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Mohate, Pratiksha, and Madhav D. Zade. "REVIEW ON DRUG REPURPOSING DRUG USEFUL AGAINST COVID-19." International Journal of Engineering Applied Sciences and Technology 5, no. 2 (June 30, 2020): 449–55. http://dx.doi.org/10.33564/ijeast.2020.v05i02.074.
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Rodrigues, Liliana, Renata Bento Cunha, Tatiana Vassilevskaia, Miguel Viveiros, and Celso Cunha. "Drug Repurposing for COVID-19: A Review and a Novel Strategy to Identify New Targets and Potential Drug Candidates." Molecules 27, no. 9 (April 23, 2022): 2723. http://dx.doi.org/10.3390/molecules27092723.
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In December 2019, the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19) was first identified in the province of Wuhan, China. Since then, there have been over 400 million confirmed cases and 5.8 million deaths by COVID-19 reported worldwide. The urgent need for therapies against SARS-CoV-2 led researchers to use drug repurposing approaches. This strategy allows the reduction in risks, time, and costs associated with drug development. In many cases, a repurposed drug can enter directly to preclinical testing and clinical trials, thus accelerating the whole drug discovery process. In this work, we will give a general overview of the main developments in COVID-19 treatment, focusing on the contribution of the drug repurposing paradigm to find effective drugs against this disease. Finally, we will present our findings using a new drug repurposing strategy that identified 11 compounds that may be potentially effective against COVID-19. To our knowledge, seven of these drugs have never been tested against SARS-CoV-2 and are potential candidates for in vitro and in vivo studies to evaluate their effectiveness in COVID-19 treatment.
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Khataniar, Ankita, Upasana Pathak, Sanchaita Rajkhowa, and Anupam Nath Jha. "A Comprehensive Review of Drug Repurposing Strategies against Known Drug Targets of COVID-19." COVID 2, no. 2 (January 26, 2022): 148–67. http://dx.doi.org/10.3390/covid2020011.
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Drug repurposing is a more inexpensive and shorter approach than the traditional drug discovery and development process. The concept of identifying a potent molecule from a library of pre-existing molecules or an already approved drug has become a go-to tactic to accelerate the identification of drugs that can prevent COVID-19. This seemingly uncontrollable disease is caused by SARS-CoV-2. It is a novel virus of the Betacoronavirus genus, exhibiting similarities to the previously reported SAR-CoV genome structure and viral pathogenesis. The emergence of SARS-CoV-2 and the rapid outbreak of COVID-19 have resulted in a global pandemic. Researchers are hard-pressed to develop new drugs for total containment of the disease, thus making the cost-effective drug repurposing a much more feasible approach. Therefore, the current review attempts to collate both the experimental and computational drug repurposing strategies that have been utilized against significant drug targets of SARS-CoV-2. Along with the strategies, the available druggable targets shall also be discussed. However, the occurrence of frequent recombination of the viral genome and time-bound primary analysis, resulting in insignificant data, are two major challenges that drug repurposing still faces.
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Puccetti, Matteo, Claudio Costantini, Maurizio Ricci, and Stefano Giovagnoli. "Tackling Immune Pathogenesis of COVID-19 through Molecular Pharmaceutics." Pharmaceutics 13, no. 4 (April 5, 2021): 494. http://dx.doi.org/10.3390/pharmaceutics13040494.
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An increasing number of clinical studies worldwide are investigating the repurposing of antiviral, immune-modulatory, and anti-inflammatory agents to face the coronavirus disease-19 (COVID-19) pandemic. Nevertheless, few effective therapies exist to prevent or treat COVID-19, which demands increased drug discovery and repurposing efforts. In fact, many currently tested drugs show unknown efficacy and unpredictable drug interactions, such that interventions are needed to guarantee access to effective and safe medicines. Anti-inflammatory therapy has proven to be effective in preventing further injury in COVID-19 patients, but the benefit comes at a cost, as targeting inflammatory pathways can imply an increased risk of infection. Thus, optimization of the risk/benefit ratio is required in the anti-inflammatory strategy against COVID-19, which accounts for drug formulations and delivery towards regionalization and personalization of treatment approaches. In this perspective, we discuss how better knowledge of endogenous immunomodulatory pathways may optimize the clinical use of novel and repurposed drugs against COVID-19 in inpatient, outpatient, and home settings through innovative drug discovery, appropriate drug delivery systems and dedicated molecular pharmaceutics.
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Wahedi, Hussain Mustatab, and Deeba Amraiz. "Repurposing of Antiviral Drugs for Covid-19 Therapy." Life and Science 1, supplement (December 23, 2020): 10. http://dx.doi.org/10.37185/lns.1.1.151.
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Coronavirus disease (COVID-19) caused by severe acute respiratory syndrome-associated coronavirus 2 (SARS- CoV-2) is one of the biggest health challenges across the globe ever since its eruption in late 2019. Novelty, contagiousness, and lethality of the virus demand the expedited production of potential therapeutic agents and strategies against it. Since no COVID-19 specific drug is available yet, it persists a crucial challenge to determine what therapeutic strategies should be adopted for the treatment of coronavirus patients. Until there is any specific drug for COVID-19, repurposing of the existing FDA-approved drugs is the most suitable approach to treat the severely ill patients of COVID-19. This review will summarize the existing antiviral drugs being repurposed and probed for their potential as effective anti-COVID-19 drugs all over the world.
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Kumari, Priyanka, Bikram Pradhan, Maria Koromina, George P. Patrinos, and Kristel Van Steen. "Discovery of new drug indications for COVID-19: A drug repurposing approach." PLOS ONE 17, no. 5 (May 24, 2022): e0267095. http://dx.doi.org/10.1371/journal.pone.0267095.
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Motivation The outbreak of coronavirus health issues caused by COVID-19(SARS-CoV-2) creates a global threat to public health. Therefore, there is a need for effective remedial measures using existing and approved therapies with proven safety measures has several advantages. Dexamethasone (Pubchem ID: CID0000005743), baricitinib(Pubchem ID: CID44205240), remdesivir (PubchemID: CID121304016) are three generic drugs that have demonstrated in-vitro high antiviral activity against SARS-CoV-2. The present study aims to widen the search and explore the anti-SARS-CoV-2 properties of these potential drugs while looking for new drug indications with optimised benefits via in-silico research. Method Here, we designed a unique drug-similarity model to repurpose existing drugs against SARS-CoV-2, using the anti-Covid properties of dexamethasone, baricitinib, and remdesivir as references. Known chemical-chemical interactions of reference drugs help extract interactive compounds withimprovedanti-SARS-CoV-2 properties. Here, we calculated the likelihood of these drug compounds treating SARS-CoV-2 related symptoms using chemical-protein interactions between the interactive compounds of the reference drugs and SARS-CoV-2 target genes. In particular, we adopted a two-tier clustering approach to generate a drug similarity model for the final selection of potential anti-SARS-CoV-2 drug molecules. Tier-1 clustering was based on t-Distributed Stochastic Neighbor Embedding (t-SNE) and aimed to filter and discard outlier drugs. The tier-2 analysis incorporated two cluster analyses performed in parallel using Ordering Points To Identify the Clustering Structure (OPTICS) and Hierarchical Agglomerative Clustering (HAC). As a result, itidentified clusters of drugs with similar actions. In addition, we carried out a docking study for in-silico validation of top candidate drugs. Result Our drug similarity model highlighted ten drugs, including reference drugs that can act as potential therapeutics against SARS-CoV-2. The docking results suggested that doxorubicin showed the least binding energy compared to reference drugs. Their practical utility as anti-SARS-CoV-2 drugs, either individually or in combination, warrants further investigation.
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Kumari, Kanchan, and Sandip K Mishra. "Artemisinin and its Derivatives as Repurposing Drug against COVID-19." Acta Scientific Cancer Biology 4, no. 7 (June 22, 2020): 21–23. http://dx.doi.org/10.31080/ascb.2020.04.0237.
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Parvathaneni, Vineela, and Vivek Gupta. "Utilizing drug repurposing against COVID-19 – Efficacy, limitations, and challenges." Life Sciences 259 (October 2020): 118275. http://dx.doi.org/10.1016/j.lfs.2020.118275.
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Ciliberto, Gennaro, and Luca Cardone. "Boosting the arsenal against COVID-19 through computational drug repurposing." Drug Discovery Today 25, no. 6 (June 2020): 946–48. http://dx.doi.org/10.1016/j.drudis.2020.04.005.
