Targeting the Pentose Phosphate Pathway for SARS-CoV-2 Therapy

Abstract

SARS-CoV-2 is causing the coronavirus disease 2019 (COVID-19) pandemic, for which effective pharmacological therapies are needed. SARS-CoV-2 induces a shift of the host cell metabolism towards glycolysis, and the glycolysis inhibitor 2-deoxy-d-glucose (2DG), which interferes with SARS-CoV-2 infection, is under development for the treatment of COVID-19 patients. The glycolytic pathway generates intermediates that supply the non-oxidative branch of the pentose phosphate pathway (PPP). In this study, the analysis of proteomics data indicated increased transketolase (TKT) levels in SARS-CoV-2-infected cells, suggesting that a role is played by the non-oxidative PPP. In agreement, the TKT inhibitor benfooxythiamine (BOT) inhibited SARS-CoV-2 replication and increased the anti-SARS-CoV-2 activity of 2DG. In conclusion, SARS-CoV-2 infection is associated with changes in the regulation of the PPP. The TKT inhibitor BOT inhibited SARS-CoV-2 replication and increased the activity of the glycolysis inhibitor 2DG. Notably, metabolic drugs like BOT and 2DG may also interfere with COVID-19-associated immunopathology by modifying the metabolism of immune cells in addition to inhibiting SARS-CoV-2 replication. Hence, they may improve COVID-19 therapy outcomes by exerting antiviral and immunomodulatory effects.

Platelet Phenotype Analysis of COVID-19 Patients Reveals Progressive Changes in the Activation of Integrin αIIbβ3, F13A1, the SARS-CoV-2 Target EIF4A1 and Annexin A5

“…Likewise, the increased amount of the enzyme TALDO1 can be linked to increased activity of the pentose phosphate pathway, which supplies the virus with ribonucleotides, essential building blocks for its replication. In addition, an unbiased proteome analysis has previously demonstrated that the infection of Caco-2 cells with SARS-CoV-2 increases the expression of TALDO 1 ( 74 ).…”

Implication of COVID-19 on Erythrocytes Functionality: Red Blood Cell Biochemical Implications and Morpho-Functional Aspects

“…The metabolic shift towards ATP production in the glycolytic pathway clearly, also influences other metabolic pathways, such as the pentose phosphate pathway (PPP). In these conditions, the non-oxidative phase of PPP is increased, in which glycolysis intermediates are converted into the ribose-5-phosphate required for the synthesis of the nucleic acids, which is necessary for the virus replication [25,26]. In addition, high levels of oxidized glutathione and a significant decrease in enzymes forming part of the cellular defense line against oxidative stress were found, including superoxide dismutase 1 (SOD1), glucose-6-phosphate dehydrogenase, and peroxiredoxin [27][28][29].…”

Dissecting the Role of the Human Microbiome in COVID-19 via Metagenome-assembled Genomes

“…Importantly, a previous study reported a significant increase in the levels of some intermediates of the glycolytic and pentose phosphate pathways in sera of COVID-19 positive patients 50 . Moreover, SARS-CoV-2 infection was found to be associated with changes in the regulation of the pentose phosphate pathway in both in vivo (Caco-2 cells) 51 and in vitro (ferret model) 52 studies. These findings provide evidence of potential metabolic pathways linking the gut microbes to the clinical manifestations of COVID-19.…”