Infect Dis (Lond). 2025 Feb 20:1-8. doi: 10.1080/23744235.2025.2468510. Online ahead of print.

ABSTRACT

BACKGROUND: Tick-borne encephalitis (TBE) is a neurological disease caused by the tick-borne encephalitis virus (TBEV). Despite available vaccines, breakthrough infections occur, some fatal.

OBJECTIVES: As no antiviral therapy for TBE is currently approved, this study evaluated the in vitro activity of already licenced remdesivir (RDV) and sofosbuvir (SOF) for possible drug repurposing against TBEV.

METHODS: TBEV was cultured in A549 cells, and the inhibitory effects of RDV (GS-5734), its parent nucleotide GS-441524, and SOF (GS-7977) were assessed.

RESULTS: After 78 h, RDV demonstrated significantly lower EC50 values than SOF (0.14 vs. 11 µM) based on TBEV RNA levels measured by RT-qPCR. RDV also had a lower mean EC50 (0.55 µM) compared to GS-441524 and SOF (>8.9 and 13.1 µM, respectively) using crystal violet staining after 5 days. After 11 passages of TBEV in the presence of RDV, emergence of virus with a higher EC50 (1.32 vs. 0.55 µM) was detected with two mutations (L3122F and Y3278F) in NS5, the viral RNA-dependent RNA polymerase (RdRp), and one substitution in envelope (E) protein (E402G). Similarly, SOF resistance appeared after 20 passages, increasing EC50 values (35.5 vs. 10 µM).

CONCLUSION: RDV exhibits potent in vitro antiviral activity against TBEV via specific targeting of the viral RdRp as confirmed by the emergence of resistance-associated double NS5 substitutions in vitro in the presence of RDV. While the potential in vivo implications of the observed RDV resistance remain to be determined, these in vitro data support further assessment of RDV for the treatment of TBEV infection.

PMID:39973341 | DOI:10.1080/23744235.2025.2468510

Brief Bioinform. 2024 Nov 22;26(1):bbaf054. doi: 10.1093/bib/bbaf054.

ABSTRACT

Combination therapy has become increasingly important for treating complex diseases which often involve multiple pathways and targets. However, experimental screening of drug combinations is costly and time-consuming. The availability of large-scale transcriptomic datasets (e.g. CMap and LINCS) from in vitro drug treatment experiments makes it possible to computationally predict drug combinations with synergistic effects. Towards this end, we developed a computational approach, termed Identification of Drug Combinations via Multi-Set Operations (iDOMO), to predict drug synergy based on multi-set operations of drug and disease gene signatures. iDOMO quantifies the synergistic effect of a pair of drugs by taking into account the combination's beneficial and detrimental effects on treating a disease. We evaluated iDOMO, in a DREAM Challenge dataset with the matched, pre- and post-treatment gene expression data and cell viability information. We further evaluated the performance of iDOMO by concordance index and Spearman correlation on predicting the Highest Single Agency (HSA) synergy scores for four most common cancer types in two large-scale drug combination databases, showing that iDOMO significantly outperformed two existing popular drug combination approaches including the Therapeutic Score and the SynergySeq Orthogonality Score. Application of iDOMO to triple-negative breast cancer (TNBC) identified drug pairs with potential synergistic effects, with the combination of trifluridine and monobenzone being the most synergistic. Our in vitro experiments confirmed that the top predicted drug combination exerted a significant synergistic effect in inhibiting TNBC cell growth. In summary, iDOMO is an effective method for the in silico screening of synergistic drug combinations and will be a valuable tool for the development of novel therapeutics for complex diseases.

PMID:39973082 | DOI:10.1093/bib/bbaf054

Nat Commun. 2025 Feb 19;16(1):1755. doi: 10.1038/s41467-025-56690-4.

ABSTRACT

Repurposed drugs provide a rich source of potential therapies for Alzheimer's disease (AD) and other neurodegenerative disorders (NDD). Repurposed drugs have information from non-clinical studies, phase 1 dosing, and safety and tolerability data collected with the original indication. Computational approaches, "omic" studies, drug databases, and electronic medical records help identify candidate therapies. Generic repurposed agents lack intellectual property protection and are rarely advanced to late-stage trials for AD/NDD. In this review we define repurposing, describe the advantages and challenges of repurposing, offer strategies for overcoming the obstacles, and describe the key contributions of repurposing to the drug development ecosystem.