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Kolitz, Sarah, Jason Kim, Jenny Zhang, Yoonjeong Cha, Sailaja Battula, Rebecca Kusko, Rajaraman Krishnan, Benjamin Zeskind, and Howard Kaufman. "477 Deep learning to drive COVID-19 rapid drug repurposing." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A509. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0477.
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BackgroundCOVID-19 is a global public health crisis with no effective therapeutic strategies or vaccines available. The disease is caused by the SARS-CoV-2 virus, a novel coronavirus that enters cells through the ACE2 receptor. To rapidly identify existing drugs that might preferentially bind to the ACE2 receptor we sought to use an artificial intelligence platform to evaluate ~3,000 known drugs in the FDA approved drug library (Selleckchem).MethodsFluency is a quantitative structure–activity relationship (QSAR) deep learning-based platform that evaluates small molecule drug binding to protein targets. All drug structures from the FDA approved library were evaluated for binding to the ACE2 receptor and re-filtered for preferential ACE2 vs. ACE1 receptor binding. Top hits were evaluated for specificity by predicting binding across the human proteome and filtered by evaluating rankings from each of two models along with average ranks and combined scores from both models. The drugs were then evaluated for classification, potential availability and prioritized for in vitro validation. Selected compounds were screened using a high-throughput SARS-CoV-2 cell-based assay as described previously (Jonsson et al. J Biomol Screen 2007 12: 33. DOI: 10.1177/1087057106296688). Plates are quality-controlled in each run using Z score and CV statistics. Positive controls consisting of cells only and negative controls consisting of virus were used to normalize the data. Individual drugs are added to each plate at a single dose with at least four doses tested. For titer reduction assays, VeroE6 cells are infected with virus at MOI of 0.1 for one hour to promote adsorption. After two days, the supernatant is harvested and the amount of virus in each well is measured using TCID50 or plaque assay.ResultsWe identified 25 top drugs that were predicted to bind to ACE2 receptors and could theoretically block SARS-CoV-2 cell entry. Of these drugs, we prioritized 12 drugs for validation covering multiple pharmacologic classes and after assessing drug availability (table 1). They included an ALK/EGFR inhibitor, JAK inhibitor, two electrolyte channel inhibitors, \an antibiotic, and several anti-viral drugs, ACE inhibitors and anticoagulants. Validation studies are in progress and viral inhibition and titer reduction data will be presented.ConclusionsOur data show that machine learning platforms can be used to rapidly identify existing drugs that may have activity against SARS-CoV-2 infection. This hybrid computational and experimental approach enables rapid discovery of drugs for clinical testing against COVID-19 and other emerging human diseases.AcknowledgementsWe would like to thank Dr. Colleen Jonsson and Dr. Jeremy Smith at Oak Ridge National Laboratories and the University of Tennessee Regional Biocontainment Laboratory for assistance with in vitro validation studies.Trial RegistrationN/AEthics ApprovalN/AConsentN.A
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Sonkar, Charu, Pawan Kumar Doharey, Anuranjan Singh Rathore, Vishal Singh, Dharmendra Kashyap, Amaresh Kumar Sahoo, Nitish Mittal, Bechan Sharma, and Hem Chandra Jha. "Repurposing of gastric cancer drugs against COVID-19." Computers in Biology and Medicine 137 (October 2021): 104826. http://dx.doi.org/10.1016/j.compbiomed.2021.104826.
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Piplani, Sakshi, Puneet Singh, Nikolai Petrovsky, and David A. Winkler. "Identifying SARS-CoV-2 Drugs Binding to the Spike Fatty Acid Binding Pocket Using In Silico Docking and Molecular Dynamics." International Journal of Molecular Sciences 24, no. 4 (February 20, 2023): 4192. http://dx.doi.org/10.3390/ijms24044192.
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Drugs against novel targets are needed to treat COVID-19 patients, especially as SARS-CoV-2 is capable of rapid mutation. Structure-based de novo drug design and repurposing of drugs and natural products is a rational approach to discovering potentially effective therapies. These in silico simulations can quickly identify existing drugs with known safety profiles that can be repurposed for COVID-19 treatment. Here, we employ the newly identified spike protein free fatty acid binding pocket structure to identify repurposing candidates as potential SARS-CoV-2 therapies. Using a validated docking and molecular dynamics protocol effective at identifying repurposing candidates inhibiting other SARS-CoV-2 molecular targets, this study provides novel insights into the SARS-CoV-2 spike protein and its potential regulation by endogenous hormones and drugs. Some of the predicted repurposing candidates have already been demonstrated experimentally to inhibit SARS-CoV-2 activity, but most of the candidate drugs have yet to be tested for activity against the virus. We also elucidated a rationale for the effects of steroid and sex hormones and some vitamins on SARS-CoV-2 infection and COVID-19 recovery.
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Hossain, Md Shahadat, Ithmam Hami, Md Sad Salabi Sawrav, Md Fazley Rabbi, Otun Saha, Newaz Mohammed Bahadur, and Md Mizanur Rahaman. "Drug Repurposing for Prevention and Treatment of COVID-19: A Clinical Landscape." Discoveries 8, no. 4 (December 16, 2020): e121. http://dx.doi.org/10.15190/d.2020.18.
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SARS-CoV-2, the novel coronavirus strain responsible for the current pandemic of COVID-19, has rendered the entire humanity suffering. Several months have passed since the pandemic has struck. However, the world is still looking for an effective treatment plan to battle the viral infection. The first vaccine just received emergency approval in December 2020 for use in USA and UK. These are excellent news, however, the worldwide distribution of such vaccine, the possibility of virus mutation and the lack of data regarding the long-term effects of such vaccines are a significant concern. In addition, although remdesivir was recently approved by the FDA to be used as a clinical drug against COVID-19, it hasn’t stood out yet as a proven form of therapeutics. Such inability to produce a novel therapy has caused enough inconveniences for the affected people worldwide. Repurposing the already available drugs to fight against the virus seems to be a reasonable option amidst such uncertainty. Given the vast collection of potential treatment candidates to be explored against COVID-19, there is a decent chance that a success in this regard will serve the intermediary purpose of clinically treating the infection until a COVID-19 vaccine is widely distributed worldwide and will be able to treat COVID-19 patients that do not adequately respond to vaccines. Such treatments may prove very useful in future coronavirus outbreaks too. Proper research into these repurposing treatments may yield a certain insight into the field of novel treatment production as well. This review study accumulates a relevant set of information about drugs and vaccines against COVID-19, in terms of their repurposing properties and the specific phases of clinical trials they are undergoing across the world. A potential timeline is also suggested to estimate when an effective result can be expected from the ongoing clinical trials for a better anticipation of the drug landscape. This study will hopefully help accelerate investment of resources into development and discovery of drugs and vaccines against the infection.
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Han, Namshik, Woochang Hwang, Konstantinos Tzelepis, Patrick Schmerer, Eliza Yankova, Méabh MacMahon, Winnie Lei, et al. "Identification of SARS-CoV-2–induced pathways reveals drug repurposing strategies." Science Advances 7, no. 27 (June 2021): eabh3032. http://dx.doi.org/10.1126/sciadv.abh3032.
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The global outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) necessitates the rapid development of new therapies against coronavirus disease 2019 (COVID-19) infection. Here, we present the identification of 200 approved drugs, appropriate for repurposing against COVID-19. We constructed a SARS-CoV-2–induced protein network, based on disease signatures defined by COVID-19 multiomics datasets, and cross-examined these pathways against approved drugs. This analysis identified 200 drugs predicted to target SARS-CoV-2–induced pathways, 40 of which are already in COVID-19 clinical trials, testifying to the validity of the approach. Using artificial neural network analysis, we classified these 200 drugs into nine distinct pathways, within two overarching mechanisms of action (MoAs): viral replication (126) and immune response (74). Two drugs (proguanil and sulfasalazine) implicated in viral replication were shown to inhibit replication in cell assays. This unbiased and validated analysis opens new avenues for the rapid repurposing of approved drugs into clinical trials.
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Ben Moftah, Moayed, and Asma Eswayah. "Repurposing of Hydroxyurea Against COVID-19: A Promising Immunomodulatory Role." ASSAY and Drug Development Technologies 20, no. 1 (January 1, 2022): 55–62. http://dx.doi.org/10.1089/adt.2021.090.
