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

Overview

Journal Metabolites

Publisher MDPI

Date 2021 Oct 22

PMID 34677415

Citations 28

Authors

Denisa Bojkova

Rui Costa

Philipp Reus

Marco Bechtel

Mark-Christian Jaboreck

Ruth Olmer

Ulrich Martin

Sandra Ciesek

Martin Michaelis

Jindrich Cinatl Jr

Affiliations

Soon will be listed here.

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.

Citing Articles

STING exerts antiviral innate immune response by activating pentose phosphate pathway.

Wu D, Zhao Z, Yin W, Liu H, Xiang X, Zhu L Cell Commun Signal. 2024; 22(1):599.

PMID: 39695767 PMC: 11656958. DOI: 10.1186/s12964-024-01983-2.

Role of the receptor for advanced glycation end products in the severity of SARS-CoV-2 infection in diabetic patients.

Pedreanez A, Mosquera-Sulbaran J, Tene D Diabetol Int. 2024; 15(4):732-744.

PMID: 39469543 PMC: 11512988. DOI: 10.1007/s13340-024-00746-1.

Interactions of SARS-CoV-2 with Human Target Cells-A Metabolic View.

Eisenreich W, Leberfing J, Rudel T, Heesemann J, Goebel W Int J Mol Sci. 2024; 25(18).

PMID: 39337465 PMC: 11432161. DOI: 10.3390/ijms25189977.

Proteomic analysis of lung responses to SARS-CoV-2 infection in aged non-human primates: clinical and research relevance.

Garcia-Vilanova A, Allue-Guardia A, Chacon N, Akhter A, Singh D, Kaushal D Geroscience. 2024; 46(6):6395-6417.

PMID: 38969861 PMC: 11493886. DOI: 10.1007/s11357-024-01264-3.

The immune response to RNA suppresses nucleic acid synthesis by limiting ribose 5-phosphate.

Bhattacharjee P, Wang D, Anderson D, Buckler J, de Geus E, Yan F EMBO J. 2024; 43(13):2636-2660.

PMID: 38778156 PMC: 11217295. DOI: 10.1038/s44318-024-00100-w.

References

Tylicki A, Lotowski Z, Siemieniuk M, Ratkiewicz A . Thiamine and selected thiamine antivitamins - biological activity and methods of synthesis. Biosci Rep. 2017; 38(1). PMC: 6435462. DOI: 10.1042/BSR20171148. View

Blazquez A, Saiz J . Potential for Protein Kinase Pharmacological Regulation in Infections. Int J Mol Sci. 2020; 21(24). PMC: 7765220. DOI: 10.3390/ijms21249524. View

Zhu L, She Z, Cheng X, Qin J, Zhang X, Cai J . Association of Blood Glucose Control and Outcomes in Patients with COVID-19 and Pre-existing Type 2 Diabetes. Cell Metab. 2020; 31(6):1068-1077.e3. PMC: 7252168. DOI: 10.1016/j.cmet.2020.04.021. View

Riyapa D, Rinchai D, Muangsombut V, Wuttinontananchai C, Toufiq M, Chaussabel D . Transketolase and vitamin B1 influence on ROS-dependent neutrophil extracellular traps (NETs) formation. PLoS One. 2019; 14(8):e0221016. PMC: 6695114. DOI: 10.1371/journal.pone.0221016. View

Potaczek D, Unger S, Zhang N, Taka S, Michel S, Akdag N . Development and characterization of DNAzyme candidates demonstrating significant efficiency against human rhinoviruses. J Allergy Clin Immunol. 2018; 143(4):1403-1415. DOI: 10.1016/j.jaci.2018.07.026. View

Bojkova D, Bechtel M, McLaughlin K, McGreig J, Klann K, Bellinghausen C . Aprotinin Inhibits SARS-CoV-2 Replication. Cells. 2020; 9(11). PMC: 7692688. DOI: 10.3390/cells9112377. View

Ayres J . A metabolic handbook for the COVID-19 pandemic. Nat Metab. 2020; 2(7):572-585. PMC: 7325641. DOI: 10.1038/s42255-020-0237-2. View