PMID:39971900 | DOI:10.1038/s41467-025-56690-4

Eur J Med Chem. 2025 Feb 15;288:117385. doi: 10.1016/j.ejmech.2025.117385. Online ahead of print.

ABSTRACT

Non-alcoholic fatty liver disease (NAFLD) is implicated in steatohepatitis (NASH), liver cirrhosis (LC) to hepatocellular carcinoma (HCC), sequentially. Herein, our aim was to unravel the nuanced key components (compounds, and targets) to deter the progressive severity concerning hepatocellular diseases. We incorporated rigor bioinformatics and computational screening tools to decode effector(s) against NAFLD, NASH, LC, and HCC. The corresponding ligands of PDX1 (transcription factor of INS; one agonist), and IL6 (thirty-two antagonists) were identified by Selleckchem. Molecular docking test (MDT) revealed that PDX1- BRD7552 conformer (-12.1 kcal/mol), and IL6- Forsythoside B (-11.4 kcal/mol) conformer formed most stable complex. In parallel, DFT proposed that BRD7552, and Forsythoside B had significant chemical properties to react the targets, respectively. In conclusion, we decoded causatives of the progressive liver disease with web-based tools in drug repositioning theory. BRD7552 as PDX1 agonist, and Forsythoside B as IL6 antagonist were attributed to synergistic efficacy against NAFLD-derived HCC.

PMID:39970728 | DOI:10.1016/j.ejmech.2025.117385

Cancer Med. 2025 Feb;14(4):e70681. doi: 10.1002/cam4.70681.

ABSTRACT

BACKGROUND: Ovarian cancer (OC) is the most lethal gynecological malignancy and a major global health concern, often diagnosed at advanced stages with poor survival rates. Despite advancements in treatment, resistance to standard chemotherapy remains a critical challenge with limited treatment options available. In recent years, the role of metabolic reprogramming in OC has emerged as a key factor driving tumor progression, therapy resistance, and poor clinical outcomes.

METHODS: This review explores the intricate connections between metabolic syndrome, enhanced glycolysis, and altered lipid metabolism within OC cells, which fuel the aggressive nature of the disease. We discuss how metabolic pathways are rewired in OC to support uncontrolled cell proliferation, survival under hypoxic conditions, and evasion of cell death mechanisms, positioning metabolic alterations as central to disease progression. The review also highlights the potential of repurposed metabolic-targeting drugs, such as metformin and statins, which have shown promise in preclinical studies for their ability to disrupt these altered metabolic pathways.

CONCLUSION: Drug repurposing offers a promising strategy to overcome chemoresistance and improve patient outcomes. Future research should focus on unraveling the complex metabolic networks in OC to develop innovative, targeted therapies that can enhance treatment efficacy and patient survival.

PMID:39969135 | DOI:10.1002/cam4.70681

Expert Rev Neurother. 2025 Feb 19. doi: 10.1080/14737175.2025.2469041. Online ahead of print.

ABSTRACT

INTRODUCTION: Post-traumatic epilepsy (PTE) accounts for 10% to 20% of all symptomatic epilepsies and 5% of all forms of epilepsy, and drug resistance is reported in up to 45% of cases.

AREAS COVERED: This is a focused narrative review that discusses the available data on the current and new PTE treatments, giving particular attention to the last 10 years.

EXPERT OPINION: Despite the disappointing results of many antiseizure medications (ASMs) in preventing epileptogenicity, it is still unclear whether the early intervention could lead to different clinical phenotypes in terms, for example, of seizure severity, drug resistance and comorbidity patterns. The same applies to compounds targeting neuroinflammation, oxidative stress and neurotransmission modulation. The heterogeneity of etiologies leading to PTE has limited the investigation and implementation of specific interventions. New studies must focus on identifying common pathways and mechanisms shared by different etiological processes, identifying biomarkers, and validating animal models of epileptogenesis concerning PTE. Drug repurposing research will facilitate rapid translation into clinical research. Multitarget drug combinations will also receive increasing attention. In terms of non-pharmacological treatments, Vagus Nerve Stimulation seems to be a good option, while epilepsy surgery and Deep Brain Stimulation deserve further attention.

PMID:39968755 | DOI:10.1080/14737175.2025.2469041

Front Cell Neurosci. 2025 Feb 4;19:1559821. doi: 10.3389/fncel.2025.1559821. eCollection 2025.

