SARS-CoV-2: Pathogenesis, Molecular Targets and Experimental Models.

G Kanimozhi,N Rajendra Prasad,Haseeb A Khan,B Pradhapsingh,Charan Singh Pawar,Salman H Alrokayan

doi:10.3389/fphar.2021.638334

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recent pandemic outbreak threatening human beings worldwide. This novel coronavirus disease-19 (COVID-19) infection causes severe morbidity and mortality and rapidly spreading across the countries. Therefore, there is an urgent need for basic fundamental research to understand the pathogenesis and druggable molecular targets of SARS-CoV-2. Recent sequencing data of the viral genome and X-ray crystallographic data of the viral proteins illustrate potential molecular targets that need to be investigated for structure-based drug design. Further, the SARS-CoV-2 viral pathogen isolated from clinical samples needs to be cultivated and titrated. All of these scenarios demand suitable laboratory experimental models. The experimental models should mimic the viral life cycle as it happens in the human lung epithelial cells. Recently, researchers employing primary human lung epithelial cells, intestinal epithelial cells, experimental cell lines like Vero cells, CaCo-2 cells, HEK-293, H1299, Calu-3 for understanding viral titer values. The human iPSC-derived lung organoids, small intestinal organoids, and blood vessel organoids increase interest among researchers to understand SARS-CoV-2 biology and treatment outcome. The SARS-CoV-2 enters the human lung epithelial cells using viral Spike (S1) protein and human angiotensin-converting enzyme 2 (ACE-2) receptor. The laboratory mouse show poor ACE-2 expression and thereby inefficient SARS-CoV-2 infection. Therefore, there was an urgent need to develop transgenic hACE-2 mouse models to understand antiviral agents’ therapeutic outcomes. This review highlighted the viral pathogenesis, potential druggable molecular targets, and suitable experimental models for basic fundamental research.

Highlights

The coronavirus disease-19 (COVID-19) is a pandemic outbreak caused by a novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) (Rothan and Byrareddy, 2020)
A clinically proven protease inhibitor, camostat mesylate, inhibits Calu-3 infection caused by SARS-cov-2 The flow cytometric approach employed to assess spike-specific IgG and IgM antibody responses Mapped the expression pattern of N-glycosylation on hACE2 on human HEK 293 cells Full-length human ACE2 was expressed HEK 293 F cells, purified and used for the structural determination of ACE2 Human intestinal epithelial cells used for the production of SARS-CoV-2 virus particles
Used as a potential ex vivo infection model for novel treatment and prevention strategies Analyzed transcriptome analysis after SARS-CoV-2 infection Performed a high throughput and identified FDA-approved as inhibitors of SARScov-2 entry Conducted single-cell RNA-seq and immunostaining to show entry of viral particles through angiotensin-converting enzyme 2 (ACE-2); hPSC-COs organoids were employed as a high-throughput screening system for FDA-approved drugs Allow both COVID-19 infection and serves as an experimental model for nerotropism of COVID-19

Summary

Introduction

The coronavirus disease-19 (COVID-19) is a pandemic outbreak caused by a novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) (Rothan and Byrareddy, 2020). Identifying the novel molecular targets by understanding the viral-human protein interaction might lead to therapeutics against SARS-CoV-2 infection (Aziz et al, 2020).

Results

Conclusion