Genome-scale metabolic modeling reveals SARS-CoV-2-induced metabolic changes and antiviral targets

Abstract

Tremendous progress has been made to control the COVID-19 pandemic, including the development and approval of vaccines as well as the drug remdesivir, which inhibits the SARS-CoV-2 virus that causes COVID-19. However, remdesivir confers only mild benefits to a subset of patients, and additional effective therapeutic options are needed. Drug repurposing and drug combinations may represent practical strategies to address these urgent unmet medical needs. Viruses, including coronaviruses, are known to hijack the host metabolism to facilitate their own 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). We find that SARS-CoV-2 infection can induce recurrent and complicated metabolic reprogramming spanning a wide range of metabolic pathways. We next applied the GEM-based metabolic transformation algorithm (MTA) to predict anti-SARS-CoV-2 targets that counteract the virus-induced metabolic changes. These predictions are enriched for validated targets from various published experimental drug and genetic screens. Further analyzing the RNA-sequencing data of remdesivir-treated Vero E6 cell samples that we generated, we predicted metabolic targets that act in combination with remdesivir. These predictions are enriched for previously reported synergistic drugs with remdesivir. Since our predictions are based in part on human patient data, they are likely to be clinically relevant. We provide our top high-confidence candidate targets for their evaluation in further studies, demonstrating host metabolism-targeting as a promising antiviral strategy.

DCcov: Repositioning of drugs and drug combinations for SARS-CoV-2 infected lung through constraint-based modeling

“…OPEN ACCESS iScience 24, 103331, November 19, 2021 iScience Article essentiality and safety score. Also, pyrimidine biosynthesis was among the pathways with consistent flux changes in the metabolic modeling of multiple cell lines (Cheng et al, 2021). Furthermore, three essential genes (DTYMK, CMPK1, and TYMS) are part of pyrimidine metabolism (through pyrimidine deoxyribonucleotides de novo biosynthesis) that were enriched in all conditions in the severity study, but for the last time point of the time-series study in the Calu-3 cell line.…”

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Synergistic Effects of Multiple Factors Involved in COVID-19-dependent Muscle Loss

“…Thus, treatment with antivirals like ribavirin may also negatively affect patients' ability to repair muscle. We did find data from a study treating Vero E6 cells with remdesivir to determine changes in gene expression [ 47 ]. CCND1 was downregulated in the remdesivir treated cells, as was demonstrated by ribavirin in the previous study.…”