NO ABSTRACT

PMID:39968391 | PMC:PMC11832465 | DOI:10.3389/fncel.2025.1559821

Heliyon. 2025 Jan 10;11(3):e41894. doi: 10.1016/j.heliyon.2025.e41894. eCollection 2025 Feb 15.

ABSTRACT

Despite the vast vaccination campaigns against SARS-CoV-2, vaccine-resistant variants have emerged, and COVID-19 is continuing to spread with the fear of emergence of new variants that are resistant to the currently available anti-viral drugs. Hence, there is an urgent need to discover potential host-directed - rather than virus-directed - therapies against COVID-19. SARS-CoV-2 enters host cells through binding of the viral spike (S)-protein to the host angiotensin-converting enzyme 2 (ACE2) receptor, rendering the viral port of entry an attractive therapeutic target. Accordingly, this study aimed to investigate FDA-approved drugs for their potential repurposing to inhibit the entry point of SARS-CoV-2. Accordingly, the FDA-approved drugs library was enrolled in docking simulations to identify drugs that bind to the Spike-ACE2 interface. The drugs list retrieved by the docking simulations was shortlisted to 19 drugs based on docking scores and safety profiles. These drugs were screened for their ability to prevent binding between ACE2 and S-protein using an ELISA-based Spike-ACE2 binding assay. Five drugs showed statistically significant inhibition of binding between ACE2 and S-protein, ranging from 4 % to 37 %. Of those five, argatroban, glimepiride and ranolazine showed potential antiviral activity at IC50 concentrations well below their CC50 assessed by the plaque assay. Their mode of antiviral action was then determined using the plaque assay with some modifications, which revealed that argatroban acted mainly through a direct virucidal mechanism, while glimepiride largely inhibited viral replication, and ranolazine exerted its antiviral impact primarily through inhibiting viral adsorption. In conclusion, this study has identified three FDA-approved drugs - argatroban, glimepiride and ranolazine - which could potentially be repurposed and used for the management of COVID-19.

PMID:39968139 | PMC:PMC11834051 | DOI:10.1016/j.heliyon.2025.e41894

Small. 2025 Feb 19:e2409126. doi: 10.1002/smll.202409126. Online ahead of print.

ABSTRACT

This study advances sustainable pharmaceutical research for endometriosis by developing in vitro 3D cell culture models of endometriotic pathophysiology that allow antifibrotic drug candidates to be tested. Fibrosis is a key aspect of endometriosis, yet current cell models to study it remain limited. This work aims to bridge the translational gap between in vitro fibrosis research and preclinical testing of non-hormonal drug candidates. When grown in a 3D matrix of sustainably produced silk protein functionalized with a fibronectin-derived cell adhesion motif (FN-silk), endometrial stromal and epithelial cells respond to transforming growth factor beta-1 (TGF-β1) in a physiological manner as probed at the messenger RNA (mRNA) level. For stromal cells, this response to TGF-β1 is not observed in spheroids, while epithelial cell spheroids behave similarly to epithelial cell FN-silk networks. Pirfenidone, an antifibrotic drug approved for the treatment of idiopathic pulmonary fibrosis, reverses TGF-β1-induced upregulation of mRNA transcripts involved in fibroblast-to-myofibroblast transdifferentiation of endometrial stromal cells in FN-silk networks, supporting pirfenidone's potential as a repurposed non-hormonal endometriosis therapy. Overall, endometrial stromal cells cultured in FN-silk networks-which are composed of a sustainably produced, fully defined FN-silk protein-recapitulate fibrotic cellular behavior with high fidelity and enable antifibrotic drug testing.

PMID:39967482 | DOI:10.1002/smll.202409126

NPJ Antimicrob Resist. 2025 Feb 18;3(1):9. doi: 10.1038/s44259-024-00070-3.

ABSTRACT

Antimicrobial resistance (AMR) poses a growing global health threat. Nanomedicine, combined with drug repurposing, may help extend the effective lifespan of current and new antimicrobials. This review, presents an Australian perspective on nanotechnology-based therapies, highlighting scientific and clinical challenges. Early consideration of the potential barriers to market access may help to accelerate research translation, regulatory approval and patient access to nano-antimicrobial (NAM) drugs for resistant pathogens, not only in Australia, but globally.

PMID:39966608 | DOI:10.1038/s44259-024-00070-3

Neurotherapeutics. 2025 Feb 17:e00553. doi: 10.1016/j.neurot.2025.e00553. Online ahead of print.

