Researchers use drug repositioning libraries to investigate potential SARS-CoV-2 antivirals

In December 2019, the emergence of a new coronavirus, later identified as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), was reported in Wuhan, China. Due to the high global prevalence of the virus, the World Health Organization (WHO) announced on March 11, 2020 that Coronavirus Disease 2019 (COVID-19) will be a 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 belongs to the family. Coronaviridae.. Other viruses of the same family with a history of causing epidemics are SARS-CoV and MERS-CoV. According to recent data, the virus has already infected more than 145 million people worldwide, killing about 3.07 million people. Recently, vaccination programs have been launched in many countries, but demand is greater than supply. In addition, the incidence of more toxic SARS-CoV-2 mutants, which may evade the vaccine-induced immune response, raises concerns among scientists and public health authorities. Therefore, it is very important to develop an effective treatment for COVID-19 that can reduce the severity of the disease.

One approach is to identify pre-existing drugs that may be effective in treating COVID-19. This is possible by establishing a series of diversion screens of various sizes. In this regard, ReFRAME, which has screened approximately 12,000 compound libraries, is considered to be the largest diversion screen to date. Similar previous studies have succeeded in identifying several compounds that are PIKfyve inhibitors, protease inhibitors (MG132), kinase inhibitors, and cyclosporine, but more detailed evaluation of these compounds is needed. is.

New research released bioRxiv* A preprint server that handles screening of drug repositioning hub (DRH) libraries to identify small compounds that can inhibit SARS-CoV-2 using both. In vitro And In vivo Experimental study. These molecules can be used to design new therapeutic systems for SARS-CoV-2 infection.

The DRH library consists primarily of 6,710 compounds approved by the Food and Drug Administration (FDA). Some of the compounds present in the library are either participating in clinical trials or are widely characterized in preclinical studies. In addition, it consists of structurally related molecules with conserved molecular motifs and an annotated database of host drug targets. This helps in a preliminary understanding of the structural activity of the compound and also determines the host target site. These data are very important for designing drugs for SARS-CoV-2.

The primary screen helps identify all compounds ranked based on activity. The strongest active compound is placed in the higher rank, followed by the weakest compound. This study is a continuation of previous computational studies that established the SARS-CoV-2 related protein network and can be used in the design of new drugs. In this study, only 200 of the 6710 small molecules may inhibit SARS-CoV-2 infection. In addition, only 40 compounds, including procilaridine, emetine, obatoclax, sangibamycin, omiparicib, and BAY2402234, were determined as inhibitors of SARS-CoV-2 replication by a variety of mechanisms. The most potent compounds that achieved an outstanding rank in computational studies were further evaluated using an orthogonal assay. These assays were performed on human primary cell-based tissue models and human cell lines (Huh-7 and A549 cells).

Current studies have confirmed the activity of several previously identified compounds, including PIKfyve inhibitors, cathepsins, and protein synthesis, and are recognized as promising agents for the treatment of COVID-19. However, obatoclax was reported to be the most prominent small molecule that consistently remained active in all cell-based assays. This compound has been used primarily in the treatment of cancer due to its BCL-2 homologous domain 3 inhibitory effect, apoptosis, and increased autophagy. The other seven 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 titer by up to a tenth.Such a decrease Viral load It may be associated with reduced mortality in COVID-19 patients.

This study reveals a class of compounds that have not previously been identified as effective against COVID-19 as BET inhibitors. Previous studies have reported that there are four BET proteins to which the viral E protein attaches.Viral E protein is associated with the assembly and emergence of newly formed ones Coronavirus From the cell. Previous studies have reported that endosome trafficking is an important route of entry and replication point for most viruses, including coronavirus. Current research has identified apilimod as an effective inhibitor compound that can be used as a therapeutic agent for SARS-CoV-2. The two compounds reported in this study, apilimod and VBY-825, overlap with an analysis involving the ReFRAME library.

The results of the current study show that drug repositioning is an important tool that helps to quickly identify effective drugs and may help prevent COVID-19. However, before using it, you need to validate the calculation result as follows: In vitro And In vivo Research and further clinical trials need to be conducted for proper validation.

*Important Notices

bioRxiv publishes unpeer-reviewed preliminary scientific reports and should not be considered definitive, guide clinical / health-related behaviors, or be treated as established information.