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

Area of Science:

• Virology
• Metabolic pathways
• Immunology

Background:

• The COVID-19 pandemic necessitates effective pharmacological treatments.
• SARS-CoV-2 infection alters host cell metabolism, favoring glycolysis.
• The glycolysis inhibitor 2-deoxy-d-glucose (2DG) is being investigated for COVID-19 treatment.

Purpose of the Study:

• To investigate the role of the pentose phosphate pathway (PPP) in SARS-CoV-2 infection.
• To evaluate the efficacy of transketolase (TKT) inhibitors, such as benfooxythiamine (BOT), against SARS-CoV-2.
• To assess the combined effect of BOT and 2DG on SARS-CoV-2 replication.

Main Methods:

• Proteomic analysis of SARS-CoV-2-infected cells to identify metabolic changes.
• In vitro experiments using TKT inhibitor benfooxythiamine (BOT) and glycolysis inhibitor 2-deoxy-d-glucose (2DG).
• Assessment of viral replication and drug efficacy in cell culture models.

Main Results:

• Proteomics data revealed increased transketolase (TKT) levels in infected cells, implicating the non-oxidative PPP.
• Benfooxythiamine (BOT) demonstrated significant inhibition of SARS-CoV-2 replication.
• Combined treatment with BOT and 2DG enhanced the anti-SARS-CoV-2 activity of 2DG.

Conclusions:

• SARS-CoV-2 infection is associated with altered regulation of the pentose phosphate pathway (PPP).
• The TKT inhibitor BOT effectively inhibits SARS-CoV-2 replication and potentiates the antiviral activity of 2DG.
• Metabolic drugs like BOT and 2DG offer potential dual benefits: direct antiviral effects and immunomodulatory actions, improving COVID-19 therapy outcomes.