Potential antiviral target for SARS-CoV-2

In a recent study published in iScience Journals and researchers have evaluated potential targets for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Thousands of registered clinical trials around the world are working to develop safe and effective treatments for coronavirus disease 2019 (COVID-19). Despite these efforts, it is most urgent to determine additional effective anti-SARS-CoV-2 targets in order to develop agents that directly or indirectly target the virus.

About research

In this study, researchers applied clinically relevant synthetic lethality (ISLE) identification to a cohort that included: In vivo When In vitro SARS-CoV-2 Ribonucleic Acid (RNA)-Sequence data set for identifying antiviral targets as synthetic lethality (SL) or synthetic lethality (SDL).

By acquiring and analyzing multiple transcriptmics datasets containing SARS-CoV-2 infection, the team identified host cell genes that showed altered expression after SARS-CoV-2 infection. These datasets have In vitro Samples and samples from Vero E6 cells and human A549-angiotensin converting enzyme-2 (ACE-2) cells In vivo Samples collected from the nasopharyngeal swab of COVID-19 patients.The team also performed using single-cell RNA sequencing data associated with bronchial and nasopharyngeal samples. In vivo analysis.

The differential expression (DE) gene identified in the SARS-CoV-2 infected sample was compared to the gene in the corresponding virus-negative control sample. DE analysis was performed only on epithelial cells of the single cell dataset, which was the main focus of SL / SDL-based antiviral strategies.

The team also evaluated SL / SDL partners for the identified DE gene. This is because it constitutes a potential target for antiviral activity that can selectively damage infected host cells and limit their ability to proliferate. The ISLE algorithm was applied to predict the SL partner of the downregulated DE gene after SARS-CoV-2 infection, while the upregulated gene was predicted by a modified version of ISLE.

In addition, the team has two published, clustered, regularly spaced short palindrome repeats (CRISPRs) and CRISPR-related proteins-9 (Cas9) that determine the host genes that regulate SARS-CoV-2 replication. ) Obtained data from gene screening. These included screening Vero E6 cell lines and human A549 cell lines at two different multiplicity of infections (MOIs).

result

The study results showed that mutations were found in the DE gene identified throughout the SARS-CoV-2 infection and the corresponding virus-negative dataset.However, the team also has a low odds ratio of 2.7. In vitro With A549 cell dataset In vivo In the RNA sequence sample, the odds ratio is the highest at 12.4, In vivo With single cell samples In vivo Bulk swab. Pathogenic analysis of the DE genes showed that these genes were enriched to function in similar pathways while changing between different datasets.

The SL / SDL partners recognized throughout the dataset showed higher similarity than those displayed by the DE gene. In particular, duplication was observed between SL / SDL partners across the A549 cell dataset. In vivo RNA sequence samples higher than the overlap found between related DE genes. This indicates that the DE genes identified across the cellular dataset are likely to be functionally similar and likely to induce SL / SDL interactions with the same DE gene.

The team found that the predicted 454 SL / SDL-based target was substantially enriched for host proteins that interact with the SARS-CoV-2 viral protein. This indicated that these predicted targets are important for SARS-CoV-2 biology and infection. Of the 454 targets, 140 genes showed significant activity in reducing cell viability. These 140 targets contained genes that were inhibited by available drugs such as warfarin and dicoumarol, which target the VKORC1 gene.

Analysis of 140 targets showed enrichment of pathways including stress response, cell cycle processes, deoxyribonucleic acid (DNA) cleavage repair processes, RNA polymerase II transcription, and RNA metabolism processes. In addition, the DE gene showed enrichment for pathways such as complement cascade, innate immune processes, ion channel transport, cytokine signaling, neutrophil degranulation, and interferon signaling. Analysis of pathway enrichment based on matched pairs also showed several SL / SDL interactions, including cell-cell communication, post-translational protein modification, and the innate immune system.

A total of 26 top-ranked SL / SDL targets out of 140 targets were selected for additional analysis. These top-ranked targets included VKORC1, an anticoagulant that binds to the open reading frame (ORF) -7a of SARS-CoV-2, which was the target of warfarin. MED8, a gene required for transcriptional activation. EIF4G1 is known for its function in cell growth, differentiation and proliferation.

The research results show a synthetic lethality inference method that predicts SARS-CoV-2 targets throughout the viral genome. This study provided potential antiviral targets that could prove essential in the development of new therapeutic approaches to COVID-19.