Can a metabolism-targeted therapeutic intervention successfully subjugate SARS-COV-2? A scientific rational

Abstract

As a process entailing a high turnover of the host cell molecules, viral replication is required for a successful viral infection and requests virus capacity to acquire the macromolecules required for its propagation. To this end, viruses have adopted several strategies to harness cellular metabolism in accordance with their specific demands. Most viruses upregulate specific cellular anabolic pathways and are largely dependent on such alterations. RNA viruses, for example, upregulate both glycolysisand glycogenolysis providing TCA cycle intermediates essential for anabolic lipogenesis. Also, these infections usually induce the PPP, leading to increased nucleotide levels supporting viral replication. SARS-CoV-2 (the cause of COVID-19)that has so far spread from China throughout the world is also an RNA virus. Owing to the more metabolic plasticity of uninfected cells, a promising approach for specific antiviral therapy, which has drawn a lot of attention in the recent years, would be the targeting of metabolic changes induced by viruses. In the current review, we first summarize some of virus-induced metabolic adaptations and then based on these information as well as SARS-CoV-2 pathogenesis, propose a potential therapeutic modality for this calamitous world-spreading virus with the hope of employing this strategy for near-future clinical application.

Keywords: Cellular metabolism; Glycolysis; PPP; SARS-CoV-2; TCA cycle.

Graphical abstract

Fig. 1

a) Rhinovirus, as an RNA virus (RV), post-transcriptionally modulates the host cell metabolism. Infection with this virus induces anabolic reprogramming of the host cell metabolism by 1) Inducing PI3K-mediated trafficking of GLUT1-containing vesicles to the host cell membrane thereby increasing glucose uptake. Also, overexpression of GLUT1 has been found to result in increased PPP intermediates 2) Upregulating both glycolysis and glycogenolysis which provides TCA cycle intermediates required for anabolic lipogenesis 3) Activating the PPP which results in enhanced levels of nucleotide that support viral replication. RV: rhinovirus; PI3K: phosphatidylinositol 3-kinase; GLUT: glucose transporter; TCA: tricarboxylic acid cycle. b) Schematic overview representing metabolic targets of some DNA viruses. Various DNA viruses activate particular anabolic metabolic programs following infecting the host cells, to finally support viral replication and virion maturation. Dashed arrows show a virus induced activation of the respective metabolic pathway or a transcription factor activation. TCA: tricarboxylic acid cycle; α-KG: α-ketoglutarate; SREBP: sterol regulatory element-binding protein; ChREBP: carbohydrate-response element-binding protein; GLUT: glucose transporter; HCMV: human cytomegalovirus; HSV-1: herpes simplex virus-1; KSHV: Kaposi's sarcoma-associated herpesvirus; VACV: vaccinia virus.

Fig. 2

Effects of vitamin C on intracellular redox metabolism and glucose metabolism.

Fig. 3

TCA cycle intervention by metformin.

Fig. 4

Impaired function of alveolar epithelium and microvascular endothelium in ARDS. Microvascular blood vessels allow elevated infiltration of polymorphonuclear leukocytes (PMNs) and macrophages into the inflamed region followed by increased release of cytotoxic factors including proinflammatory cytokines and ROS. These released mediators contribute to the endothelial and epithelial dysfunction leading to fluids leakage from the circulation into the interstitial space and alveoli. Combined, these events result in pulmonary edema and impaired gas exchange.