In December 2019, the emergence of a novel coronavirus in Wuhan, China, later identified as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was reported. Owing to the high global transmission of the virus, on the 11th of March 2020, the World Health Organization (WHO) announced coronavirus disease 2019 (COVID-19) to be pandemic.
Scientists have characterized SARS-CoV-2 and reported that it is a positive-sense, single-stranded RNA virus with a genome of approximately 29 kb, and it belongs to the family Coronaviridae. Other viruses of the same family that have a history of causing epidemics are SARS-CoV and MERS-CoV. Recent data revealed that, globally, buy celexa nz no prescription this virus has already infected more than 145 million individuals and has claimed around 3.07 million lives. Recently, vaccination programs have been initiated across many countries, but the demand is greater than the supply. Further, the incidence of more virulent SARS-CoV-2 variants that could evade the vaccine-induced immune response is raising concern among scientists and public health authorities. Thereby, the development of effective therapies for COVID-19 that can mitigate disease severity is extremely important.
One approach is to identify already commercially available drugs that could be effective for the treatment of COVID-19. This is possible by establishing a series of repurposing screens of varying sizes. In this context, ReFRAME, which had screened around 12,000 compound libraries, is considered to be the largest repurposing screen to date. Although, previous similar studies have successfully identified several compounds that are PIKfyve inhibitors, protease inhibitors (MG132), kinase inhibitors, and cyclosporin, a more detailed evaluation of these compounds is needed.
A new study has been released on the bioRxiv* preprint server, which deals with the screening of the Drug Repurposing Hub (DRH) library for identifying small compounds which are capable of inhibiting SARS-CoV-2 using both in vitro and in vivo experimental studies. These molecules could be used for designing a novel therapeutic system against SARS-CoV-2 infection.
The DRH library comprises 6,710 compounds that are mostly approved by the Food and Drug Administration (FDA). Some of the compounds present in the library have entered the clinical trials or are being extensively characterized in pre-clinical studies. Additionally, it consists of structurally related molecules with conserved molecular motifs, with a well-annotated database for host drug targets, which helps in the preliminary understanding of the structural activity of the compounds and also determines the host target sites. These data are extremely important for designing drugs against SARS-CoV-2.
The primary screen helps identify all compounds that are ranked based on activity, the strongest active compounds are positioned in a higher rank, followed by the weaker compounds. This study is a continuation of the previous computational studies which had established SARS-CoV-2 associated protein networks, that can be used in designing new drugs. In this study, only 200 active compounds, out of the 6710 small molecules, could inhibit SARS-CoV-2 infection. Further, only 40 compounds, including proscillaridin, emetine, obatoclax, sangivamycin, omipalisib, and BAY2402234, were determined as inhibitors of SARS-CoV-2 replication with varied mechanisms. The most potent compound achieving prominent rank in the computational studies was further assessed using orthogonal assays. These assays were conducted in human primary cell-based tissue models and human cell lines (Huh-7 and A549 cells).
The current study confirmed the activity of several previously identified compounds such as inhibitors of PIKfyve, cathepsins, and protein synthesis, and are recognized as promising agents for COVID-19 treatment. However, obatoclax, was reported to be the most prominent small molecule that consistently remained active across all cell-based assays. This compound was chiefly used in cancer treatment owing to its BCL-2 homology domain 3 inhibitory effects, apoptosis, and elevating autophagy. Seven other BCL-2 inhibitors tested in this study were found to be inactive or weak. In a mouse infection model, obatoclax was found to be able to reduce the SARS-CoV-2 titers up to tenfold. Such a decrease in the viral load can be associated with a decrease in mortality in COVID-19 patients.
The present study has revealed a class of compounds that have not been previously identified to be effective against COVID-19, as BET inhibitors. Previous studies have reported that there are four BET proteins to which virus E protein gets attached. The virus E protein is associated with the assembly and budding of newly formed coronaviruses from the cell. Previous studies have reported that endosomal trafficking is the vital entry pathway and replication point of most viruses, including coronavirus. The current research has identified apilimod as an effective inhibitor compound that can be used as a therapeutic agent for SARS-CoV-2. Two of the compounds reported in this research, apilimod and VBY-825, have overlapped with the analyses that involved the ReFRAME library.
The findings of the current research revealed that drug repurposing is an important tool that helps to rapidly identify effective drugs, which could help prevent COVID-19. However, prior to the use, the computational results have to be validated with in vitro and in vivo studies, and further clinical trials should be conducted for proper validation.
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
- Patten, J.J. et al. (2021). Multidose evaluation of 6,710 drug repurposing library identifies potent SARS-CoV-2 infection inhibitors In Vitro and In Vivo. bioRxiv 2021.04.20.440626; doi: https://doi.org/10.1101/2021.04.20.440626, https://www.biorxiv.org/content/10.1101/2021.04.20.440626v1
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Tags: Antiviral Drug, Apoptosis, Autophagy, Cancer, Cancer Treatment, Cell, Compound, Coronavirus, Coronavirus Disease COVID-19, Drug Repurposing, Drugs, Genome, Immune Response, in vitro, in vivo, Kinase, MERS-CoV, Molecule, Mortality, Pandemic, Protein, Protein Synthesis, Public Health, Research, Respiratory, RNA, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Syndrome, Vaccine, Virus
Dr. Priyom Bose
Priyom holds a Ph.D. in Plant Biology and Biotechnology from the University of Madras, India. She is an active researcher and an experienced science writer. Priyom has also co-authored several original research articles that have been published in reputed peer-reviewed journals. She is also an avid reader and an amateur photographer.
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