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Aherfi, Sarah, Bruno Pradines, Christian Devaux, Stéphane Honore, Philippe Colson, Bernard La Scola, and Didier Raoult. "Drug repurposing against SARS-CoV-1, SARS-CoV-2 and MERS-CoV." Future Microbiology 16, no. 17 (November 2021): 1341–70. http://dx.doi.org/10.2217/fmb-2021-0019.
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Since the beginning of the COVID-19 pandemic, large in silico screening studies and numerous in vitro studies have assessed the antiviral activity of various drugs on SARS-CoV-2. In the context of health emergency, drug repurposing represents the most relevant strategy because of the reduced time for approval by international medicines agencies, the low cost of development and the well-known toxicity profile of such drugs. Herein, we aim to review drugs with in vitro antiviral activity against SARS-CoV-2, combined with molecular docking data and results from preliminary clinical studies. Finally, when considering all these previous findings, as well as the possibility of oral administration, 11 molecules consisting of nelfinavir, favipiravir, azithromycin, clofoctol, clofazimine, ivermectin, nitazoxanide, amodiaquine, heparin, chloroquine and hydroxychloroquine, show an interesting antiviral activity that could be exploited as possible drug candidates for COVID-19 treatment.
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Kifle, Zemene Demelash, Akeberegn Gorems Ayele, and Engidaw Fentahun Enyew. "Drug Repurposing Approach, Potential Drugs, and Novel Drug Targets for COVID-19 Treatment." Journal of Environmental and Public Health 2021 (April 22, 2021): 1–11. http://dx.doi.org/10.1155/2021/6631721.
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Novel coronavirus first appeared in Wuhan, China, in December 2019, and it speedily expanded globally. Some medications which are used to treat other diseases seem to be effective in treating COVID-19 even without explicit support. The existing drugs that are summarized in this review primarily focused on therapeutic agents that possessed activity against other RNA viruses such as MERS-CoV and SARS-CoV. Drug repurposing or repositioning is a promising field in drug discovery that identifies new therapeutic opportunities for existing drugs such as corticosteroids, RNA-dependent RNA polymerase inhibitors, interferons, protease inhibitors, ivermectin, melatonin, teicoplanin, and some others. A search for new drug/drug targets is underway. Thus, blocking coronavirus structural protein, targeting viral enzyme, dipeptidyl peptidase 4, and membrane fusion blocker (angiotensin-converting enzyme 2 and CD147 inhibitor) are major sites based on molecular targets for the management of COVID-19 infection. The possible impact of biologics for the management of COVID19 is promising and includes a wide variety of options such as cytokines, nucleic acid-based therapies targeting virus gene expression, bioengineered and vectored antibodies, and various types of vaccines. This review demonstrates that the available data are not sufficient to suggest any treatment for the eradication of COVID-19 to be used at the clinical level. This article aims to review the roles of existing drugs and drug targets for COVID-19 treatment.
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Singh, Sanjeet, and Jayaram R. "A Review of Potential Antiviral Drugs and Vaccines to Treat COVID-19." Journal of Pure and Applied Microbiology 14, suppl 1 (May 28, 2020): 765–74. http://dx.doi.org/10.22207/jpam.14.spl1.14.
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Coronavirus disease 19 (COVID-19) is a challenge to the whole humanity. COVID-19 was first reported in China and rigorous researches are going on for developing vaccine for the pandemic. This review was prepared by following PRISMA guidelines and used the resources from the Web of Science and PubMed. This research focuses on the niches of symptoms and vaccines for COVID-19. The research for vaccine involves research for new vaccine and drug repurposing. Out of various drug repurposing options, Remdesivir, and Favipiravir, Chloroquine and Lopinavir/Ritonavir were found to be the popular ones for treating COVID-19 patients across the world. Even though there are concerns regarding asymptotic patients, the most dominant symptoms of COVID-19 are fever and cough, followed by Dyspnoea and muscle ache. This review concludes that the COVID-19 related research should focus on developing immunity vaccines, and repurposing of drugs. Research on the problems of quarantine life, patient monitoring, and usage of information technology in facing COVID-19 will improve the quality of patient handling during the pandemic. The research on the effectiveness of various models of lockdown and regulation of social life during lockdown periods, improving the safety of health care workers in the workplace will definitely help the governments in their fight against COVID-19.
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Nunes, Paulo, Pedro Henrique de Oliveira Santiago, Cecilia Carolina Pinheiro da Silva, and Javier Ellena. "Drug Repurposing of the Antiviral Drug Acyclovir: New Pharmaceutical Salts." Crystals 13, no. 5 (May 8, 2023): 782. http://dx.doi.org/10.3390/cryst13050782.
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Drug repurposing is becoming interesting in terms of offering advantages over the traditional drug development, once drug discovery is a costly, time-consuming, and highly risky process. In particular, with the coronavirus disease (COVID-19) declared by World Health Organization as a global pandemic, there has emerged a considerable need to develop therapeutic agents capable of preventing viral outbreaks. Concomitantly, well-known and long-used drugs such as acyclovir (Acv) have been tested against COVID-19. Acv is a guanosine analogue that acts as an antiviral drug, commonly used to treat herpes simplex virus (HSV), genital herpes, and varicella zoster virus (VZV). Acv showed to inhibit viral proteases, multiple viral genes expression, and RNA-Dependent RNA Polymerase, helping to recover COVID-19 patients. However, ACV is a BCS class III/IV drug, with low permeability and/or slight water solubility (concentration-dependent). Given the repurposing eligibility of Acv, in this work, two new salts of this drug are presented (nitrate and sulfate), with the aim of improving its pharmacokinetic properties. The new salts were evaluated by X-ray diffraction, and thermal and spectroscopic analyses. A third salt, a chloride one, was also characterized and used for comparison.
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Anand, Jigisha, Tanmay Ghildiyal, Aakanksha Madhwal, Rishabh Bhatt, Devvret Verma, and Nishant Rai. "Computational guided approach for drug repurposing against SARS-CoV-2." Future Virology 16, no. 3 (March 2021): 211–43. http://dx.doi.org/10.2217/fvl-2020-0403.
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Background: In the current SARS-CoV-2 outbreak, drug repositioning emerges as a promising approach to develop efficient therapeutics in comparison to de novo drug development. The present investigation screened 130 US FDA-approved drugs including hypertension, cardiovascular diseases, respiratory tract infections (RTI), antibiotics and antiviral drugs for their inhibitory potential against SARS-CoV-2. Materials & methods: The molecular drug targets against SARS-CoV-2 proteins were determined by the iGEMDOCK computational docking tool. The protein homology models were generated through SWISS Model workspace. The pharmacokinetics of all the ligands was determined by ADMET analysis. Results: The study identified 15 potent drugs exhibiting significant inhibitory potential against SARS-CoV-2. Conclusion: Our investigation has identified possible repurposed drug candidates to improve the current modus operandi of the treatment given to COVID-19 patients.
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Loganathan, Tamizhini, Srimathy Ramachandran, Prakash Shankaran, Devipriya Nagarajan, and Suma Mohan S. "Host transcriptome-guided drug repurposing for COVID-19 treatment: a meta-analysis based approach." PeerJ 8 (June 10, 2020): e9357. http://dx.doi.org/10.7717/peerj.9357.
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Background Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been declared a pandemic by the World Health Organization, and the identification of effective therapeutic strategy is a need of the hour to combat SARS-CoV-2 infection. In this scenario, the drug repurposing approach is widely used for the rapid identification of potential drugs against SARS-CoV-2, considering viral and host factors. Methods We adopted a host transcriptome-based drug repurposing strategy utilizing the publicly available high throughput gene expression data on SARS-CoV-2 and other respiratory infection viruses. Based on the consistency in expression status of host factors in different cell types and previous evidence reported in the literature, pro-viral factors of SARS-CoV-2 identified and subject to drug repurposing analysis based on DrugBank and Connectivity Map (CMap) using the web tool, CLUE. Results The upregulated pro-viral factors such as TYMP, PTGS2, C1S, CFB, IFI44, XAF1, CXCL2, and CXCL3 were identified in early infection models of SARS-CoV-2. By further analysis of the drug-perturbed expression profiles in the connectivity map, 27 drugs that can reverse the expression of pro-viral factors were identified, and importantly, twelve of them reported to have anti-viral activity. The direct inhibition of the PTGS2 gene product can be considered as another therapeutic strategy for SARS-CoV-2 infection and could suggest six approved PTGS2 inhibitor drugs for the treatment of COVID-19. The computational study could propose candidate repurposable drugs against COVID-19, and further experimental studies are required for validation.
