Journal
MOLECULAR SYSTEMS BIOLOGY
Volume 17, Issue 11, Pages -Publisher
WILEY
DOI: 10.15252/msb.202110260
Keywords
antiviral target; genome-scale metabolic modeling; remdesivir; RNAi screen; SARS-CoV-2
Categories
Funding
- Intramural Research Program of the National Institutes of Health, NCI
- National Cancer Institute
- Sanford Burnham Prebys Medical Discovery Institute [DoD: W81XWH-20-1-0270, DHIPC: U19 AI118610, Fluomics/NOSI: U19 AI135972]
- NCI-UMD Partnership for Integrative Cancer Research Program
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The study utilized genome-scale metabolic modeling to analyze host metabolism changes during SARS-CoV-2 infection, predicted anti-viral targets, validated these targets using drug and genetic screening data, and provided potential anti-SARS-CoV-2 targets supported by clinical data for future evaluation.
Tremendous progress has been made to control the COVID-19 pandemic caused by the SARS-CoV-2 virus. However, effective therapeutic options are still rare. Drug repurposing and combination represent practical strategies to address this urgent unmet medical need. Viruses, including coronaviruses, are known to hijack host metabolism to facilitate viral proliferation, making targeting host metabolism a promising antiviral approach. Here, we describe an integrated analysis of 12 published in vitro and human patient gene expression datasets on SARS-CoV-2 infection using genome-scale metabolic modeling (GEM), revealing complicated host metabolism reprogramming during SARS-CoV-2 infection. We next applied the GEM-based metabolic transformation algorithm to predict anti-SARS-CoV-2 targets that counteract the virus-induced metabolic changes. We successfully validated these targets using published drug and genetic screen data and by performing an siRNA assay in Caco-2 cells. Further generating and analyzing RNA-sequencing data of remdesivir-treated Vero E6 cell samples, we predicted metabolic targets acting in combination with remdesivir, an approved anti-SARS-CoV-2 drug. Our study provides clinical data-supported candidate anti-SARS-CoV-2 targets for future evaluation, demonstrating host metabolism targeting as a promising antiviral strategy.
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