ABSTRACT

Alzheimer's disease (AD) presents significant challenges in drug discovery and development due to its complex and poorly understood pathology and etiology. Digital twins (DTs) are recently developed virtual real-time representations of physical entities that enable rapid assessment of the bidirectional interaction between the virtual and physical domains. With recent advances in artificial intelligence (AI) and the growing accumulation of multi-omics and clinical data, application of DTs in healthcare is gaining traction. Digital twin technology, in the form of multiscale virtual models of patients or organ systems, can track health status in real time with continuous feedback, thereby driving model updates that enhance clinical decision-making. Here, we posit an additional role for DTs in drug discovery, with particular utility for complex diseases like AD. In this review, we discuss salient challenges in AD drug development, including complex disease pathology and comorbidities, difficulty in early diagnosis, and the current high failure rate of clinical trials. We also review DTs and discuss potential applications for predicting AD progression, discovering biomarkers, identifying new drug targets and opportunities for drug repurposing, facilitating clinical trials, and advancing precision medicine. Despite significant hurdles in this area, such as integration and standardization of dynamic medical data and issues of data security and privacy, DTs represent a promising approach for revolutionizing drug discovery in AD.

PMID:39965994 | DOI:10.1016/j.neurot.2025.e00553

Int J Biol Macromol. 2025 Feb 16:141057. doi: 10.1016/j.ijbiomac.2025.141057. Online ahead of print.

ABSTRACT

Of all isoforms, human carbonic anhydrase II (PF00194; EC 4.2.1.1), which is mostly found in red cells, kidneys, and the eyes, plays a pivotal role in numerous physiological processes, and its dysregulation has been linked to the wide range of illnesses, such as glaucoma. Finding new inhibitors that target Carbonic anhydrase II, therefore has great potential in drug discovery. Using drug repurposing approach, this study focused on the investigation of different drugs as Carbonic anhydrase II inhibitors and their structural studies using X-ray crystallography. For this purpose, 100 different drugs were evaluated for bovine and human carbonic anhydrase II inhibitory activity. Among all, two drugs, i.e. acetohexamide (1) and levosulpiride (54) were found to be active, with IC50 = 437.0 ± 0.2 and 1128 ± 0.75 μM, respectively. Mechanistic studies suggested that both drugs are competitive inhibitors of the human carbonic anhydrase II enzyme. The X-ray crystal structure analysis revealed that acetohexamide (1) interacts via terminal acetyl group with the active site residues of the carbonic anhydrase II enzyme, and showed strong hydrogen bonding with Zn, His94, His119, and Asn67. The sulfonamide group of levosulpiride was involved in strong hydrogen bonding with Zn, His94, His119, and Thr199. From in vivo studies, we found that carbonic anhydrase activity was significantly inhibited by the intraperitoneal administration of levosulpiride for up to 5 h. Our findings provide comprehensive insights for the optimization of the pharmacological profile of these drugs, and provide avenues for the exploration of different derivatives of these drugs with enhanced efficacy and fewer adverse effects.

PMID:39965680 | DOI:10.1016/j.ijbiomac.2025.141057

J Am Med Inform Assoc. 2025 Feb 18:ocaf035. doi: 10.1093/jamia/ocaf035. Online ahead of print.

ABSTRACT

OBJECTIVE: This study addresses the significant challenges posed by emerging SARS-CoV-2 variants, particularly in developing diagnostics and therapeutics. Drug repurposing is investigated by identifying critical regulatory proteins impacted by the virus, providing rapid and effective therapeutic solutions for better disease management.

MATERIALS AND METHODS: We employed a comprehensive approach combining mathematical modeling and efficient parameter estimation to study the transient responses of regulatory proteins in both normal and virus-infected cells. Proportional-integral-derivative (PID) controllers were used to pinpoint specific protein targets for therapeutic intervention. Additionally, advanced deep learning models and molecular docking techniques were applied to analyze drug-target and drug-drug interactions, ensuring both efficacy and safety of the proposed treatments. This approach was applied to a case study focused on the cytokine storm in COVID-19, centering on Angiotensin-converting enzyme 2 (ACE2), which plays a key role in SARS-CoV-2 infection.