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De Vita, Simona, Maria Giovanna Chini, Gianluigi Lauro, and Giuseppe Bifulco. "Accelerating the repurposing of FDA-approved drugs against coronavirus disease-19 (COVID-19)." RSC Advances 10, no. 67 (2020): 40867–75. http://dx.doi.org/10.1039/d0ra09010g.
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Lee, Jong hoon. "Treatment mechanism of immune triad from the repurposing drug against COVID-19." Translational Medicine of Aging 7 (2023): 33–45. http://dx.doi.org/10.1016/j.tma.2023.06.005.
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Instiaty, I. Gusti Agung Ayu Putu Sri Darmayani, Jefman Efendi Marzuki, Ferina Angelia, William, Angelina Siane, Lela Dwi Sary, et al. "Antiviral treatment of COVID-19: a clinical pharmacology narrative review." Medical Journal of Indonesia 29, no. 3 (July 18, 2020): 332–45. http://dx.doi.org/10.13181/mji.rev.204652.
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The outbreak of coronavirus disease 2019 (COVID-19) in December 2019 in China, has become a pandemic in March 2020. Repurposing old and relatively safe drugs becomes an advantageous option to obtain the urgently needed effective treatment. Repurposing chloroquine, hydroxychloroquine, oseltamivir, lopinavir/ritonavir, andfavipiravir, and the use of investigational drug remdesivir for treatment of COVID-19, are reviewed from the clinical pharmacology perspective, particularly its efficacy and safety. Limited clinical studies of chloroquine, hydroxychloroquine, favipiravir, and remdesivir showed some efficacy in COVID-19 treatment with tolerable adverse effects. Potential serious adverse effect of chloroquine and hydroxychloroquine is cardiac arrhythmia. Oseltamivir has no documented activity against SARS-CoV-2, while lopinavir/ritonavir showed limited efficacy in COVID-19. Currently, there is no sufficient evidence to recommend any specific anti-COVID-19 treatment. The decision to use these drugs during the COVID-19 pandemic must be based on careful consideration of the potential benefits and risks to the patient.
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Chowdhury, Kamrul Hasan, Md Riad Chowdhury, Shafi Mahmud, Abu Montakim Tareq, Nujhat Binte Hanif, Naureen Banu, A. S. M. Ali Reza, Talha Bin Emran, and Jesus Simal-Gandara. "Drug Repurposing Approach against Novel Coronavirus Disease (COVID-19) through Virtual Screening Targeting SARS-CoV-2 Main Protease." Biology 10, no. 1 (December 23, 2020): 2. http://dx.doi.org/10.3390/biology10010002.
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Novel coronavirus disease (COVID-19) was identified from China in December 2019 and spread rapidly through human-to-human transmission, affecting so many people worldwide. Until now, there has been no specific treatment against the disease and repurposing of the drug. Our investigation aimed to screen potential inhibitors against coronavirus for the repurposing of drugs. Our study analyzed sequence comparison among SARS-CoV, SARS-CoV-2, and MERS-CoV to determine the identity matrix using discovery studio. SARS-CoV-2 Mpro was targeted to generate an E-pharmacophore hypothesis to screen drugs from the DrugBank database having similar features. Promising drugs were used for docking-based virtual screening at several precisions. Best hits from virtual screening were subjected to MM/GBSA analysis to evaluate binding free energy, followed by the analysis of binding interactions. Furthermore, the molecular dynamics simulation approaches were carried out to assess the docked complex’s conformational stability. A total of 33 drug classes were found from virtual screening based on their docking scores. Among them, seven potential drugs with several anticancer, antibiotic, and immunometabolic categories were screened and showed promising MM/GBSA scores. During interaction analysis, these drugs exhibited different types of hydrogen and hydrophobic interactions with amino acid residue. Besides, 17 experimental drugs selected from virtual screening might be crucial for drug discovery against COVID-19. The RMSD, RMSF, SASA, Rg, and MM/PBSA descriptors from molecular dynamics simulation confirmed the complex’s firm nature. Seven promising drugs for repurposing against SARS-CoV-2 main protease (Mpro), namely sapanisertib, ornidazole, napabucasin, lenalidomide, daniquidone, indoximod, and salicylamide, could be vital for the treatment of COVID-19. However, extensive in vivo and in vitro studies are required to evaluate the mentioned drug’s activity.
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Jang, Woo Dae, Sangeun Jeon, Seungtaek Kim, and Sang Yup Lee. "Drugs repurposed for COVID-19 by virtual screening of 6,218 drugs and cell-based assay." Proceedings of the National Academy of Sciences 118, no. 30 (July 7, 2021): e2024302118. http://dx.doi.org/10.1073/pnas.2024302118.
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The COVID-19 pandemic caused by SARS-CoV-2 is an unprecedentedly significant health threat, prompting the need for rapidly developing antiviral drugs for the treatment. Drug repurposing is currently one of the most tangible options for rapidly developing drugs for emerging and reemerging viruses. In general, drug repurposing starts with virtual screening of approved drugs employing various computational methods. However, the actual hit rate of virtual screening is very low, and most of the predicted compounds are false positives. Here, we developed a strategy for virtual screening with much reduced false positives through incorporating predocking filtering based on shape similarity and postdocking filtering based on interaction similarity. We applied this advanced virtual screening approach to repurpose 6,218 approved and clinical trial drugs for COVID-19. All 6,218 compounds were screened against main protease and RNA-dependent RNA polymerase of SARS-CoV-2, resulting in 15 and 23 potential repurposed drugs, respectively. Among them, seven compounds can inhibit SARS-CoV-2 replication in Vero cells. Three of these drugs, emodin, omipalisib, and tipifarnib, show anti-SARS-CoV-2 activities in human lung cells, Calu-3. Notably, the activity of omipalisib is 200-fold higher than that of remdesivir in Calu-3. Furthermore, three drug combinations, omipalisib/remdesivir, tipifarnib/omipalisib, and tipifarnib/remdesivir, show strong synergistic effects in inhibiting SARS-CoV-2. Such drug combination therapy improves antiviral efficacy in SARS-CoV-2 infection and reduces the risk of each drug’s toxicity. The drug repurposing strategy reported here will be useful for rapidly developing drugs for treating COVID-19 and other viruses.
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Taibe, Noha Samir, Maimona A. Kord, Mohamed Ahmed Badawy, Iart Luca Shytaj, and Mahmoud M. Elhefnawi. "Progress, pitfalls, and path forward of drug repurposing for COVID-19 treatment." Therapeutic Advances in Respiratory Disease 16 (January 2022): 175346662211327. http://dx.doi.org/10.1177/17534666221132736.
Full textAbstract:
On 30 January 2020, the World Health Organization (WHO) declared the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic a public health emergency of international concern. The viral outbreak led in turn to an exponential growth of coronavirus disease 2019 (COVID-19) cases, that is, a multiorgan disease that has led to more than 6.3 million deaths worldwide, as of June 2022. There are currently few effective drugs approved for treatment of SARS-CoV-2/COVID-19 patients. Many of the compounds tested so far have been selected through a drug repurposing approach, that is, by identifying novel indications for drugs already approved for other conditions. We here present an up-to-date review of the main Food and Drug Administration (FDA)–approved drugs repurposed against SARS-CoV-2 infection, discussing their mechanism of action and their most important preclinical and clinical results. Reviewed compounds were chosen to privilege those that have been approved for use in SARS-CoV-2 patients or that have completed phase III clinical trials. Moreover, we also summarize the evidence on some novel and promising repurposed drugs in the pipeline. Finally, we discuss the current stage and possible steps toward the development of broadly effective drug combinations to suppress the onset or progression of COVID-19.
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Gupta, Rajesh Kumar, Girish R. Apte, Kiran Bharat Lokhande, Satyendra Mishra, and Jayanta K. Pal. "Carbohydrate-Binding Agents: Potential of Repurposing for COVID-19 Therapy." Current Protein & Peptide Science 21, no. 11 (December 31, 2020): 1085–96. http://dx.doi.org/10.2174/1389203721666200918153717.
