Sci Transl Med. 2023 Jun 21;15(701):eabq7839. doi: 10.1126/scitranslmed.abq7839. Epub 2023 Jun 21.

ABSTRACT

Ca2+/calmodulin-dependent protein kinase II (CaMKII) hyperactivity causes cardiac arrhythmias, a major source of morbidity and mortality worldwide. Despite proven benefits of CaMKII inhibition in numerous preclinical models of heart disease, translation of CaMKII antagonists into humans has been stymied by low potency, toxicity, and an enduring concern for adverse effects on cognition due to an established role of CaMKII in learning and memory. To address these challenges, we asked whether any clinically approved drugs, developed for other purposes, were potent CaMKII inhibitors. For this, we engineered an improved fluorescent reporter, CaMKAR (CaMKII activity reporter), which features superior sensitivity, kinetics, and tractability for high-throughput screening. Using this tool, we carried out a drug repurposing screen (4475 compounds in clinical use) in human cells expressing constitutively active CaMKII. This yielded five previously unrecognized CaMKII inhibitors with clinically relevant potency: ruxolitinib, baricitinib, silmitasertib, crenolanib, and abemaciclib. We found that ruxolitinib, an orally bioavailable and U.S. Food and Drug Administration-approved medication, inhibited CaMKII in cultured cardiomyocytes and in mice. Ruxolitinib abolished arrhythmogenesis in mouse and patient-derived models of CaMKII-driven arrhythmias. A 10-min pretreatment in vivo was sufficient to prevent catecholaminergic polymorphic ventricular tachycardia, a congenital source of pediatric cardiac arrest, and rescue atrial fibrillation, the most common clinical arrhythmia. At cardioprotective doses, ruxolitinib-treated mice did not show any adverse effects in established cognitive assays. Our results support further clinical investigation of ruxolitinib as a potential treatment for cardiac indications.

PMID:37343080 | DOI:10.1126/scitranslmed.abq7839

Eur J Pharm Sci. 2023 Jun 18:106501. doi: 10.1016/j.ejps.2023.106501. Online ahead of print.

ABSTRACT

Gynaecological health is a neglected field of research that includes conditions such as endometriosis, uterine fibroids, infertility, viral and bacterial infections, and cancers. There is a clinical need to develop dosage forms for gynecological diseases that increase efficacy and reduce side effects and explore new materials with properties tailored to the vaginal mucosa and milieu. Here, we developed a 3D printed semisolid vaginal ovule containing pirfenidone, a repurposed drug candidate for endometriosis. Vaginal drug delivery allows direct targeting of the reproductive organs via the first uterine pass effect, but vaginal dosage forms can be challenging to self-administer and retain in situ for periods of more than 1-3 h. Here, we show that a semisoft alginate-based vaginal suppository manufactured using semisolid extrusion additive manufacturing is superior to vaginal ovules made using standard excipients. The 3D-printed ovule showed a controlled release profile of pirfenidone in vitro in standard and biorelevant release tests, as well as better mucoadhesive properties ex vivo. An exposure time of 24 h of pirfenidone to a monolayer culture of an endometriotic epithelial cell line, 12Z, is necessary to reduce the cells' metabolic activity, which demonstrates the need for a sustained release formulation of pirfenidone. 3D printing allowed us to formulate mucoadhesive polymers into a semisolid ovule with controlled release of pirfenidone. This work enables further preclinical and clinical studies into vaginally administered pirfenidone to assess its efficacy as a repurposed endometriosis treatment.

PMID:37339708 | DOI:10.1016/j.ejps.2023.106501

BMC Med. 2023 Jun 21;21(1):209. doi: 10.1186/s12916-023-02877-9.

ABSTRACT

BACKGROUND: Currently, the main pharmaceutical intervention for COVID-19 is vaccination. While antidepressant (AD) drugs have shown some efficacy in treatment of symptomatic COVID-19, their preventative potential remains largely unexplored. Analysis of association between prescription of ADs and COVID-19 incidence in the population would be beneficial for assessing the utility of ADs in COVID-19 prevention.