Vignier N, Berot V, Bonnave N, Peugny S, Ballet M, Jacoud E . Breakthrough Infections of SARS-CoV-2 Gamma Variant in Fully Vaccinated Gold Miners, French Guiana, 2021. Emerg Infect Dis. 2021; 27(10):2673-2676. PMC: 8462339. DOI: 10.3201/eid2710.211427. View

Brown C, Vostok J, Johnson H, Burns M, Gharpure R, Sami S . Outbreak of SARS-CoV-2 Infections, Including COVID-19 Vaccine Breakthrough Infections, Associated with Large Public Gatherings - Barnstable County, Massachusetts, July 2021. MMWR Morb Mortal Wkly Rep. 2021; 70(31):1059-1062. PMC: 8367314. DOI: 10.15585/mmwr.mm7031e2. View

10.

Bandyopadhyay G, Huyck H, Misra R, Bhattacharya S, Wang Q, Mereness J . Dissociation, cellular isolation, and initial molecular characterization of neonatal and pediatric human lung tissues. Am J Physiol Lung Cell Mol Physiol. 2018; 315(4):L576-L583. PMC: 6230879. DOI: 10.1152/ajplung.00041.2018. View

11.

Peiro C, Romacho T, Azcutia V, Villalobos L, Fernandez E, Bolanos J . Inflammation, glucose, and vascular cell damage: the role of the pentose phosphate pathway. Cardiovasc Diabetol. 2016; 15:82. PMC: 4888494. DOI: 10.1186/s12933-016-0397-2. View

12.

Beale D, Shah R, Karpe A, Hillyer K, McAuley A, Au G . Metabolic Profiling from an Asymptomatic Ferret Model of SARS-CoV-2 Infection. Metabolites. 2021; 11(5). PMC: 8160988. DOI: 10.3390/metabo11050327. View

13.

Shen B, Yi X, Sun Y, Bi X, Du J, Zhang C . Proteomic and Metabolomic Characterization of COVID-19 Patient Sera. Cell. 2020; 182(1):59-72.e15. PMC: 7254001. DOI: 10.1016/j.cell.2020.05.032. View

14.

Chalasova K, Pacal L, Pleskacova A, Knopfova L, rehorova J, Tomandlova M . Transketolase Activity but not Thiamine Membrane Transport Change in Response to Hyperglycaemia and Kidney Dysfunction. Exp Clin Endocrinol Diabetes. 2017; 126(4):255-262. DOI: 10.1055/s-0043-115009. View

15.

Smadja D, Mentzer S, Fontenay M, Laffan M, Ackermann M, Helms J . COVID-19 is a systemic vascular hemopathy: insight for mechanistic and clinical aspects. Angiogenesis. 2021; 24(4):755-788. PMC: 8238037. DOI: 10.1007/s10456-021-09805-6. View

16.

Halder S, Mehta A . 2-Deoxy-D-glucose: is this the final cure for COVID-19: or yet another mirage?. Eur Rev Med Pharmacol Sci. 2021; 25(13):4448-4450. DOI: 10.26355/eurrev_202107_26234. View

17.

Lingappa J, Lingappa V, Reed J . Addressing Antiretroviral Drug Resistance with Host-Targeting Drugs-First Steps towards Developing a Host-Targeting HIV-1 Assembly Inhibitor. Viruses. 2021; 13(3). PMC: 8001593. DOI: 10.3390/v13030451. View

18.

Horby P, Lim W, Emberson J, Mafham M, Bell J, Linsell L . Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med. 2020; 384(8):693-704. PMC: 7383595. DOI: 10.1056/NEJMoa2021436. View

19.

Weisblum Y, Schmidt F, Zhang F, DaSilva J, Poston D, Lorenzi J . Escape from neutralizing antibodies by SARS-CoV-2 spike protein variants. Elife. 2020; 9. PMC: 7723407. DOI: 10.7554/eLife.61312. View

20.

Mahrooz A, Muscogiuri G, Buzzetti R, Maddaloni E . The complex combination of COVID-19 and diabetes: pleiotropic changes in glucose metabolism. Endocrine. 2021; 72(2):317-325. PMC: 8060688. DOI: 10.1007/s12020-021-02729-7. View