Full textAbstract:
: With the emergence of the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the whole world is suffering from atypical pneumonia, which resulted in more than 559,047 deaths worldwide. In this time of crisis and urgency, the only hope comes from new candidate vaccines and potential antivirals. However, formulating new vaccines and synthesizing new antivirals are a laborious task. Therefore, considering the high infection rate and mortality due to COVID-19, utilization of previous information, and repurposing of existing drugs against valid viral targets have emerged as a novel drug discovery approach in this challenging time. The transmembrane spike (S) glycoprotein of coronaviruses (CoVs), which facilitates the virus’s entry into the host cells, exists in a homotrimeric form and is covered with N-linked glycans. S glycoprotein is known as the main target of antibodies having neutralizing potency and is also considered as an attractive target for therapeutic or vaccine development. Similarly, targeting of N-linked glycans of S glycoprotein envelope of CoV via carbohydrate-binding agents (CBAs) could serve as an attractive therapeutic approach for developing novel antivirals. CBAs from natural sources like lectins from plants, marine algae and prokaryotes and lectin mimics like Pradimicin-A (PRM-A) have shown antiviral activities against CoV and other enveloped viruses. However, the potential use of CBAs specifically lectins was limited due to unfavorable responses like immunogenicity, mitogenicity, hemagglutination, inflammatory activity, cellular toxicity, etc. Here, we reviewed the current scenario of CBAs as antivirals against CoVs, presented strategies to improve the efficacy of CBAs against CoVs; and studied the molecular interactions between CBAs (lectins and PRM-A) with Man9 by molecular docking for potential repurposing against CoVs in general, and SARSCoV- 2, in particular.
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BR, Bharath, Hrishikesh Damle, Shiban Ganju, and Latha Damle. "In silico screening of known small molecules to bind ACE2 specific RBD on Spike glycoprotein of SARS-CoV-2 for repurposing against COVID-19." F1000Research 9 (July 1, 2020): 663. http://dx.doi.org/10.12688/f1000research.24143.1.
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Background: Human coronavirus (SARS-CoV-2) is causing a pandemic with significant morbidity and mortality. As no effective novel drugs are available currently, drug repurposing is an alternative intervention strategy. Here we present an in silico drug repurposing study that implements successful concepts of computer-aided drug design (CADD) technology for repurposing known drugs to interfere with viral cellular entry via the spike glycoprotein (SARS-CoV-2-S), which mediates host cell entry via the hACE2 receptor. Methods: A total of 4015 known and approved small molecules were screened for interaction with SARS-CoV-2-S through docking studies and 15 lead molecules were shortlisted. Additionally, streptomycin, ciprofloxacin, and glycyrrhizic acid (GA) were selected based on their reported anti-viral activity, safety, availability and affordability. The 18 molecules were subjected to molecular dynamics (MD) simulation. Results: The MD simulation results indicate that GA of plant origin may be repurposed for SARS-CoV-2 intervention, pending further studies. Conclusions: Repurposing is a beneficial strategy for treating COVID-19 with existing drugs. It is aimed at using docking studies to screen molecules for clinical application and investigating their efficacy in inhibiting SARS-CoV-2-S. SARS-CoV-2-S is a key pathogenic protein that mediates pathogen-host interaction. Hence, the molecules screened for inhibitory properties against SARS-CoV-2-S can be clinically used to treat COVID-19 since the safety profile is already known.
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MacRaild, Christopher A., Muzaffar-Ur-Rehman Mohammed, Faheem, Sankaranarayanan Murugesan, Ian K. Styles, Amanda L. Peterson, Carl M. J. Kirkpatrick, et al. "Systematic Down-Selection of Repurposed Drug Candidates for COVID-19." International Journal of Molecular Sciences 23, no. 19 (October 6, 2022): 11851. http://dx.doi.org/10.3390/ijms231911851.
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SARS-CoV-2 is the cause of the COVID-19 pandemic which has claimed more than 6.5 million lives worldwide, devastating the economy and overwhelming healthcare systems globally. The development of new drug molecules and vaccines has played a critical role in managing the pandemic; however, new variants of concern still pose a significant threat as the current vaccines cannot prevent all infections. This situation calls for the collaboration of biomedical scientists and healthcare workers across the world. Repurposing approved drugs is an effective way of fast-tracking new treatments for recently emerged diseases. To this end, we have assembled and curated a database consisting of 7817 compounds from the Compounds Australia Open Drug collection. We developed a set of eight filters based on indicators of efficacy and safety that were applied sequentially to down-select drugs that showed promise for drug repurposing efforts against SARS-CoV-2. Considerable effort was made to evaluate approximately 14,000 assay data points for SARS-CoV-2 FDA/TGA-approved drugs and provide an average activity score for 3539 compounds. The filtering process identified 12 FDA-approved molecules with established safety profiles that have plausible mechanisms for treating COVID-19 disease. The methodology developed in our study provides a template for prioritising drug candidates that can be repurposed for the safe, efficacious, and cost-effective treatment of COVID-19, long COVID, or any other future disease. We present our database in an easy-to-use interactive interface (CoviRx that was also developed to enable the scientific community to access to the data of over 7000 potential drugs and to implement alternative prioritisation and down-selection strategies.
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Alanazi, Khalid Mashay, Mohammad Abul Farah, and Yan-Yan Hor. "Multi-Targeted Approaches and Drug Repurposing Reveal Possible SARS-CoV-2 Inhibitors." Vaccines 10, no. 1 (December 26, 2021): 24. http://dx.doi.org/10.3390/vaccines10010024.
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The COVID-19 pandemic caused by SARS-CoV-2 is unprecedented in recent memory owing to the non-stop escalation in number of infections and deaths in almost every country of the world. The lack of treatment options further worsens the scenario, thereby necessitating the exploration of already existing US FDA-approved drugs for their effectiveness against COVID-19. In the present study, we have performed virtual screening of nutraceuticals available from DrugBank against 14 SARS-CoV-2 proteins. Molecular docking identified several inhibitors, two of which, rutin and NADH, displayed strong binding affinities and inhibitory potential against SARS-CoV-2 proteins. Further normal model-based simulations were performed to gain insights into the conformational transitions in proteins induced by the drugs. The computational analysis in the present study paves the way for experimental validation and development of multi-target guided inhibitors to fight COVID-19.
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Nashte, Aayushka. "Exploring the Potential of Natural Compounds Against Pro-Inflammatory Cytokine Proteins Involved in Worsening COVID-19 and Against COVID-19 Proteins: An in Silico Approach." International Journal of Innovative Technology and Exploring Engineering 11, no. 9 (August 30, 2022): 74–98. http://dx.doi.org/10.35940/ijitee.g9221.0811922.
Full textAbstract:
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a causative agent for global pandemic disease nCOVID’19, has directed the attention of the scientific community towards the development of effective vaccines and drugs. Attempts are being made for repurposing existing drugs known for their antiviral activities, and test the traditional herbal medicines, natural compounds, nutraceuticals known for their health benefiting and immune-boosting activity against SARSCoV-2. Multidimensional approach is employed to find effective drugs against SARS-CoV2. In this study, 108 natural compounds were examined in inhibiting human protein targets which are responsible for worsening the condition of COVID-19 through a virtual screening approach. This study has screened the natural compounds 3-Hydroxydecanedioic acid, Cucurbitacin S, Diosgenin which may exhibit inhibitory activity against IL-1 receptor,IL-6 receptor respectively. It has also revealed that Dihydro-beta-ergocryptine and cucurbitacin S may exhibit inhibitory activity against TNF-alpha receptor. Further it concluded that exfoliazone shows better inhibitory activity against P38-MAPK and NF-κB pathway inhibitory proteins. These natural compounds could lead the way for future drug discovery, design and development. This will help researchers to scout new drugs in drug discovery(in-vitro and in-vivo studies).
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Gupta, Rajaneesh K., Enyinna L. Nwachuku, Benjamin E. Zusman, Ruchira M. Jha, and Ava M. Puccio. "Drug repurposing for COVID-19 based on an integrative meta-analysis of SARS-CoV-2 induced gene signature in human airway epithelium." PLOS ONE 16, no. 9 (September 28, 2021): e0257784. http://dx.doi.org/10.1371/journal.pone.0257784.
