An insight into SARS-CoV-2 structure, pathogenesis, target hunting for drug development and vaccine initiatives

Abstract

SARS-CoV-2, the virus responsible for the COVID-19 pandemic, has been confirmed to be a new coronavirus having 79% and 50% similarity with SARS-CoV and MERS-CoV, respectively. For a better understanding of the features of the new virus SARS-CoV-2, we have discussed a possible correlation between some unique features of the genome of SARS-CoV-2 in relation to pathogenesis. We have also reviewed structural druggable viral and host targets for possible clinical application if any, as cases of reinfection and compromised protection have been noticed due to the emergence of new variants with increased infectivity even after vaccination. We have also discussed the types of vaccines that are being developed against SARS-CoV-2. In this review, we have tried to give a brief overview of the fundamental factors of COVID-19 research like basic virology, virus variants and the newly emerging techniques that can be applied to develop advanced treatment strategies for the management of COVID-19 disease.

Fig. 1. Taxonomical and epidemiological comparison of SARS-CoV-2, MERS CoV and SARS CoV.

Fig. 2. Structure of SARS-CoV-2 and organisation of the important genes in its genome.

Fig. 3. Mutations in the spike glycoprotein, Omicron variant B.1.1.529 (Source: Stanford University Coronavirus Database).

Fig. 4. Structural features and host cell entry mechanism of SARS-CoV-2. A. Interaction between the ACE II receptor and SARS-CoV-2 receptor binding domain. B. Schematic representation of the mechanism of SARS-CoV-2 cell entry.

Fig. 5. A. Interaction between 6D3 (in surface representation) and SEB (in ribbon representation), with the side-chains of the SAg motif in sticks, as obtained from the PDB (4RGN). B. The complex after mutating the SAg motif residues to map the NPH residues (373 to 382) into 4RGN.

Fig. 6. IL-17A-mediated activation of different immunopathological factors. A. Covid-19 infection leading to pleural effusion, alveolar oedema, and pulmonary fibrosis. B. Signalling transduction of IL-17A at alveolar epithelial cells of the lung. IL-17 induces inflammation by acting in synergy with IL-6, IL-1 and TNF and by expressing chemokines such as CXCL1, CXCL5, and MMPs as it is not a potent inducer of inflammatory response. Along with other chemokines and cytokines IL 17A generates a powerful inflammatory signal that results in a cytokine storm. C. Complications due to the cytokine storm in Covid 19 patients.

Fig. 7. Mechanism of coagulopathy disorder in Covid 19 patients and organ damage in Covid 19 patients.

Fig. 8. Viral and host targets and their inhibitors against SARS-CoV-2 entry in the host cell.

Fig. 9. Schematic representation of the probable cascade of drug development against Covid 19. Drug development with an in silico study like docking a repurposing library with billions of compounds can recognize several natural compounds that significantly bind with SARS-CoV-2 proteins and the top-ranked compounds can be tested in humans after successive in vitro and in vivo studies, which can finally lead to the discovery of useful new antiviral compounds against SARS-CoV-2.

Fig. 10. The origin and features of the spike protein receptor binding domain of SARS-CoV-2. A. Zoonotic evolution of SARS-CoV-2, SARS CoV and MERS CoV. B. Sequence alignment of the spike protein of SARS-CoV-2, bat and pangolin CoV. C. Structure and amino acid sequence of the furin recognition motif observed only in human SARS-CoV-2 spike protein.

Fig. 11. Mechanism of antigenic response of different vaccines under development against SARS-CoV-2. A. DNA vaccine. B. RNA vaccine. C. Attenuated vaccine. D. Inactivated vaccine. E. Viral vector vaccine. F. Viral protein and viral-like particle vaccine.