Computational profiling of natural compounds as promising inhibitors against the spike proteins of SARS-CoV-2 wild-type and the variants of concern, viral cell-entry process, and cytokine storm in COVID-19.

The continuous spread and evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the rapid surge in infection cases in the coronavirus disease 2019 (COVID-19) evoke a dire need for effective therapeutics. In this study, we explored the inhibitory potential of a library of 605 phytocompounds, selected from Indian medicinal plants with reported antiviral and anti-inflammatory activities, against the receptor-binding domain of spike proteins of the SARS-CoV-2 wild-type and the variants of concern, including variants B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), B.1.617.2 (Delta), and B.1.1.529 (Omicron). Our approach was based on extensive molecular docking, assessment of drug-likeness, and robust molecular dynamics simulations. We also identified promising inhibitory candidates against the host (human) proteins associated with SARS-CoV-2 spike activation and attachment, namely, ACE2 receptor, proteases TMPRSS2 and CTSL, and the endocytic regulator AAK1. In addition, we screened promising inhibitory compounds against the human proinflammatory cytokines- IL-6, IL-1ß, TNF-α, and IFN-γ, that are associated with the adverse cytokine storm in COVID-19 patients. Our analysis returned an encouraging list of promising inhibitory candidates that includes: abietatriene against the spike proteins of the SARS-CoV-2 wild-type and the variants of concern; taraxerol against the human ACE2, CTSL and TNF-α; ß-amyrin against the human TMPRSS2; cynaroside against the human AAK1 and IL-1ß; and friedelin against the human IL-6 and IFN-γ. Our findings provide substantial evidence for the inhibitory potential of these compounds and encourage further in vitro and in vivo studies to validate their use as safe and effective therapeutics against COVID-19.

Genome-scale metabolic modelling of SARS-CoV-2 in cancer cells reveals an increased shift to glycolytic energy production.

Cancer is considered a high-risk condition for severe illness resulting from COVID-19. The interaction between severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and human metabolism is key to elucidating the risk posed by COVID-19 for cancer patients and identifying effective treatments, yet it is largely uncharacterised on a mechanistic level. We present a genome-scale map of short-term metabolic alterations triggered by SARS-CoV-2 infection of cancer cells. Through transcriptomic- and proteomic-informed genome-scale metabolic modelling, we characterise the role of RNA and fatty acid biosynthesis in conjunction with a rewiring in energy production pathways and enhanced cytokine secretion. These findings link together complementary aspects of viral invasion of cancer cells, while providing mechanistic insights that can inform the development of treatment strategies.