Abstract
Viruses rely on their host for reproduction. Here, we made use of genomic and structural information to create a biomass function capturing the amino and nucleic acid requirements of SARS-CoV-2. Incorporating this biomass function into a stoichiometric metabolic model of the human lung cell and applying metabolic flux balance analysis, we identified host-based metabolic perturbations inhibiting SARS-CoV-2 reproduction. Our results highlight reactions in the central metabolism, as well as amino acid and nucleotide biosynthesis pathways. By incorporating host cellular maintenance into the model based on available protein expression data from human lung cells, we find that only few of these metabolic perturbations are able to selectively inhibit virus reproduction. Some of the catalysing enzymes of such reactions have demonstrated interactions with existing drugs, which can be used for experimental testing of the presented predictions using gene knockouts and RNA interference techniques. In summary, the developed computational approach offers a platform for rapid, experimentally testable generation of drug predictions against existing and emerging viruses based on their biomass requirements.
Highlights
One of the crucial steps in the virus life cycle is the synthesis of the virus particles within the host cell
System-level metabolic studies have highlighted changes in glucose uptake and glycolysis (El-Bacha et al, 2004; Munger et al, 2006), which might be related to an increased demand for biosynthetic precursors as viral production becomes the dominant process within infected cells (Berzin et al, 1974)
These analyses have shown that reactions which must carry flux for optimal viral biomass production include glycolysis, oxidative phosphorylation, fatty acid oxidation, and specific amino and nucleic acid biosynthesis pathways (Fig 1C and Table S1)
Summary
One of the crucial steps in the virus life cycle is the synthesis of the virus particles within the host cell. An even more specific metabolic approach to inhibit virus production was demonstrated in the case of human cytomegalovirus For this virus, metabolic analyses highlighted a shifting of metabolic fluxes within central carbon metabolism and fatty acid biosynthesis pathways during infection (Munger et al, 2008). Systematic analysis of gene knockout effects on infection of bacteria with phage identified many metabolic genes associated with central carbon metabolism and substrate transport (Maynard et al, 2010b), leading to the proposition of using host metabolic engineering to modulate viral production (Maynard et al, 2010a) Such metabolic control has been explored in virusbased bioproduction using insect cells, where alterations in the culture media allowed alteration of metabolic fluxes and production levels (Carinhas et al, 2010)
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