Immune dysregulation in COVID-19 and its therapeutic implications

Many countries in the world are affected by severe acute respiratory syndrome (SARS) coronavirus-2 (SARS-CoV-2) disease-2019 (COVID-19) pandemic. Approximately 80% of the cases are mild symptomatic, 15% are severe and approximately 5% are critically ill. The mortality among severe and critically ill patients ranges from 17% to 78%. Elderly and patients with comorbidities have higher chances of progression to severe disease and subsequent mortality. There are no proven antiviral agents available for the management of COVID-19. Besides the viral cytopathic effects, dysregulation in immunity also contributes substantially to the pathogenesis. Treatment with immunomodulatory agents such as interleukin-6 blockers, glucocorticoids and mesenchymal stem cell therapy has been observed to be potentially beneficial. In this review, the immune response in SARS-CoV-2, the mechanism of immune dysregulation as well as potential therapeutic targets for immunomodulatory therapies are discussed.

Identification of novel TMPRSS2 inhibitors against SARS-CoV-2 infection: a structure-based virtual screening and molecular dynamics study.

The scientific insights gained from the severe acute respiratory syndrome (SARS) and the middle east respiratory syndrome (MERS) outbreaks are helping scientists to fast-track the antiviral drug discovery process against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Coronaviruses, as well as influenza viruses, depend on host type 2 transmembrane serine protease, TMPRSS2, for entry and propagation in the human cell. Recent studies show that SARS-CoV-2 also uses TMPRSS2 for its cell entry. In the present study, a structure-based virtual screening of 52,337, protease ligands downloaded from the Zinc database was carried out against the homology model of TMPRSS2 protein followed by the molecular dynamics-based simulation to identify potential TMPRSS2 hits. The virtual screening has identified 13 hits with a docking score range of -10.447 to -9.863 and glide energy range of -60.737 to -40.479 kcal/mol. The binding mode analysis shows that the hit molecules form H-bond (Asp180, Gly184 & Gly209), Pi-Pi stacking (His41), and salt bridge (Asp180) type of contacts with the active site residues of TMPRSS2. In the MD simulation of ZINC000013444414, ZINC000137976768, and ZINC000143375720 hits show that these molecules form a stable complex with TMPRSS2. The complex equilibrates well with a minimal RMSD and RMSF fluctuation. All three structures, as predicted in Glide XP docking, show a prominent interaction with the Asp180, Gly184, Gly209, and His41. Further, MD simulation also identifies a notable H-bond interaction with Ser181 for all three hits. Among these hits, ZINC000143375720 shows the most stable binding interaction with TMPRSS2. The present study is successful in identifying TMPRSS2 ligands from zinc data base for a possible application in the treatment of COVID-19.