METHODS: Retrospective study of association between AD prescription and COVID-19 diagnosis was performed in a cohort of community-dwelling adult mental health outpatients during the 1st wave of COVID-19 pandemic in the UK. Clinical record interactive search (CRIS) was performed for mentions of ADs within 3 months preceding admission to inpatient care of the South London and Maudsley (SLaM) NHS Foundation Trust. Incidence of positive COVID-19 tests upon admission and during inpatient treatment was the primary outcome measure.

RESULTS: AD mention was associated with approximately 40% lower incidence of positive COVID-19 test results when adjusted for socioeconomic parameters and physical health. This association was also observed for prescription of ADs of the selective serotonin reuptake inhibitor (SSRI) class.

CONCLUSIONS: This preliminary study suggests that ADs, and SSRIs in particular, may be of benefit for preventing COVID-19 infection spread in the community. The key limitations of the study are its retrospective nature and the focus on a mental health patient cohort. A more definitive assessment of AD and SSRI preventative potential warrants prospective studies in the wider demographic.

PMID:37340474 | DOI:10.1186/s12916-023-02877-9

Sci Rep. 2023 Jun 20;13(1):10032. doi: 10.1038/s41598-023-37120-1.

ABSTRACT

Diabetic foot ulcers (DFUs) are a common complication of diabetes and can lead to severe disability and even amputation. Despite advances in treatment, there is currently no cure for DFUs and available drugs for treatment are limited. This study aimed to identify new candidate drugs and repurpose existing drugs to treat DFUs based on transcriptomics analysis. A total of 31 differentially expressed genes (DEGs) were identified and used to prioritize the biological risk genes for DFUs. Further investigation using the database DGIdb revealed 12 druggable target genes among 50 biological DFU risk genes, corresponding to 31 drugs. Interestingly, we highlighted that two drugs (urokinase and lidocaine) are under clinical investigation for DFU and 29 drugs are potential candidates to be repurposed for DFU therapy. The top 5 potential biomarkers for DFU from our findings are IL6ST, CXCL9, IL1R1, CXCR2, and IL10. This study highlights IL1R1 as a highly promising biomarker for DFU due to its high systemic score in functional annotations, that can be targeted with an existing drug, Anakinra. Our study proposed that the integration of transcriptomic and bioinformatic-based approaches has the potential to drive drug repurposing for DFUs. Further research will further examine the mechanisms by which targeting IL1R1 can be used to treat DFU.

PMID:37340026 | DOI:10.1038/s41598-023-37120-1

Sci Rep. 2023 Jun 19;13(1):9952. doi: 10.1038/s41598-023-36872-0.

ABSTRACT

Modifications in the epigenetic landscape have been considered a hallmark of cancer. Histone deacetylation is one of the crucial epigenetic modulations associated with the aggressive progression of various cancer subtypes. Herein, we have repurposed the neprilysin inhibitor sacubitrilat as a potent anticancer agent using in-silico protein-ligand interaction profiler (PLIP) analysis, molecular docking, and in vitro studies. The screening of PLIP profiles between vorinostat/panobinostat and HDACs/LTA4H followed by molecular docking resulted in five (Sacubitrilat, B65, BDS, BIR, and NPV) FDA-approved, experimental and investigational drugs. Sacubitrilat has demonstrated promising anticancer activity against colorectal cancer (SW-480) and triple-negative breast cancer (MDA-MB-231) cells, with IC50 values of 14.07 μg/mL and 23.02 μg/mL, respectively. FACS analysis revealed that sacubitrilat arrests the cell cycle at the G0/G1 phase and induces apoptotic-mediated cell death in SW-480 cells. In addition, sacubitrilat inhibited HDAC isoforms at the transcriptomic level by 0.7-0.9 fold and at the proteomic level by 0.5-0.6 fold as compared to the control. Sacubitrilat increased the protein expression of tumor-suppressor (p53) and pro-apoptotic makers (Bax and Bid) by 0.2-2.5 fold while decreasing the expression of anti-apoptotic Bcl2 and Nrf2 proteins by 0.2-0.5 fold with respect to control. The observed cleaved PARP product indicates that sacubitrilat induces apoptotic-mediated cell death. This study may pave the way to identify the anticancer potential of sacubitrilat and can be explored in human clinical trials.