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Drug repurposing has the potential to bring existing de-risked drugs for effective intervention in an ongoing pandemic—COVID-19 that has infected over 131 million, with 2.8 million people succumbing to the illness globally (as of April 04, 2021). We have used a novel `gene signature’-based drug repositioning strategy by applying widely accepted gene ranking algorithms to prioritize the FDA approved or under trial drugs. We mined publically available RNA sequencing (RNA-Seq) data using CLC Genomics Workbench 20 (QIAGEN) and identified 283 differentially expressed genes (FDR<0.05, log2FC>1) after a meta-analysis of three independent studies which were based on severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) infection in primary human airway epithelial cells. Ingenuity Pathway Analysis (IPA) revealed that SARS-CoV-2 activated key canonical pathways and gene networks that intricately regulate general anti-viral as well as specific inflammatory pathways. Drug database, extracted from the Metacore and IPA, identified 15 drug targets (with information on COVID-19 pathogenesis) with 46 existing drugs as potential-novel candidates for repurposing for COVID-19 treatment. We found 35 novel drugs that inhibit targets (ALPL, CXCL8, and IL6) already in clinical trials for COVID-19. Also, we found 6 existing drugs against 4 potential anti-COVID-19 targets (CCL20, CSF3, CXCL1, CXCL10) that might have novel anti-COVID-19 indications. Finally, these drug targets were computationally prioritized based on gene ranking algorithms, which revealed CXCL10 as the common and strongest candidate with 2 existing drugs. Furthermore, the list of 283 SARS-CoV-2-associated proteins could be valuable not only as anti-COVID-19 targets but also useful for COVID-19 biomarker development.
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Hassanzadeganroudsari, Majid, Amir Hossein Ahmadi, Niloufar Rashidi, Md Kamal Hossain, Amanda Habib, and Vasso Apostolopoulos. "Computational Chemistry to Repurposing Drugs for the Control of COVID-19." Biologics 1, no. 2 (July 15, 2021): 111–28. http://dx.doi.org/10.3390/biologics1020007.
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Thus far, in 2021, 219 countries with over 175 million people have been infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 is a positive sense, single-stranded RNA virus, and is the causal agent for coronavirus disease (COVID-19). Due to the urgency of the situation, virtual screening as a computational modeling method offers a fast and effective modality of identifying drugs that may be effective against SARS-CoV-2. There has been an overwhelming abundance of molecular docking against SARS-CoV-2 in the last year. Due to the massive volume of computational studies, this systematic review has been created to evaluate and summarize the findings of existing studies. Herein, we report on computational articles of drugs which target, (1) viral protease, (2) Spike protein-ACE 2 interaction, (3) RNA-dependent RNA polymerase, and (4) other proteins and nonstructural proteins of SARS-CoV-2. Based on the studies presented, there are 55 identified natural or drug compounds with potential anti-viral activity. The next step is to show anti-viral activity in vitro and translation to determine effectiveness into human clinical trials.
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Mudatsir, Mudatsir, Amanda Yufika, Firzan Nainu, Andri Frediansyah, Dewi Megawati, Agung Pranata, Wilda Mahdani, Ichsan Ichsan, Kuldeep Dhama, and Harapan Harapan. "Antiviral Activity of Ivermectin Against SARS-CoV-2: An Old-Fashioned Dog with a New Trick—A Literature Review." Scientia Pharmaceutica 88, no. 3 (August 17, 2020): 36. http://dx.doi.org/10.3390/scipharm88030036.
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The coronavirus disease 2019 (COVID-19) pandemic is a major global threat. With no effective antiviral drugs, the repurposing of many currently available drugs has been considered. One such drug is ivermectin, an FDA-approved antiparasitic agent that has been shown to exhibit antiviral activity against a broad range of viruses. Recent studies have suggested that ivermectin inhibits the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), thus suggesting its potential for use against COVID-19. This review has summarized the evidence derived from docking and modeling analysis, in vitro and in vivo studies, and results from new investigational drug protocols, as well as clinical trials, if available, which will be effective in supporting the prospective use of ivermectin as an alternative treatment for COVID-19.
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Morselli Gysi, Deisy, Ítalo do Valle, Marinka Zitnik, Asher Ameli, Xiao Gan, Onur Varol, Susan Dina Ghiassian, et al. "Network medicine framework for identifying drug-repurposing opportunities for COVID-19." Proceedings of the National Academy of Sciences 118, no. 19 (April 27, 2021): e2025581118. http://dx.doi.org/10.1073/pnas.2025581118.
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The COVID-19 pandemic has highlighted the need to quickly and reliably prioritize clinically approved compounds for their potential effectiveness for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Here, we deployed algorithms relying on artificial intelligence, network diffusion, and network proximity, tasking each of them to rank 6,340 drugs for their expected efficacy against SARS-CoV-2. To test the predictions, we used as ground truth 918 drugs experimentally screened in VeroE6 cells, as well as the list of drugs in clinical trials that capture the medical community’s assessment of drugs with potential COVID-19 efficacy. We find that no single predictive algorithm offers consistently reliable outcomes across all datasets and metrics. This outcome prompted us to develop a multimodal technology that fuses the predictions of all algorithms, finding that a consensus among the different predictive methods consistently exceeds the performance of the best individual pipelines. We screened in human cells the top-ranked drugs, obtaining a 62% success rate, in contrast to the 0.8% hit rate of nonguided screenings. Of the six drugs that reduced viral infection, four could be directly repurposed to treat COVID-19, proposing novel treatments for COVID-19. We also found that 76 of the 77 drugs that successfully reduced viral infection do not bind the proteins targeted by SARS-CoV-2, indicating that these network drugs rely on network-based mechanisms that cannot be identified using docking-based strategies. These advances offer a methodological pathway to identify repurposable drugs for future pathogens and neglected diseases underserved by the costs and extended timeline of de novo drug development.
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Asai, Ayumu, Masamitsu Konno, Miyuki Ozaki, Chihiro Otsuka, Andrea Vecchione, Takahiro Arai, Toru Kitagawa, et al. "COVID-19 Drug Discovery Using Intensive Approaches." International Journal of Molecular Sciences 21, no. 8 (April 18, 2020): 2839. http://dx.doi.org/10.3390/ijms21082839.
Full textAbstract:
Since the infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was reported in China during December 2019, the coronavirus disease 2019 (COVID-19) has spread on a global scale, causing the World Health Organization (WHO) to issue a warning. While novel vaccines and drugs that target SARS-CoV-2 are under development, this review provides information on therapeutics which are under clinical trials or are proposed to antagonize SARS-CoV-2. Based on the information gained from the responses to other RNA coronaviruses, including the strains that cause severe acute respiratory syndrome (SARS)-coronaviruses and Middle East respiratory syndrome (MERS), drug repurposing might be a viable strategy. Since several antiviral therapies can inhibit viral replication cycles or relieve symptoms, mechanisms unique to RNA viruses will be important for the clinical development of antivirals against SARS-CoV-2. Given that several currently marketed drugs may be efficient therapeutic agents for severe COVID-19 cases, they may be beneficial for future viral pandemics and other infections caused by RNA viruses when standard treatments are unavailable.
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Günther, Sebastian, Patrick Y. A. Reinke, Yaiza Fernández-García, Julia Lieske, Thomas J. Lane, Helen M. Ginn, Faisal H. M. Koua, et al. "X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease." Science 372, no. 6542 (April 2, 2021): 642–46. http://dx.doi.org/10.1126/science.abf7945.
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The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous human suffering. To date, no effective drug is available to directly treat the disease. In a search for a drug against COVID-19, we have performed a high-throughput x-ray crystallographic screen of two repurposing drug libraries against the SARS-CoV-2 main protease (Mpro), which is essential for viral replication. In contrast to commonly applied x-ray fragment screening experiments with molecules of low complexity, our screen tested already-approved drugs and drugs in clinical trials. From the three-dimensional protein structures, we identified 37 compounds that bind to Mpro. In subsequent cell-based viral reduction assays, one peptidomimetic and six nonpeptidic compounds showed antiviral activity at nontoxic concentrations. We identified two allosteric binding sites representing attractive targets for drug development against SARS-CoV-2.
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Narayanan, Anoop, Shay A. Toner, and Joyce Jose. "Structure-based inhibitor design and repurposing clinical drugs to target SARS-CoV-2 proteases." Biochemical Society Transactions 50, no. 1 (January 11, 2021): 151–65. http://dx.doi.org/10.1042/bst20211180.
