Glycolytic inhibitor 2-deoxy-d-glucose attenuates SARS-CoV-2 multiplication in host cells and weakens the infective potential of progeny virions

Bhatt, Anant Narayan; Kumar, Abhishek; Rai, Yogesh; Kumari, Neeraj; Vedagiri, Dhiviya; Harshan, Krishnan Harinivas; Chinnadurai, Vijayakumar; Chandna, Sudhir

doi:10.1016/j.lfs.2022.120411

Cited by 43 publications

(25 citation statements)

References 32 publications

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“…. Given its role as a hexokinase inhibitor, proven safety of usage in other diseases, and the prognostic improvement in SARS-CoV-2-infected cells in in vitro studies [ 126 ], 2-DG deserves further rigorous trials as a potential treatment for SARS-CoV-2-infected patients.…”

Section: Therapeutic Strategies Against Covid-19 Involving Mitochondriamentioning

confidence: 99%

Pathophysiological involvement of host mitochondria in SARS-CoV-2 infection that causes COVID-19: a comprehensive evidential insight

et al. 2022

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SARS-CoV-2 is a positive-strand RNA virus that infects humans through the nasopharyngeal and oral route causing COVID-19. Scientists left no stone unturned to explore a targetable key player in COVID-19 pathogenesis against which therapeutic interventions can be initiated. This article has attempted to review, coordinate and accumulate the most recent observations in support of the hypothesis predicting the altered state of mitochondria concerning mitochondrial redox homeostasis, inflammatory regulations, morphology, bioenergetics and antiviral signalling in SARS-CoV-2 infection. Mitochondria is extremely susceptible to physiological as well as pathological stimuli, including viral infections. Recent studies suggest that SARS-CoV-2 pathogeneses alter mitochondrial integrity, in turn mitochondria modulate cellular response against the infection. SARS-CoV-2 M protein inhibited mitochondrial antiviral signalling (MAVS) protein aggregation in turn hinders innate antiviral response. Viral open reading frames (ORFs) also play an instrumental role in altering mitochondrial regulation of immune response. Notably, ORF-9b and ORF-6 impair MAVS activation. In aged persons, the NLRP3 inflammasome is over-activated due to impaired mitochondrial function, increased mitochondrial reactive oxygen species (mtROS), and/or circulating free mitochondrial DNA, resulting in a hyper-response of classically activated macrophages. This article also tries to understand how mitochondrial fission–fusion dynamics is affected by the virus. This review comprehends the overall mitochondrial attribute in pathogenesis as well as prognosis in patients infected with COVID-19 taking into account pertinent in vitro, pre-clinical and clinical data encompassing subjects with a broad range of severity and morbidity. This endeavour may help in exploring novel non-canonical therapeutic strategies to COVID-19 disease and associated complications.

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Section: Therapeutic Strategies Against Covid-19 Involving Mitochondriamentioning

confidence: 99%

Pathophysiological involvement of host mitochondria in SARS-CoV-2 infection that causes COVID-19: a comprehensive evidential insight

et al. 2022

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“…The EC 50 values for cyanorona-20 for SARS-COV-2 replication in Vero E6 cells, was 0.48 µM, while for Favipiravir and Remdesivir, it is reported as > 100 µM and 23.88 µM respectively (Rabie 2021 ). For Molnupiravir, EC 50 values is against HCoV-NL63 replication with a value of 8.8 µM (Wang et al 2021 ) and 0.7 mM for 2 DG (Bhatt et al 2022 ). The active metabolite of Molnupiravir has a half-life of 1–1.75 h (Painter et al 2021 ), and 2DG has a half-life of 1.5 h (Dwarakanath and Jain 2009 ).…”