PMID:37336927 | PMC:PMC10279647 | DOI:10.1038/s41598-023-36872-0

Genes Dis. 2023 Jul;10(4):1402-1428. doi: 10.1016/j.gendis.2022.12.019. Epub 2023 Apr 7.

ABSTRACT

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes the complicated disease COVID-19. Clinicians are continuously facing huge problems in the treatment of patients, as COVID-19-specific drugs are not available, hence the principle of drug repurposing serves as a one-and-only hope. Globally, the repurposing of many drugs is underway; few of them are already approved by the regulatory bodies for their clinical use and most of them are in different phases of clinical trials. Here in this review, our main aim is to discuss in detail the up-to-date information on the target-based pharmacological classification of repurposed drugs, the potential mechanism of actions, and the current clinical trial status of various drugs which are under repurposing since early 2020. At last, we briefly proposed the probable pharmacological and therapeutic drug targets that may be preferred as a futuristic drug discovery approach in the development of effective medicines.

PMID:37334160 | PMC:PMC10079314 | DOI:10.1016/j.gendis.2022.12.019

Front Aging Neurosci. 2023 Jun 2;15:1161405. doi: 10.3389/fnagi.2023.1161405. eCollection 2023.

ABSTRACT

BACKGROUND: Neuroinflammation is one of the key factors leading to neuron death and synapse dysfunction in Alzheimer's disease (AD). Amyloid-β (Aβ) is thought to have an association with microglia activation and trigger neuroinflammation in AD. However, inflammation response in brain disorders is heterogenous, and thus, it is necessary to unveil the specific gene module of neuroinflammation caused by Aβ in AD, which might provide novel biomarkers for AD diagnosis and help understand the mechanism of the disease.

METHODS: Transcriptomic datasets of brain region tissues from AD patients and the corresponding normal tissues were first used to identify gene modules through the weighted gene co-expression network analysis (WGCNA) method. Then, key modules highly associated with Aβ accumulation and neuroinflammatory response were pinpointed by combining module expression score and functional information. Meanwhile, the relationship of the Aβ-associated module to the neuron and microglia was explored based on snRNA-seq data. Afterward, transcription factor (TF) enrichment and the SCENIC analysis were performed on the Aβ-associated module to discover the related upstream regulators, and then a PPI network proximity method was employed to repurpose the potential approved drugs for AD.

RESULTS: A total of 16 co-expression modules were primarily obtained by the WGCNA method. Among them, the green module was significantly correlated with Aβ accumulation, and its function was mainly involved in neuroinflammation response and neuron death. Thus, the module was termed the amyloid-β induced neuroinflammation module (AIM). Moreover, the module was negatively correlated with neuron percentage and showed a close association with inflammatory microglia. Finally, based on the module, several important TFs were recognized as potential diagnostic biomarkers for AD, and then 20 possible drugs including ibrutinib and ponatinib were picked out for the disease.

CONCLUSION: In this study, a specific gene module, termed AIM, was identified as a key sub-network of Aβ accumulation and neuroinflammation in AD. Moreover, the module was verified as having an association with neuron degeneration and inflammatory microglia transformation. Moreover, some promising TFs and potential repurposing drugs were presented for AD based on the module. The findings of the study shed new light on the mechanistic investigation of AD and might make benefits the treatment of the disease.

PMID:37333458 | PMC:PMC10272561 | DOI:10.3389/fnagi.2023.1161405

ArXiv. 2023 May 24:arXiv:2305.15453v1. Preprint.