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SARS-CoV-2, the coronavirus responsible for the current COVID-19 pandemic, encodes two proteases, 3CLpro and PLpro, two of the main antiviral research targets. Here we provide an overview of the structures and functions of 3CLpro and PLpro and examine strategies of structure-based drug designing and drug repurposing against these proteases. Rational structure-based drug design enables the generation of potent and target-specific antivirals. Drug repurposing offers an attractive prospect with an accelerated turnaround. Thus far, several protease inhibitors have been identified, and some candidates are undergoing trials that may well prove to be effective antivirals against SARS-CoV-2.
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Wang, Bing, Dmitri Svetlov, Dylan Bartikofsky, Christiane E. Wobus, and Irina Artsimovitch. "Going Retro, Going Viral: Experiences and Lessons in Drug Discovery from COVID-19." Molecules 27, no. 12 (June 14, 2022): 3815. http://dx.doi.org/10.3390/molecules27123815.
Full textAbstract:
The severity of the COVID-19 pandemic and the pace of its global spread have motivated researchers to opt for repurposing existing drugs against SARS-CoV-2 rather than discover or develop novel ones. For reasons of speed, throughput, and cost-effectiveness, virtual screening campaigns, relying heavily on in silico docking, have dominated published reports. A particular focus as a drug target has been the principal active site (i.e., RNA synthesis) of RNA-dependent RNA polymerase (RdRp), despite the existence of a second, and also indispensable, active site in the same enzyme. Here we report the results of our experimental interrogation of several small-molecule inhibitors, including natural products proposed to be effective by in silico studies. Notably, we find that two antibiotics in clinical use, fidaxomicin and rifabutin, inhibit RNA synthesis by SARS-CoV-2 RdRp in vitro and inhibit viral replication in cell culture. However, our mutagenesis studies contradict the binding sites predicted computationally. We discuss the implications of these and other findings for computational studies predicting the binding of ligands to large and flexible protein complexes and therefore for drug discovery or repurposing efforts utilizing such studies. Finally, we suggest several improvements on such efforts ongoing against SARS-CoV-2 and future pathogens as they arise.
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Campbell, Courtney M., Avirup Guha, Tamanna Haque, Tomas G. Neilan, and Daniel Addison. "Repurposing Immunomodulatory Therapies against Coronavirus Disease 2019 (COVID-19) in the Era of Cardiac Vigilance: A Systematic Review." Journal of Clinical Medicine 9, no. 9 (September 11, 2020): 2935. http://dx.doi.org/10.3390/jcm9092935.
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The ongoing coronavirus disease 2019 (COVID-19) pandemic has resulted in efforts to identify therapies to ameliorate adverse clinical outcomes. The recognition of the key role for increased inflammation in COVID-19 has led to a proliferation of clinical trials targeting inflammation. The purpose of this review is to characterize the current state of immunotherapy trials in COVID-19, and focuses on associated cardiotoxicities, given the importance of pharmacovigilance. The search terms related to COVID-19 were queried in ClinicalTrials.gov. A total of 1621 trials were identified and screened for interventional trials directed at inflammation. Trials (n = 226) were fully assessed for the use of a repurposed drug, identifying a total of 141 therapeutic trials using a repurposed drug to target inflammation in COVID-19 infection. Building on the results of the Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial demonstrating the benefit of low dose dexamethasone in COVID-19, repurposed drugs targeting inflammation are promising. Repurposed drugs directed at inflammation in COVID-19 primarily have been drawn from cancer therapies and immunomodulatory therapies, specifically targeted anti-inflammatory, anti-complement, and anti-rejection agents. The proposed mechanisms for many cytokine-directed and anti-rejection drugs are focused on evidence of efficacy in cytokine release syndromes in humans or animal models. Anti-complement-based therapies have the potential to decrease both inflammation and microvascular thrombosis. Cancer therapies are hypothesized to decrease vascular permeability and inflammation. Few publications to date describe using these drugs in COVID-19. Early COVID-19 intervention trials have re-emphasized the subtle, but important cardiotoxic sequelae of potential therapies on outcomes. The volume of trials targeting the COVID-19 hyper-inflammatory phase continues to grow rapidly with the evaluation of repurposed drugs and late-stage investigational agents. Leveraging known clinical safety profiles and pharmacodynamics allows swift investigation in clinical trials for a novel indication. Physicians should remain vigilant for cardiotoxicity, often not fully appreciated in small trials or in short time frames.
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Gediz Erturk, Aliye, Arzu Sahin, Ebru Bati Ay, Emel Pelit, Emine Bagdatli, Irem Kulu, Melek Gul, et al. "A Multidisciplinary Approach to Coronavirus Disease (COVID-19)." Molecules 26, no. 12 (June 9, 2021): 3526. http://dx.doi.org/10.3390/molecules26123526.
Full textAbstract:
Since December 2019, humanity has faced an important global threat. Many studies have been published on the origin, structure, and mechanism of action of the SARS-CoV-2 virus and the treatment of its disease. The priority of scientists all over the world has been to direct their time to research this subject. In this review, we highlight chemical studies and therapeutic approaches to overcome COVID-19 with seven different sections. These sections are the structure and mechanism of action of SARS-CoV-2, immunotherapy and vaccine, computer-aided drug design, repurposing therapeutics for COVID-19, synthesis of new molecular structures against COVID-19, food safety/security and functional food components, and potential natural products against COVID-19. In this work, we aimed to screen all the newly synthesized compounds, repurposing chemicals covering antiviral, anti-inflammatory, antibacterial, antiparasitic, anticancer, antipsychotic, and antihistamine compounds against COVID-19. We also highlight computer-aided approaches to develop an anti-COVID-19 molecule. We explain that some phytochemicals and dietary supplements have been identified as antiviral bioproducts, which have almost been successfully tested against COVID-19. In addition, we present immunotherapy types, targets, immunotherapy and inflammation/mutations of the virus, immune response, and vaccine issues.
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Trivedi, Jay, Mahesh Mohan, and Siddappa N. Byrareddy. "Drug Repurposing Approaches to Combating Viral Infections." Journal of Clinical Medicine 9, no. 11 (November 23, 2020): 3777. http://dx.doi.org/10.3390/jcm9113777.
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Development of novel antiviral molecules from the beginning costs an average of $350 million to $2 billion per drug, and the journey from the laboratory to the clinic takes about 10–15 years. Utilization of drug repurposing approaches has generated substantial interest in order to overcome these drawbacks. A drastic reduction in the failure rate, which otherwise is ~92%, is achieved with the drug repurposing approach. The recent exploration of the drug repurposing approach to combat the COVID-19 pandemic has further validated the fact that it is more beneficial to reinvestigate the in-practice drugs for a new application instead of designing novel drugs. The first successful example of drug repurposing is zidovudine (AZT), which was developed as an anti-cancer agent in the 1960s and was later approved by the US FDA as an anti-HIV therapeutic drug in the late 1980s after fast track clinical trials. Since that time, the drug repurposing approach has been successfully utilized to develop effective therapeutic strategies against a plethora of diseases. Hence, an extensive application of the drug repurposing approach will not only help to fight the current pandemics more efficiently but also predict and prepare for newly emerging viral infections. In this review, we discuss in detail the drug repurposing approach and its advancements related to viral infections such as Human Immunodeficiency Virus (HIV) and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).
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Baby, Krishnaprasad, Swastika Maity, Chetan H. Mehta, Akhil Suresh, Usha Y. Nayak, and Yogendra Nayak. "Targeting SARS-CoV-2 RNA-dependent RNA polymerase: An in silico drug repurposing for COVID-19." F1000Research 9 (September 23, 2020): 1166. http://dx.doi.org/10.12688/f1000research.26359.1.
Full textAbstract:
Background: The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), took more lives than combined epidemics of SARS, MERS, H1N1, and Ebola. Currently, the prevention and control of spread are the goals in COVID-19 management as there are no specific drugs to cure or vaccines available for prevention. Hence, the drug repurposing was explored by many research groups, and many target proteins have been examined. The major protease (Mpro), and RNA-dependent RNA polymerase (RdRp) are two target proteins in SARS-CoV-2 that have been validated and extensively studied for drug development in COVID-19. The RdRp shares a high degree of homology between those of two previously known coronaviruses, SARS-CoV and MERS-CoV. Methods: In this study, the FDA approved library of drugs were docked against the active site of RdRp using Schrodinger's computer-aided drug discovery tools for in silico drug-repurposing. Results: We have shortlisted 14 drugs from the Standard Precision docking and interaction-wise study of drug-binding with the active site on the enzyme. These drugs are antibiotics, NSAIDs, hypolipidemic, coagulant, thrombolytic, and anti-allergics. In molecular dynamics simulations, pitavastatin, ridogrel and rosoxacin displayed superior binding with the active site through ARG555 and divalent magnesium. Conclusion: Pitavastatin, ridogrel and rosoxacin can be further optimized in preclinical and clinical studies to determine their possible role in COVID-19 treatment.
