Carfilzomib for COVID-19

Abstract Background Viruses such as Ebola, Marburg, influenza, mpox, MERS-CoV, SARS-CoV, and SARS-CoV-2 pose a significant risk for future pandemics. Developing novel antiviral medicines can be time-consuming and resource intensive. Repurposing existing medicines with antiviral activity offers a faster, cost-effective strategy to expand treatment options during public health emergencies. This scan aimed to identify and synthesise recent evidence on repurposed antiviral medicines under investigation for these viruses. Method A horizon scanning approach was employed, starting with a targeted search in Embase, followed by a systematic search of ClinicalTrials.gov to capture the developmental stages of the technologies. Eligible technologies included UK- or EU-licensed medicines repurposed as antiviral therapies for the viruses of interest. Vaccines, unlicensed medicines, and already approved treatments for the targeted viruses were excluded. Results A total of 196 repurposed technologies targeting the viruses were identified from published literature, and the expanded search on the clinical trials registry yielded 58 technologies in active clinical development. Interventional clinical trial activity was limited to influenza and COVID-19, with 29 technologies for COVID-19 and two for influenza advancing to phase III evaluation. For other viruses, proposed antiviral candidates were identified in the literature but had not progressed into clinical development. Commonly investigated pharmacological classes included direct-acting antivirals, tyrosine kinase inhibitors, immunomodulators, and anti-inflammatory agents. Conclusion Repurposing antiviral medicines represents a pragmatic strategy for rapid therapeutic deployment against emerging viral threats. Collaboration among researchers, policymakers, research funders, and regulatory bodies will be essential to improve pandemic preparedness and support repurposing efforts in emergency situations.

The COVID-19 pandemic has demanded urgent and accelerated action toward developing effective therapeutic strategies. Drug repurposing models (in silico) are in high demand and require accurate and reliable molecular interaction data. While experimentally verified viral–host interaction data (SARS-CoV-2–human interactions published on April 30, 2020) provide an invaluable resource, these datasets include only a limited number of high-confidence interactions. Here, we extend these resources using a deep learning–based multiview graph neural network approach, coupled with optimal transport–based integration. Our comprehensive validation strategy confirms 472 high-confidence predicted interactions between 280 host proteins and 27 SARS-CoV-2 proteins. The proposed model demonstrates robust predictive performance, achieving ROC-AUC scores of 85.9% (PPI network), 83.5% (GO similarity network), and 83.1% (sequence similarity network), with corresponding average precision scores of 86.4%, 82.8%, and 82.3% on independent test sets. Comparative evaluation shows that our multiview approach consistently outperforms conventional single-view and baseline graph learning methods. The model combines features derived from protein sequences, gene ontology terms, and physical interaction information to improve interaction prediction. Furthermore, we systematically map the predicted host factors to FDA-approved drugs and identify several candidates, including lenalidomide and pirfenidone, which have established or emerging roles in COVID-19 therapy. Overall, our framework provides comprehensive and accurate predictions of SARS-CoV-2–host protein interactions and represents a valuable resource for drug repurposing efforts.

Background and purposeThe coronavirus disease 2019 (COVID-19) pandemic has devastated global health and the economy, underscoring the urgent need for extensive research into the mechanisms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral entry and the development of effective therapeutic interventions.Experimental approachWe established a cell line expressing human angiotensin-converting enzyme 2 (ACE2). We used it as a model of pseudotyped viral entry using murine leukemia virus (MLV) expressing SARS-CoV-2 spike (S) protein on its surface and firefly luciferase as a reporter. We screened an U.S. Food and Drug Administration (FDA)-approved compound library for inhibiting ACE2-dependent SARS-CoV-2 pseudotyped viral entry and identified several drug-repurposing candidates.Key resultsWe identified 18 drugs and drug candidates, including 14 previously reported inhibitors of viral entry and four novel candidates. Pyridoxal 5′-phosphate, Dovitinib, Adefovir dipivoxil, and Biapenem potently inhibit ACE2-dependent viral entry with inhibitory concentration 50% (IC50) values of 57nM, 74 nM, 130 nM, and 183 nM, respectively.Conclusion and implicationsWe identified four novel FDA-approved candidate drugs for anti-SARS-CoV-2 combination therapy. Our findings contribute to the growing body of evidence supporting drug repurposing as a viable strategy for rapidly developing COVID-19 treatments.

AbstractTo attain promising pharmacotherapies, researchers have applied drug repurposing (DR) techniques to discover the candidate medicines to combat the coronavirus disease 2019 (COVID-19) outbreak. Although many DR approaches have been introduced for treating different diseases, only structure-based DR (SBDR) methods can be employed as the first therapeutic option against the COVID-19 pandemic because they rely on the rudimentary information about the diseases such as the sequence of the severe acute respiratory syndrome coronavirus 2 genome. Hence, to try out new treatments for the disease, the first attempts have been made based on the SBDR methods which seem to be among the proper choices for discovering the potential medications against the emerging and re-emerging infectious diseases. Given the importance of SBDR approaches, in the present review, well-known SBDR methods are summarized, and their merits are investigated. Then, the databases and software applications, utilized for repurposing the drugs against COVID-19, are introduced. Besides, the identified drugs are categorized based on their targets. Finally, a comparison is made between the SBDR approaches and other DR methods, and some possible future directions are proposed.