ABSTRACT

In recent decades, the development of new drugs has become increasingly expensive and inefficient, and the molecular mechanisms of most pharmaceuticals remain poorly understood. In response, computational systems and network medicine tools have emerged to identify potential drug repurposing candidates. However, these tools often require complex installation and lack intuitive visual network mining capabilities. To tackle these challenges, we introduce Drugst.One, a platform that assists specialized computational medicine tools in becoming user-friendly, web-based utilities for drug repurposing. With just three lines of code, Drugst.One turns any systems biology software into an interactive web tool for modeling and analyzing complex protein-drug-disease networks. Demonstrating its broad adaptability, Drugst.One has been successfully integrated with 21 computational systems medicine tools. Available at https://drugst.one, Drugst.One has significant potential for streamlining the drug discovery process, allowing researchers to focus on essential aspects of pharmaceutical treatment research.

PMID:37332567 | PMC:PMC10274948

FEMS Microbes. 2022 Apr 26;3:xtac014. doi: 10.1093/femsmc/xtac014. eCollection 2022.

ABSTRACT

A total of 1253 compounds approved as therapeutic drugs in Japan (Pharmaceuticals and Medical Devices Agency (PMDA)-approved compounds) were screened for their therapeutic effects against Staphylococcus aureus infection using the silkworm infection model. In the first stage of screening with an index of prolonged survival, 80 compounds were identified as hits. Of these, 64 compounds were clinically used as antimicrobial agents, and the remaining 16 compounds were not. The 16 compounds were examined for their dose-dependent therapeutic effects on the silkworm model as a second screening step, and we obtained five compounds as a result. One of the compounds (capecitabine) had no documented in vitro minimum inhibitory concentration (MIC) value against S. aureus. The MIC value of capecitabine against S. aureus strains ranged from 125 to 250 µg/ml, and capecitabine was therapeutically effective at a dose of 200 mg/kg in a murine model of S. aureus infection. These results suggest that silkworm-based drug repositioning studies are of potential value. Furthermore, the therapeutic effects of capecitabine demonstrated in this study provide an important scientific rationale for clinical observational studies examining the association between staphylococcal infection events and capecitabine administration in cancer chemotherapy patients.

PMID:37332511 | PMC:PMC10117882 | DOI:10.1093/femsmc/xtac014

Int J Antimicrob Agents. 2023 Jun 14:106888. doi: 10.1016/j.ijantimicag.2023.106888. Online ahead of print.

ABSTRACT

The rapid emergence and spread of multidrug- or pan-drug-resistant bacterial pathogens, such as ESKAPE, pose a serious threat to global health. However, the development of novel antibiotics is hindered by difficulties in identifying new antibiotic targets and the rapid development of drug resistance. Drug repurposing is an effective alternative strategy for combating antibiotic resistance that both saves resources and extends the life of existing antibiotics in combination treatment regimens. Screening of a chemical compound library identified BMS-833923 (BMS), a smoothened antagonist, that directly kills Gram-positive bacteria and potentiates colistin to destroy various Gram-negative bacteria. BMS did not induce detectable antibiotic resistance in vitro and showed effective activity against drug-resistant bacteria in vivo. Mechanistic studies revealed that BMS caused membrane disruption by targeting membrane phospholipid phosphatidylglycerol (PG) and cardiolipin (CL), promoting membrane dysfunction, metabolic disturbance, leakage of cellular components, and ultimately cell death. The current study describes a potential strategy to enhance colistin efficacy and combat multidrug-resistant ESKAPE pathogens.

PMID:37328075 | DOI:10.1016/j.ijantimicag.2023.106888

J Pathol. 2023 Jun 16. doi: 10.1002/path.6142. Online ahead of print.