Section: Resultsmentioning

confidence: 99%

“…Favipiravir and Molnupiravir are viral protease inhibitors while 2DG affects infection-induced cytopathic effect through inhibition of cellular glycolysis (Sahu and Kumar 2021 ; Vangeel et al 2022 ). Bhatt et al ( 2022 ) in a recent finding, suggest that 2-DG can be used as a treatment regimen for COVID-19 since it effectively inhibits the SARS-CoV-2 multiplication and it weakens the potential of the progeny virus for further infection since glycolysis is a crucial step for replication of SARS-CoV-2 (Ajaz et al 2021 ; Shen and Wang 2021 ).…”

Section: Introductionmentioning

confidence: 99%

A novel property of hexokinase inhibition by Favipiravir and proposed advantages over Molnupiravir and 2 Deoxy d glucose in treating COVID-19

Kulkarni¹,

Padmanabhan²

2022

Biotechnol Lett

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Purpose In the wake of SARS-CoV-2’s global spread, human activities from health to social life to education have been affected. Favipiravir and Molnupiravir exhibited novel hexokinase inhibition and we discuss advantages of this property in their COVID-19 inhibition potential. Methods This paper describes molecular docking data of human hexokinase II with Favipiravir, Cyan 20, Remdesivir, 2DG, and Molnupiravir along with hexokinase inhibition assays. Results Favipiravir, an antiviral drug previously cleared for treating the flu and ebola, has shown some promise in early trials to treat COVID-19. We observed potent human hexokinase inhibiting potential of Favipiravir (50%) as against 4% and merely 0.3% hexokinase inhibition with Molnupiravir and 2 Deoxy d glucose at 0.1 mM concentration supported by molecular docking studies. Conclusion Favipiravir could continue to be part of the COVID-19 treatment regimen due to its resistance to host esterases, hexokinase inhibition potential and proven safety through human trials.

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“…Along with CoVs dependence on host glucose metabolism for replication [24], they are also dependent on the host cell machinery for glycosylation of viral proteins [50]. Thus, the reduction in CoV viral load could originate from 2-DG not only inhibiting glycolysis but also affecting protein and lipid glycosylation [51]. However, further studies are required to decipher a possible role of 2-DG in the production of defective virions in enveloped viruses.…”

Section: Discussionmentioning

confidence: 99%

Host-directed therapy with 2-Deoxy-D-glucose inhibits human rhinoviruses, endemic coronaviruses, and SARS-CoV-2

Wali¹,

Karbiener

Chou³

et al. 2022

Preprint

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Rhinoviruses (RVs) and coronaviruses (CoVs) upregulate host cell metabolic pathways including glycolysis to meet their bioenergetic demands for rapid multiplication. Using the glycolysis inhibitor 2-deoxy-D-glucose (2-DG), we confirm the dose-dependent inhibition of minor- and major-receptor group RV replication. We demonstrate that 2-DG suppresses viral positive- as well as negative-strand RNA synthesis, resulting in lower amounts of progeny virus and RV-mediated cell death. In tissue culture with physiologic glucose levels, 2-DG has a pronounced antiviral effect. Further, assessment of 2-DG's intracellular kinetics revealed that the active intermediate, 2-DG6P, is stored intracellularly for several hours. Our concurrent study of 2-DG's impact on pandemic SARS-CoV-2 and endemic HCoVs demonstrated a significant reduction in viral load. Collectively, these results suggest 2-DG to be a broad-spectrum antiviral.

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Glycolytic inhibitor 2-deoxy-d-glucose attenuates SARS-CoV-2 multiplication in host cells and weakens the infective potential of progeny virions

Cited by 43 publications

References 32 publications

Pathophysiological involvement of host mitochondria in SARS-CoV-2 infection that causes COVID-19: a comprehensive evidential insight

Pathophysiological involvement of host mitochondria in SARS-CoV-2 infection that causes COVID-19: a comprehensive evidential insight

A novel property of hexokinase inhibition by Favipiravir and proposed advantages over Molnupiravir and 2 Deoxy d glucose in treating COVID-19

Host-directed therapy with 2-Deoxy-D-glucose inhibits human rhinoviruses, endemic coronaviruses, and SARS-CoV-2

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