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Sourimant, Julien, Megha Aggarwal, and Richard K. Plemper. "Progress and pitfalls of a year of drug repurposing screens against COVID-19." Current Opinion in Virology 49 (August 2021): 183–93. http://dx.doi.org/10.1016/j.coviro.2021.06.004.
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Rana, Prabha, and Vagisha Rawal. "Repurposing of drugs and leading vaccines work against COVID-19." Environment Conservation Journal 23, no. 1&2 (February 1, 2022): 39–48. http://dx.doi.org/10.36953/ecj.021904-2161.
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The novel coronavirus disease 19 (COVID-19) is a highly contagious and pathogenic viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The first known case was reported / identified in Wuhan, China. In March 2020, the World Health Organization (WHO) declared it a ‘pandemic’ due to its Worldwide spread. Researchers have been trying to find a suitable treatment from available drugs like Dexamethasone, and Remdesivir to fight the novel coronavirus outbreak. AstraZeneca-SK Bio, Moderna, Pfizer-BioNTech and Janssen vaccines were added to the WHO's list of emergency use. Our review work highlights the repurposing of drugs and leading vaccines to counter COVID-19.
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Ghanbari, Reza, Ali Teimoori, Anahita Sadeghi, Ashraf Mohamadkhani, Sama Rezasoltani, Ebrahim Asadi, Abolghasem Jouyban, and Susan CJ Sumner. "Existing antiviral options against SARS-CoV-2 replication in COVID-19 patients." Future Microbiology 15, no. 18 (December 2020): 1747–58. http://dx.doi.org/10.2217/fmb-2020-0120.
Full textAbstract:
COVID-19 caused by SARS-CoV-2, is an international concern. This infection requires urgent efforts to develop new antiviral compounds. To date, no specific drug in controlling this disease has been identified. Developing the new treatment is usually time consuming, therefore using the repurposing broad-spectrum antiviral drugs could be an effective strategy to respond immediately. In this review, a number of broad-spectrum antivirals with potential efficacy to inhibit the virus replication via targeting the virus spike protein (S protein), RNA-dependent RNA polymerase (RdRp), 3-chymotrypsin-like protease (3CLpro) and papain-like protease (PLpro) that are critical in the pathogenesis and life cycle of coronavirus, have been evaluated as possible treatment options against SARS-CoV-2 in COVID-19 patients.
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Kiebish, Michael A., Punit Shah, Rangaprasad Sarangarajan, Vivek K. Vishnudas, Stephane Gesta, Poornima K. Tekumalla, Chas Bountra, et al. "Bayesian Model Infers Drug Repurposing Candidates for Treatment of COVID-19." Applied Sciences 11, no. 6 (March 10, 2021): 2466. http://dx.doi.org/10.3390/app11062466.
Full textAbstract:
The emergence of COVID-19 progressed into a global pandemic that has functionally put the world at a standstill and catapulted major healthcare systems into an overburdened state. The dire need for therapeutic strategies to mitigate and successfully treat COVID-19 is now a public health crisis with national security implications for many countries. The current study employed Bayesian networks to a longitudinal proteomic dataset generated from Caco-2 cells transfected with SARS-CoV-2 (isolated from patients returning from Wuhan to Frankfurt). Two different approaches were employed to assess the Bayesian models, a titer-center topology analysis and a drug signature enrichment analysis. Topology analysis identified a set of proteins directly linked to the SAR-CoV2 titer, including ACE2, a SARS-CoV-2 binding receptor, MAOB and CHECK1. Aligning with the topology analysis, MAOB and CHECK1 were also identified within the enriched drug-signatures. Taken together, the data output from this network has identified nodal host proteins that may be connected to 18 chemical compounds, some already marketed, which provides an immediate opportunity to rapidly triage these assets for safety and efficacy against COVID-19.
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Rogosnitzky, Moshe, Esther Berkowitz, and Alejandro R. Jadad. "No Time to Waste: Real-World Repurposing of Generic Drugs as a Multifaceted Strategy Against COVID-19." JMIRx Med 1, no. 1 (September 30, 2020): e19583. http://dx.doi.org/10.2196/19583.
Full textAbstract:
Real-world drug repurposing—the immediate “off-label” prescribing of drugs to address urgent clinical needs—is an indispensable strategy gaining rapid traction in the current COVID-19 crisis. Although off-label prescribing (ie, for a nonapproved indication) is legal in most countries, it tends to shift the burden of liability and cost to physicians and patients, respectively. Nevertheless, in urgent public health crises, it is often the only realistic source of a meaningful potential solution. To be considered for real-world repurposing, drug candidates should ideally have a track record of safety, affordability, and wide accessibility. Although thousands of such drugs are already available, the absence of a central repository of off-label uses presents a barrier to the immediate identification and selection of the safest, potentially useful interventions. Using the current COVID-19 pandemic as an example, we provide a glimpse at the extensive literature that supports the rationale behind six generic drugs, in four classes, all of which are affordable, supported by decades of safety data, and pleiotropically target the underlying pathophysiology that makes COVID-19 so dangerous. Having previously fast-tracked this paper to publication in summary form, we now expand on why cimetidine/famotidine (histamine type-2 receptor antagonists), dipyridamole (antiplatelet agent), fenofibrate/bezafibrate (cholesterol/triglyceride-lowering agents), and sildenafil (phosphodiesterase-5 inhibitor) are worth considering for patients with COVID-19 based on their antiviral, anti-inflammatory, renoprotective, cardioprotective, and anticoagulation properties. These examples also reveal the unlimited opportunity to future-proof public health by proactively mining, synthesizing, and cataloging the off-label treatment opportunities of thousands of safe, well-established, and affordable generic drugs.
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Fiscon, Giulia, Federica Conte, Lorenzo Farina, and Paola Paci. "SAveRUNNER: A network-based algorithm for drug repurposing and its application to COVID-19." PLOS Computational Biology 17, no. 2 (February 5, 2021): e1008686. http://dx.doi.org/10.1371/journal.pcbi.1008686.
Full textAbstract:
The novelty of new human coronavirus COVID-19/SARS-CoV-2 and the lack of effective drugs and vaccines gave rise to a wide variety of strategies employed to fight this worldwide pandemic. Many of these strategies rely on the repositioning of existing drugs that could shorten the time and reduce the cost compared to de novo drug discovery. In this study, we presented a new network-based algorithm for drug repositioning, called SAveRUNNER (Searching off-lAbel dRUg aNd NEtwoRk), which predicts drug–disease associations by quantifying the interplay between the drug targets and the disease-specific proteins in the human interactome via a novel network-based similarity measure that prioritizes associations between drugs and diseases locating in the same network neighborhoods. Specifically, we applied SAveRUNNER on a panel of 14 selected diseases with a consolidated knowledge about their disease-causing genes and that have been found to be related to COVID-19 for genetic similarity (i.e., SARS), comorbidity (e.g., cardiovascular diseases), or for their association to drugs tentatively repurposed to treat COVID-19 (e.g., malaria, HIV, rheumatoid arthritis). Focusing specifically on SARS subnetwork, we identified 282 repurposable drugs, including some the most rumored off-label drugs for COVID-19 treatments (e.g., chloroquine, hydroxychloroquine, tocilizumab, heparin), as well as a new combination therapy of 5 drugs (hydroxychloroquine, chloroquine, lopinavir, ritonavir, remdesivir), actually used in clinical practice. Furthermore, to maximize the efficiency of putative downstream validation experiments, we prioritized 24 potential anti-SARS-CoV repurposable drugs based on their network-based similarity values. These top-ranked drugs include ACE-inhibitors, monoclonal antibodies (e.g., anti-IFNγ, anti-TNFα, anti-IL12, anti-IL1β, anti-IL6), and thrombin inhibitors. Finally, our findings were in-silico validated by performing a gene set enrichment analysis, which confirmed that most of the network-predicted repurposable drugs may have a potential treatment effect against human coronavirus infections.