ABSTRACT

Lactic acid export from highly glycolytic cancer cells is critical to maintain cellular homeostasis. The identification of syrosingopine as an inhibitor of the lactate transporters monocarboxylate transporter (MCT) 1 and the tumor-induced isoform MCT4 suggests a potential therapeutic intervention. In a recent issue of this journal, Van der Vreken, Oudaert I and colleagues showed that syrosingopine, together with another drug metformin, had a synergistic effect in killing cultured multiple myeloma (MM) cell lines, primary MM blasts from patients, and in a mouse MM model. The antidiabetic drug metformin is currently also being investigated for anticancer efficacy. The synthetic lethality of these two drugs, which have good safety records and are approved for noncancer indications, raises the possibility of their combination for clinical anticancer therapy. © 2023 The Author. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

PMID:37325933 | DOI:10.1002/path.6142

Heliyon. 2023 Jun;9(6):e17174. doi: 10.1016/j.heliyon.2023.e17174. Epub 2023 Jun 12.

ABSTRACT

We have developed a mechanistic model of SARS-CoV-2 and SARS-CoV infection, exploring the relationship between the viral diffusion in the mucosa and viral affinity for the angiotensin converting enzyme 2 (ACE2) target. Utilising the structural similarity of SARS-CoV and SARS-CoV-2 and a shared viral target receptor (ACE2), but a dramatic difference in upper or lower respiratory tract infectivity, we were able to generate insights into the linkage of mucosal diffusion and target receptor affinity in determining the pathophysiological pathways of these two viruses. Our analysis reveals that for SARS-CoV-2 the higher affinity of ACE2 binding, the faster and more complete the mucosal diffusion in its transport from the upper airway to the region of the ACE2 target on the epithelium. This diffusional process is essential for the presentation of this virus to the furin catalysed highly efficient entry and infection process in the upper respiratory tract epithelial cells. A failure of SARS-CoV to follow this path is associated with lower respiratory tract infection and decreased infectivity. Thus, our analysis supports the view that through tropism SARS-CoV-2 has evolved a highly efficient membrane entry process that can act in concert with a high binding affinity of this virus and its variants for its ACE2 which in turn promotes enhanced movement of the virus from airway to epithelium. In this way ongoing mutations yielding higher affinities of SARS-CoV-2 for the ACE2 target becomes the basis for higher upper respiratory tract infectivity and greater viral spread. It is concluded that SARS-CoV-2 is constrained in the extent of its activities by the fundamental laws of physics and thermodynamics. Laws that describe diffusion and molecular binding. Moreover it can be speculated that the very earliest contact of this virus with the human mucosa defines the pathogenesis of this infection.

PMID:37325453 | PMC:PMC10259165 | DOI:10.1016/j.heliyon.2023.e17174

Case Rep Oncol Med. 2023 Jun 7;2023:2079654. doi: 10.1155/2023/2079654. eCollection 2023.

ABSTRACT

BACKGROUND: Recurrent platinum-resistant clear-cell ovarian cancer has a low overall survival duration of 7-8 months, making it a fatal disease. Currently, chemotherapy is the major kind of treatment, but it offers little advantage. Repurposed conventional drugs have recently been found to offer the ability to control cancer with few side effects and at a reasonable cost to healthcare organizations. Case Presentation. In this case report, we present the case of a 41-year-old Thai female patient diagnosed with recurrent platinum-resistant clear-cell ovarian cancer (PRCCC) in the year 2020. After undergoing chemotherapy for two courses and failing to respond to treatment, she began alternative medicine with repurposing drugs in November 2020. Simvastatin, metformin, niclosamide, mebendazole, itraconazole, loratadine, and chloroquine were also administered. Two months after therapy, a computerized tomography (CT) scan revealed a conflict between a decline in tumor marker levels (CA 125, CA 19-9) and an increase in the number of lymph nodes. However, after continuing all medications for 4 months, the CA 125 level decreased from 303.6 to 54 U/ml, and the CA 19-9 level decreased from 1210.3 to 386.10 U/ml. The patient's EQ-5D-5L score increased from 0.631 to 0.829 (abdominal pain and depression), indicating improved quality of life. Overall survival was 8.5 months, and progression-free survival was 2 months.

CONCLUSION: The response to drug repurposing is demonstrated by a four-month-long improvement in symptoms. This work introduces a novel strategy for the management of recurrent platinum-resistant clear-cell ovarian cancer that needs further evaluation in large-scale studies.

