RESUMO
ObjectiveTo evaluate the efficacy and safety of 2-deoxy-D-glucose (2-DG) in the treatment of COVID-19. Participants110 adults aged 18 to 65 years with moderate to severe COVID-19. Interventions63, 90, and 126 mg/kg/day 2-DG plus standard of care (SOC) versus SOC only. Main Outcome MeasuresTimes to maintaining SpO2 [≥]94% on room air discharge, clinical recovery, vital signs normalisation, improvement by 1 and 2 points on WHO 10-point ordinal scale, negative conversion on RT-PCR, intensive care, and mortality. ResultsPatients treated with 90 mg/kg/day 2-DG plus SOC showed better outcomes. Time to maintaining SpO2 [≥]94% was significantly shorter in the 2-DG 90 mg compared to SOC (median 2.5 days vs 5 days, Hazard ratio [95% confidence interval]=2.3 [1.14, 4.64], p=0.0201). Times to discharge from isolation ward, to clinical recovery, and to vital signs normalisation were significantly shorter for the 2-DG 90 mg group. All three doses of 2-DG were well tolerated. Thirty-three (30.3%) patients reported 65 adverse events and were mostly (86%) mild. Conclusion2-DG 90 mg/kg/day as adjunct to SOC showed clinical benefits over SOC alone in the treatment of moderate to severe COVID-19. The promising trends observed in current phase-II study encourage confirmatory evaluation of the efficacy and safety of 2-DG in a larger phase-III trial.
RESUMO
The COVID-19 pandemic is an ongoing public health emergency of international concern. While a lot of efforts are being invested in vaccinating the population, there is also an emergent requirement to find potential therapeutics to effectively counter this fast mutating SARS-CoV-2 virus-induced pathogenicity. Virus-infected host cells switch their metabolism to a more glycolytic phenotype. This switch induced by the virus is needed for faster production of ATP and higher levels of anabolic intermediates, required for new virion synthesis and packaging. In this study, we used 2-Deoxy-D-glucose (2-DG) to target and inhibit the metabolic reprogramming induced by SARS-CoV-2 infection. Our results showed that virus infection induces glucose influx and glycolysis resulting in selective high accumulation of the fluorescent glucose/2-DG analogue, 2-NBDG in these cells. Subsequently, 2-DG inhibits glycolysis in infected cells thereby reducing the virus multiplication and alleviates the cells from virus induced cytopathic effect (CPE) and cell death. Herein, we demonstrate that the crucial Nglycosites (N331 and N343) of RBD in spike protein of progeny virions produced from 2-DG treated cells were found unglycosylated and defective with compromised infectivity potential. In line with earlier reported observations, our study also showed that 2-DG mediated metabolic inhibiton can attenuate SARS-COV-2 multiplication. In addition, mechanistic study revealed that the inhibition of SARS-COV-2 multiplication is attributed to 2-DG induced un-glycosylation of spike protein. Our findings strengthen the notion that 2-DG effectively inhibits SARS-CoV-2 multiplication. Therefore, based on its previous human trials in different types of Cancer and Herpes patients, it could be a potential molecule to study in COVID-19 patients.
