GRP78 Inhibitor YUM70 Suppresses SARS-CoV-2 Viral Entry, Spike Protein Production and Ameliorates Lung Damage

by Selleckchem | Nov 04 2023

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the COVID-19 pandemic, has given rise to many new variants with increased transmissibility and the ability to evade vaccine protection. The 78-kDa glucose-regulated protein (GRP78) is a major endoplasmic reticulum (ER) chaperone that has been recently implicated as an essential host factor for SARS-CoV-2 entry and infection. In this study, we investigated the efficacy of YUM70, a small molecule inhibitor of GRP78, to block SARS-CoV-2 viral entry and infection in vitro and in vivo. Using human lung epithelial cells and pseudoviral particles carrying spike proteins from different SARS-CoV-2 variants, we found that YUM70 was equally effective at blocking viral entry mediated by original and variant spike proteins. Furthermore, YUM70 reduced SARS-CoV-2 infection without impacting cell viability in vitro and suppressed viral protein production following SARS-CoV-2 infection. Additionally, YUM70 rescued the cell viability of multi-cellular human lung and liver 3D organoids transfected with a SARS-CoV-2 replicon. Importantly, YUM70 treatment ameliorated lung damage in transgenic mice infected with SARS-CoV-2, which correlated with reduced weight loss and longer survival. Thus, GRP78 inhibition may be a promising approach to augment existing therapies to block SARS-CoV-2, its variants, and other viruses that utilize GRP78 for entry and infection.

Comments:

The study you described investigated the effectiveness of a small molecule inhibitor called YUM70, which targets a protein called 78-kDa glucose-regulated protein (GRP78), in blocking the entry and infection of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro and in vivo. GRP78 is a major chaperone protein found in the endoplasmic reticulum (ER) and has been identified as an important host factor for SARS-CoV-2.

The researchers conducted their experiments using human lung epithelial cells and pseudoviral particles carrying spike proteins from different variants of SARS-CoV-2. They found that YUM70 was equally effective in blocking viral entry mediated by both the original spike protein and the spike proteins from variant strains of SARS-CoV-2. The inhibitor reduced SARS-CoV-2 infection without negatively affecting the viability of the cells in vitro. YUM70 also suppressed viral protein production following SARS-CoV-2 infection.

Moreover, the study investigated the impact of YUM70 on 3D organoids derived from human lung and liver tissues. When these organoids were transfected with a SARS-CoV-2 replicon, YUM70 treatment improved their cell viability, suggesting a potential protective effect against viral infection.

Furthermore, the researchers tested the efficacy of YUM70 in transgenic mice infected with SARS-CoV-2. Treatment with YUM70 reduced lung damage, as evidenced by improved lung histology. This correlated with reduced weight loss and increased survival in the mice.

Based on these findings, the study suggests that inhibiting GRP78, using YUM70 or similar small molecule inhibitors, could be a promising approach to enhance existing therapies and prevent SARS-CoV-2 infection, including infections caused by variant strains. Furthermore, targeting GRP78 may have implications for combating other viruses that rely on GRP78 for entry and infection. However, it's important to note that further research and clinical trials are needed to validate these findings and determine the potential of GRP78 inhibition as a therapeutic strategy against COVID-19 and other viral infections.