PMID:37323625 | PMC:PMC10266906 | DOI:10.1155/2023/2079654

Biochem Pharmacol. 2023 Jun 13:115644. doi: 10.1016/j.bcp.2023.115644. Online ahead of print.

ABSTRACT

Fibrosis is a pathological repair process common among organs, that responds to damage by replacement of tissue with non-functional connective tissue. Despite the widespread prevalence of tissue fibrosis, manifesting in numerous disease states across myriad organs, therapeutic modalities to prevent or alleviate fibrosis are severely lacking in quantity and efficacy. Alongside development of new drugs, repurposing of existing drugs may be a complementary strategy to elect anti-fibrotic compounds for pharmacologic treatment of tissue fibrosis. Drug repurposing can provide key advantages to de novo drug discovery, harnessing the benefits of previously elucidated mechanisms of action and already existing pharmacokinetic profiles. One class of drugs a wealth of clinical data and extensively studied safety profiles is the statins, a class of antilipidemic drugs widely prescribed for hypercholesterolemia. In addition to these widely utilized lipid-lowering effects, increasing data from cellular, pre-clinical mammalian, and clinical human studies have also demonstrated that statins are able to alleviate tissue fibrosis originating from a variety of pathological insults via lesser-studied, pleiotropic effects of these drugs. Here we review literature demonstrating evidence for direct effects of statins antagonistic to fibrosis, as well as much of the available mechanistic data underlying these effects. A more complete understanding of the anti-fibrotic effects of statins may enable a clearer picture of their anti-fibrotic potential for various clinical indications. Additionally, more lucid comprehension of the mechanisms by which statins exert anti-fibrotic effects may aid in development of novel therapeutic agents that target similar pathways but with greater specificity or efficacy.

PMID:37321414 | DOI:10.1016/j.bcp.2023.115644

Nat Commun. 2023 Jun 15;14(1):3570. doi: 10.1038/s41467-023-39301-y.

ABSTRACT

Computational drug repurposing aims to identify new indications for existing drugs by utilizing high-throughput data, often in the form of biomedical knowledge graphs. However, learning on biomedical knowledge graphs can be challenging due to the dominance of genes and a small number of drug and disease entities, resulting in less effective representations. To overcome this challenge, we propose a "semantic multi-layer guilt-by-association" approach that leverages the principle of guilt-by-association - "similar genes share similar functions", at the drug-gene-disease level. Using this approach, our model DREAMwalk: Drug Repurposing through Exploring Associations using Multi-layer random walk uses our semantic information-guided random walk to generate drug and disease-populated node sequences, allowing for effective mapping of both drugs and diseases in a unified embedding space. Compared to state-of-the-art link prediction models, our approach improves drug-disease association prediction accuracy by up to 16.8%. Moreover, exploration of the embedding space reveals a well-aligned harmony between biological and semantic contexts. We demonstrate the effectiveness of our approach through repurposing case studies for breast carcinoma and Alzheimer's disease, highlighting the potential of multi-layer guilt-by-association perspective for drug repurposing on biomedical knowledge graphs.

PMID:37322032 | DOI:10.1038/s41467-023-39301-y

Curr Top Med Chem. 2023 Jun 14. doi: 10.2174/1568026623666230614165548. Online ahead of print.

ABSTRACT

Colorectal cancer (CRC) is a multifaceted and heterogeneous ailment that affects the colon or rectum of the digestive system. It is the second most commonly occurring form of cancer and ranks third in terms of mortality rate. The progression of CRC does not occur due to a single mutational event; rather, it is the result of the sequential and cumulative accumulation of mutations in key driver genes of signaling pathways. The most significant signaling pathways, which have oncogenic potential due to their deregulation, include Wnt/β-catenin, Notch, TGF-β, EGFR/MAPK, and PI3K/AKT pathways. Numerous drug target therapies have been developed to treat CRC using small molecule inhibitors, antibodies, or peptides. Although drug-targeted therapy is effective in most cases, the development of resistance mechanisms in CRC has raised questions about their efficacy. To overcome this issue, a novel approach of to drug repurposing has come to light, which utilizes already FDA-approved drugs to treat CRC. This approach has shown some promising experimental results, making it a crucial avenue of research in the treatment of CRC.

