Biol Macromol. 2025 May 5:143959. doi: 10.1016/j.ijbiomac.2025.143959. Online ahead of print.

ABSTRACT

Drug repositioning refers to new medical application exploration for existing drugs. Heparins, beyond their well-known anticoagulant properties widely used in clinics, present the capacity to carry biosignal molecules that is responsible for other properties such as anti-inflammatory, angiogenesis. Thus, heparins interaction with different biosignal molecules such as cytokines and growth factors have recently drawn attention and have promoted heparin repositioning as an active excipient with useful applications as drug-delivery systems and biomaterial-based tissue engineering scaffolds. Indeed, biomaterial heparinization can further help in their formulation such as in self-assembled heparin-based hydrogels or nanoparticles, and improve their biocompatibility. Moreover, the capacity of heparin to carry biosignal molecules enables the direct functionalization of heparinized biomaterial for tissue engineering. Both heparin characteristics namely the biosignal molecule carrying and biomaterial heparinization are reviewed here along their combination for biomaterial functionalization in tissue engineering applications.

PMID:40334894 | DOI:10.1016/j.ijbiomac.2025.143959

PLoS One. 2025 May 7;20(5):e0322546. doi: 10.1371/journal.pone.0322546. eCollection 2025.

ABSTRACT

Proteins are fundamental biomolecules composed of one or more chains of amino acids. They are essential for all living organisms, contributing to various biological functions and regulatory processes. Alterations in protein structures and functions are closely linked to diseases, emphasizing the need for in-depth study. A thorough understanding of these associations is crucial for developing targeted and more effective therapeutic strategies.Computational analyses of biomedical data facilitate the identification of specific patterns in proteins associated with diseases, providing novel insights into their biological roles. This study introduces a computational approach designed to detect relevant sequence patterns within proteins. These patterns, characterized by specific amino acid arrangements, can be critical for protein functionality. The proposed methodology was applied to proteins targeted by drugs used in lung cancer treatment, a disease that remains the leading cause of cancer-related mortality worldwide. Given that non-small cell lung cancer represents 85-90% of all lung cancer cases, it was selected as the primary focus of this study.Significant sequence patterns were identified, establishing connections between drug-target proteins and proteins associated with lung cancer. Based on these findings, a novel computational framework was developed to extend this pattern-based analysis to proteins linked to other diseases. By employing this approach, relationships between lung cancer drug-target proteins and proteins associated with four additional cancer types were uncovered. These associations, characterized by shared amino acid sequence features, suggest potential opportunities for drug repurposing. Furthermore, validation through an extensive literature review confirmed biological links between lung cancer drug-target proteins and proteins related to other malignancies, reinforcing the potential of this methodology for identifying new therapeutic applications.

PMID:40334012 | DOI:10.1371/journal.pone.0322546