The emergence of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected many countries throughout the world. As urgency is a necessity, most efforts have focused on identifying small molecule drugs that can be repurposed for use as anti-SARS-CoV-2 agents. Although several drug candidates have been identified using in silico method and in vitro studies, most of these drugs require the support of in vivo data before they can be considered for clinical trials. Several drugs are considered promising therapeutic agents for COVID-19. In addition to the direct-acting antiviral drugs, supportive therapies including traditional Chinese medicine, immunotherapies, immunomodulators, and nutritional therapy could contribute a major role in treating COVID-19 patients. Some of these drugs have already been included in the treatment guidelines, recommendations, and standard operating procedures. In this article, we comprehensively review the approved and potential therapeutic drugs, immune cells-based therapies, immunomodulatory agents/drugs, herbs and plant metabolites, nutritional and dietary for COVID-19.

The current pandemic has highlighted the need for methodologies that can quickly and reliably prioritize clinically approved compounds for their potential effectiveness for SARS-CoV-2 infections. In the past decade, network medicine has developed and validated multiple predictive algorithms for drug repurposing, exploiting the sub-cellular network-based relationship between a drug's targets and disease genes. 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 that had been experimentally screened in VeroE6 cells, and the list of drugs under clinical trial, that capture the medical community's assessment of drugs with potential COVID-19 efficacy. We find that while most algorithms offer predictive power for these ground truth data, no single method offers consistently reliable outcomes across all datasets and metrics. This prompted us to develop a multimodal approach that fuses the predictions of all algorithms, showing that a consensus among the different predictive methods consistently exceeds the performance of the best individual pipelines. We find that 76 of the 77 drugs that successfully reduced viral infection do not bind the proteins targeted by SARS-CoV-2, indicating that these drugs rely on network-based actions 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.

Abstract Using as a template the crystal structure of the SARS-CoV-2 main protease, we developed a pharmacophore model of functional centers of the protease inhibitor-binding pocket. With this model, we conducted data mining of the conformational database of FDA-approved drugs. This search brought 64 compounds that can be potential inhibitors of the SARS-CoV-2 protease. The conformations of these compounds undergone 3D fingerprint similarity clusterization. Then we conducted docking of possible conformers of these drugs to the binding pocket of the protease. We also conducted the same docking of random compounds. Free energies of the docking interaction for the selected compounds were clearly lower than random compounds. Three of the selected compounds were carfilzomib, cyclosporine A, and azithromycin—the drugs that already are tested for COVID-19 treatment. Among the selected compounds are two HIV protease inhibitors and two hepatitis C protease inhibitors. We recommend testing of the selected compounds for treatment of COVID-19.

Purpose: This study introduces a sophisticated computational pipeline, eVir, designed for the discovery of antiviral drugs based on their interactions within the human protein network. There is a pressing need for cost-effective therapeutics for infectious diseases (e.g., COVID-19), particularly in resource-limited countries. Therefore, our team devised an Artificial Intelligence (AI) system to explore repurposing opportunities for currently used oral therapies. The eVir system operates by identifying pharmaceutical compounds that mirror the effects of antiviral peptides (AVPs)—fragments of human proteins known to interfere with fundamental phases of the viral life cycle: entry, fusion, and replication. eVir extrapolates the probable antiviral efficacy of a given compound by analyzing its established and predicted impacts on the human protein-protein interaction network. This innovative approach provides a promising platform for drug repurposing against SARS-CoV-2 or any virus for which peptide data is available.Methods: The eVir AI software pipeline processes drug-protein and protein-protein interaction networks generated from open-source datasets. eVir uses Node2Vec, a graph embedding technique, to understand the nuanced connections among drugs and proteins. The embeddings are input a Siamese Network (SNet) and MLPs, each tailored for the specific mechanisms of entry, fusion, and replication, to evaluate the similarity between drugs and AVPs. Scores generated from the SNet and MLPs undergo a Platt probability calibration and are combined into a unified score that gauges the potential antiviral efficacy of a drug. This integrated approach seeks to boost drug identification confidence, offering a potential solution for detecting therapeutic candidates with pronounced antiviral potency. Once identified a number of compounds were tested for efficacy and toxicity in lung carcinoma cells (Calu-3) infected with SARS-CoV-2. A lead compound was further identified to determine its efficacy and toxicity in K18-hACE2 mice infected with SARS-CoV-2.Computational Predictions: The SNet confidently differentiated between similar and dissimilar drug pairs with an accuracy of 97.28% and AUC of 99.47%. Key compounds identified through these networks included Zinc, Mebendazole, Levomenol, Gefitinib, Niclosamide, and Imatinib. Notably, Mebendazole and Zinc showcased the highest similarity scores, while Imatinib, Levemenol, and Gefitinib also ranked within the top 20, suggesting their significant pharmacological potentials. Further examination of protein binding analysis using explainable AI focused on reverse engineering the causality of the networks. Protein interaction scores for Mebendazole and Imatinib revealed their effects on notable proteins such as CDPK1, VEGF2, ABL1, and several tyrosine protein kinases.Laboratory Studies: This study determined that Mebendazole, Gefitinib, Topotecan and to some extent Carfilzomib showed conventional drug-response curves,..