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

AIMS: Virus-infected host cells switch their metabolism to a more glycolytic phenotype, required for new virion synthesis and packaging. Therefore, we investigated the effect and mechanistic action of glycolytic inhibitor 2-Deoxy-d-glucose (2-DG) on virus multiplication in host cells following SARS-CoV-2 infection. MAIN METHODS: SARS-CoV-2 induced change in glycolysis was examined in Vero E6 cells. Effect of 2-DG on virus multiplication was evaluated by RT-PCR (N and RdRp genes) analysis, protein expression analysis of Nucleocapsid (N) and Spike (S) proteins and visual indication of cytopathy effect (CPE), The mass spectrometry analysis was performed to examine the 2-DG induced change in glycosylation status of receptor binding domain (RBD) in SARS-CoV-2 spike protein. KEY FINDINGS: We observed SARS-COV-2 infection induced increased glucose influx and glycolysis, resulting in selectively high accumulation of the fluorescent glucose analog, 2-NBDG in Vero E6 cells. 2-DG inhibited glycolysis, reduced virus multiplication and alleviated cells from virus-induced cytopathic effect (CPE) in SARS-CoV-2 infected cells. The progeny virions produced from 2-DG treated cells were found unglycosylated at crucial N-glycosites (N331 and N343) of the receptor-binding domain (RBD) in the spike protein, resulting in production of defective progeny virions with compromised infective potential. SIGNIFICANCE: The mechanistic study revealed that the inhibition of SARS-COV-2 multiplication is attributed to 2-DG induced glycolysis inhibition and possibly un-glycosylation of the spike protein, also. 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.

Neuromodulatory effects of SARS-CoV2 infection: Possible therapeutic targets.

INTRODUCTION: Although SARS-CoV-2 primarily manifests in the form of respiratory symptoms, emerging evidence suggests that the disease is associated with numerous neurological complications, such as stroke and Guillain-Barre syndrome. Hence, further research is necessary to seek possible therapeutic targets in the CNS for effective management of these complications. AREAS COVERED: This review examines the neurological complications associated with SARS-CoV-2 infections and the possible routes of infection. It progresses to illuminate the possible therapeutic targets for effective management of these neuromodulatory effects and the repurposing of drugs that could serve this purpose. To this end, literature from the year 1998-2021 was derived from PubMed. EXPERT OPINION: The neurological manifestations associated with COVID-19 may be related to poor prognosis and higher comorbidity. Identification of the key molecular targets in the brain that are potential indicators of the observed neuropathology, such as inflammatory mediators and chromatin modifiers, is key. The repurposing of existing drugs to target potential candidates could reduce the mortality attributed to these associated neurological complications.