RESULTS: Our findings suggest that activating ACE2 presents a promising therapeutic strategy, whereas inhibiting AT1R seems less effective. Deep learning models, combined with molecular docking, identified Lomefloxacin and Fostamatinib as stable drugs with no significant thermodynamic interactions, suggesting their safe concurrent use in managing COVID-19-induced cytokine storms.

DISCUSSION: The results highlight the potential of ACE2 activation in mitigating lung injury and severe inflammation caused by SARS-CoV-2. This integrated approach accelerates the identification of safe and effective treatment options for emerging viral variants.

CONCLUSION: This framework provides an efficient method for identifying critical regulatory proteins and advancing drug repurposing, contributing to the rapid development of therapeutic strategies for COVID-19 and future global pandemics.

PMID:39965087 | DOI:10.1093/jamia/ocaf035

Front Public Health. 2025 Feb 3;13:1520467. doi: 10.3389/fpubh.2025.1520467. eCollection 2025.

ABSTRACT

Rare diseases, affecting millions globally, pose a significant healthcare burden despite impacting a small population. While approximately 70% of all rare diseases are genetic and often begin in childhood, diagnosis remains slow and only 5% have approved treatments. The UN emphasizes improved access to primary care (diagnostic and potentially therapeutic) for these patients and their families. Next-generation sequencing (NGS) offers hope for earlier and more accurate diagnoses, potentially leading to preventative measures and targeted therapies. In here, we explore the therapeutic landscape for rare diseases, analyzing drugs in development and those already approved by the European Medicines Agency (EMA). We differentiate between orphan drugs with market exclusivity and repurposed existing drugs, both crucial for patients. By analyzing market size, segmentation, and publicly available data, this comprehensive study aims to pave the way for improved understanding of the treatment landscape and a wider knowledge accessibility for rare disease patients.

PMID:39963479 | PMC:PMC11830808 | DOI:10.3389/fpubh.2025.1520467

Med Biol Eng Comput. 2025 Feb 17. doi: 10.1007/s11517-025-03325-x. Online ahead of print.

ABSTRACT

Computational drug repositioning approaches should be investigated for the identification of new treatments for Alzheimer's patients as a huge amount of omics data has been produced during pre-clinical and clinical studies. Here, we investigated a gene network in Alzheimer's patients to detect a proper therapeutic target. We screened the targets of different drugs (34,006 compounds) using data available in the Connectivity Map database. Then, we analyzed transcriptome profiles of Alzheimer's patients to discover a network of gene-drugs based on mutual information, representing an index of dependence among genes. This study identified a network consisting of 25 genes and compounds and interconnected biological processes using computational approaches. The results also highlight the diagnostic role of the 25 genes since we obtained good classification performances using a neural network model. We also suggest 12 repurposable drugs (like KU-60019, AM-630, CP55940, enflurane, ginkgolide B, linopirdine, apremilast, ibudilast, pentoxifylline, roflumilast, acitretin, and tamibarotene) interacting with 6 genes (ATM, CNR1, GLRB, KCNQ2, PDE4B, and RARA), that we linked to retrograde endocannabinoid signaling, synaptic vesicle cycle, morphine addiction, and homologous recombination.

PMID:39961913 | DOI:10.1007/s11517-025-03325-x

J Bioinform Comput Biol. 2024 Dec;22(6):2450028. doi: 10.1142/S0219720024500288. Epub 2025 Feb 1.

ABSTRACT

The prediction of drug-target affinity (DTA) is crucial for efficiently identifying potential targets for drug repurposing, thereby reducing resource wastage. In this paper, we propose a novel graph-based deep learning model for DTA that leverages adaptive structure-aware pooling for graph processing. Our approach integrates a self-attention mechanism with an enhanced graph neural network to capture the significance of each node in the graph, marking a significant advancement in graph feature extraction. Specifically, adjacent nodes in the 2D molecular graph are aggregated into clusters, with the features of these clusters weighted according to their attention scores to form the final molecular representation. In terms of model architecture, we utilize both global and hierarchical pooling, and assess the performance of the model on multiple benchmark datasets. The evaluation results on the KIBA dataset show that our model achieved the lowest mean squared error (MSE) of 0.126, which is a 0.5% reduction compared to the best-performing baseline method. Additionally, to validate the generalization capabilities of the model, we conduct comparative experiments on regression and binary classification tasks. The results demonstrate that our model outperforms previous models in both types of tasks.

PMID:39961610 | DOI:10.1142/S0219720024500288

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