Targeting the Pentose Phosphate Pathway for SARS-CoV-2 Therapy
Denisa Bojkova,
Rui Costa,
Philipp Reus,
Marco Bechtel,
Mark-Christian Jaboreck,
Ruth Olmer,
Ulrich Martin,
Sandra Ciesek,
Martin Michaelis,
Jindrich Cinatl
Affiliations
Denisa Bojkova
Institute for Medical Virology, University Hospital, Goethe University, 60596 Frankfurt am Main, Germany
Rui Costa
Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Hvidovre Hospital and Department of Immunology and Microbiology, University of Copenhagen, 1455 Copenhagen, Denmark
Philipp Reus
Institute for Medical Virology, University Hospital, Goethe University, 60596 Frankfurt am Main, Germany
Marco Bechtel
Institute for Medical Virology, University Hospital, Goethe University, 60596 Frankfurt am Main, Germany
Mark-Christian Jaboreck
Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
Ruth Olmer
Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
Ulrich Martin
Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
Sandra Ciesek
Institute for Medical Virology, University Hospital, Goethe University, 60596 Frankfurt am Main, Germany
Martin Michaelis
School of Biosciences, University of Kent, Canterbury CT2 7NJ, UK
Jindrich Cinatl
Institute for Medical Virology, University Hospital, Goethe University, 60596 Frankfurt am Main, Germany
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.
