Cell-specific genome-scale metabolic modeling of SARS-CoV-2-infected lung to identify antiviral enzymes.

Abstract

Computational systems biology plays a key role in the discovery of suitable antiviral targets. We designed a cell-specific, constraint-based modeling technique for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected lungs. We used the gene sequence of the alpha variant of SARS-CoV-2 to build a viral biomass reaction (VBR). We also used the mass proportion of lipids between the viral biomass and its host cell to estimate the stoichiometric coefficients of viral lipids in the reaction. We then integrated the VBR, the gene expression of the alpha variant of SARS-CoV-2, and the generic human metabolic network Recon3D to reconstruct a cell-specific genome-scale metabolic model. An antiviral target discovery (AVTD) platform was introduced using this model to identify therapeutic drug targets for combating COVID-19. The AVTD platform not only identified antiviral genes for eliminating viral replication but also predicted side effects of treatments. Our computational results revealed that knocking out dihydroorotate dehydrogenase (DHODH) might reduce the synthesis rate of cytidine-5'-triphosphate and uridine-5'-triphosphate, which terminate the viral building blocks of DNA and RNA for SARS-CoV-2 replication. Our results also indicated that DHODH is a promising antiviral target that causes minor side effects, which is consistent with the results of recent reports. Moreover, we discovered that the genes that participate in the de novo biosynthesis of glycerophospholipids and ceramides become unidentifiable if the VBR does not involve the stoichiometry of lipids.