PMID:37317918 | DOI:10.2174/1568026623666230614165548

J Biomed Inform. 2023 Jun 12:104421. doi: 10.1016/j.jbi.2023.104421. Online ahead of print.

ABSTRACT

Angiogenesis is essential for tumor growth and cancer metastasis. Identifying the molecular pathways involved in this process is the first step for the rational design of new therapeutic strategies to improve cancer treatment. In the recent years, RNA-seq data analysis has helped to determine the genetic and molecular factors associated with different types of cancer. In this work we perform an integrative analysis using RNA-seq data from HUVEC and patients with angiogenesis-dependent diseases to find genes that may be potential candidates to understand both the prognosis of tumor angiogenesis deregulation and how this process is orchestrated at the genetic and molecular level. We downloaded four different RNA-seq datasets (including cellular models of tumor angiogenesis and ischaemic heart disease) from the Sequence Read Archive. Our integrative analysis includes a first step to determine differentially and co-expressed genes. For this, we used the ExpHunter Suite, an R package that performs differential expression, co-expression and functional analysis of RNA-seq data. We used both differentially and co-expressed genes to explore the human gene interaction network and determine which genes were found in the different datasets and that may be key for the angiogenesis deregulation. Finally, we performed drug repositioning analysis to find potential targets related to angiogenesis inhibition. Results show that among the transcriptional alterations identified, SEMA3D and IL33 genes are deregulated in all datasets. Microenvironment remodelling, cell cycle, lipid metabolism and vesicular transport are the main molecular pathways altered. In addition to this, interacting genes are involved in intracellular signalling pathways, specially in immune system and semaphorines, respiratory electron transport and fatty acid metabolism. This methodology can be used for finding common transcriptional alterations in other genetically-based diseases.

PMID:37315831 | DOI:10.1016/j.jbi.2023.104421

JAMA Psychiatry. 2023 Jun 14. doi: 10.1001/jamapsychiatry.2023.1808. Online ahead of print.

ABSTRACT

IMPORTANCE: Psychiatric disorders display high levels of comorbidity and genetic overlap, necessitating multivariate approaches for parsing convergent and divergent psychiatric risk pathways. Identifying gene expression patterns underlying cross-disorder risk also stands to propel drug discovery and repurposing in the face of rising levels of polypharmacy.

OBJECTIVE: To identify gene expression patterns underlying genetic convergence and divergence across psychiatric disorders along with existing pharmacological interventions that target these genes.

DESIGN, SETTING, AND PARTICIPANTS: This genomic study applied a multivariate transcriptomic method, transcriptome-wide structural equation modeling (T-SEM), to investigate gene expression patterns associated with 5 genomic factors indexing shared risk across 13 major psychiatric disorders. Follow-up tests, including overlap with gene sets for other outcomes and phenome-wide association studies, were conducted to better characterize T-SEM results. The Broad Institute Connectivity Map Drug Repurposing Database and Drug-Gene Interaction Database public databases of drug-gene pairs were used to identify drugs that could be repurposed to target genes found to be associated with cross-disorder risk. Data were collected from database inception up to February 20, 2023.

MAIN OUTCOMES AND MEASURES: Gene expression patterns associated with genomic factors or disorder-specific risk and existing drugs that target these genes.

RESULTS: In total, T-SEM identified 466 genes whose expression was significantly associated (z ≥ 5.02) with genomic factors and 36 genes with disorder-specific effects. Most associated genes were found for a thought disorders factor, defined by bipolar disorder and schizophrenia. Several existing pharmacological interventions were identified that could be repurposed to target genes whose expression was associated with the thought disorders factor or a transdiagnostic p factor defined by all 13 disorders.

