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

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.

Development and optimization of a high‐throughput screening assay for in vitro anti‐SARS‐CoV‐2 activity: Evaluation of 5676 Phase 1 Passed Structures

“…In drug discovery campaigns, assay design should incorporate mechanisms designed to reduce the risk of false positives, such as counter screens to validate the physiology of results. 41 This screen and many others 42 used the VeroE6 cell line. Although this line has proven valuable for rapid screening and clear CPE readouts, the occurrence of false positives shows that additional data in other models are invaluable in filtering out the most promising hits.…”

Experimental Models of COVID-19

“…High concentration of ACE-2 receptors was found to correlate with high rates of cell infection. Cell lines such as apical plasma membrane of polarized respiratory epithelial cells, colon carcinoma cell line (Caco-2) ( Pascoal et al., 2021 ), a lung carcinoma cell line (Calu-3) ( Kanimozhi et al., 2021 ) and Vero E6 cells ( Zupin et al., 2021 ) have been put forward as candidates for models in COVID19 research. Human cancer cell lines were screened for the SARS-CoV-2 cellular entry factors ACE2 and TMPRSS2 based on RNA-seq data of the Cancer Cell Line Encyclopedia (CCLE).…”

Radiation Recall Pneumonitis COVID-19 Infection Induced After Adjuvant Breast Cancer Radiotherapy. A Known Phenomenon in an Unknown Pandemic Disease: A Case Report

“…Another explanation could be the triggering effect of the SARS-CoV2 virus in tissues with elevated concentrations of ACE2 receptors, such as the lungs, and keratinocytes as described above, in light of the high affinity of Spike protein for host ACE receptors. 22 …”

“… 21 The ACE receptor spread in these tissues could also be involved due to their high affinity to Spike protein. 22 However, the true mechanism remains unknown. Herein, we present a case of radiation recall pneumonitis (RRP) triggered by COVID-19 in a woman who had undergone adjuvant radiotherapy for breast cancer.…”