CONCLUSIONS AND RELEVANCE: The findings from this study shed light on patterns of gene expression associated with genetic overlap and uniqueness across psychiatric disorders. Future versions of the multivariate drug repurposing framework outlined here have the potential to identify novel pharmacological interventions for increasingly common, comorbid psychiatric presentations.

PMID:37314780 | DOI:10.1001/jamapsychiatry.2023.1808

Front Cell Infect Microbiol. 2023 May 29;13:1159389. doi: 10.3389/fcimb.2023.1159389. eCollection 2023.

ABSTRACT

INTRODUCTION: Monkeypox is a zoonotic disease caused by brick-shaped enveloped monkeypox (Mpox) virus that belongs to the family of ancient viruses known as Poxviridae. Subsequently, the viruses have been reported in various countries. The virus is transmitted by respiratory droplets, skin lesions, and infected body fluids. The infected patients experience fluid-filled blisters, maculopapular rash, myalgia, and fever. Due to the lack of effective drugs or vaccines, there is a need to identify the most potent and effective drugs to reduce the spread of monkeypox. The current study aimed to use computational methods to quickly identify potentially effective drugs against the Mpox virus.

METHODS: In our study, the Mpox protein thymidylate kinase (A48R) was targeted because it is a unique drug target. We screened a library of 9000 FDA-approved compounds of the DrugBank database by using various in silico approaches, such as molecular docking and molecular dynamic (MD) simulation.

RESULTS: Based on docking score and interaction analysis, compounds DB12380, DB13276, DB13276, DB11740, DB14675, DB11978, DB08526, DB06573, DB15796, DB08223, DB11736, DB16250, and DB16335 were predicted as the most potent. To examine the dynamic behavior and stability of the docked complexes, three compounds-DB16335, DB15796, and DB16250 -along with the Apo state were simulated for 300ns. The results revealed that compound DB16335 revealed the best docking score (-9.57 kcal/mol) against the Mpox protein thymidylate kinase.

DISCUSSION: Additionally, during the 300 ns MD simulation period, thymidylate kinase DB16335 showed great stability. Further, in vitro and in vivo study is recommended for the final predicted compounds.

PMID:37313340 | PMC:PMC10258308 | DOI:10.3389/fcimb.2023.1159389

Br Med Bull. 2023 Jun 13:ldac037. doi: 10.1093/bmb/ldac037. Online ahead of print.

ABSTRACT

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic resulted in a race to develop effective treatments largely through drug repurposing via adaptive platform trials on a global scale. Drug repurposing trials have focused on potential antiviral therapies aimed at preventing viral replication, anti-inflammatory agents, antithrombotic agents and immune modulators through a number of adaptive platform trials. Living systematic reviews have also enabled evidence synthesis and network meta-analysis as clinical trial data emerge globally.

SOURCES OF DATA: Recent published literature.

AREAS OF AGREEMENT: Corticosteroids and immunomodulators that antagonize the interleukin-6 (IL-6) receptor have been shown to play a critical role in modulating inflammation and improving clinical outcomes in hospitalized patients. Inhaled budesonide reduces the time to recovery in older patients with mild-to-moderate COVID-19 managed in the community.

AREAS OF CONTROVERSY: The clinical benefit of remdesivir remains controversial with conflicting evidence from different trials. Remdesivir led to a reduction in time to clinical recovery in the ACTT-1 trial. However, the World Health Organization SOLIDARITY and DISCOVERY trial did not find a significant benefit on 28-day mortality and clinical recovery.

GROWING POINTS: Other treatments currently being investigated include antidiabetic drug empagliflozin, antimalarial drug artesunate, tyrosine kinase inhibitor imatinib, immunomodulatory drug infliximab, antiviral drug favipiravir, antiparasitic drug ivermectin and antidepressant drug fluvoxamine.

AREAS TIMELY FOR DEVELOPING RESEARCH: The timing of therapeutic interventions based on postulated mechanisms of action and the selection of clinically meaningful primary end points remain important considerations in the design and implementation of COVID-19 therapeutic trials.

PMID:37312588 | DOI:10.1093/bmb/ldac037