RT Journal Article SR Electronic T1 SARS-CoV-2 Spike protein promotes hyper-inflammatory response that can be ameliorated by Spike-antagonistic peptide and FDA-approved ER stress and MAP kinase inhibitors in vitro JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.09.30.317818 DO 10.1101/2020.09.30.317818 A1 Alan C-Y. Hsu A1 Guoqiang Wang A1 Andrew T. Reid A1 Punnam Chander Veerati A1 Prabuddha S. Pathinayake A1 Katie Daly A1 Jemma R. Mayall A1 Philip M. Hansbro A1 Jay C. Horvat A1 Fang Wang A1 Peter A. Wark YR 2020 UL http://biorxiv.org/content/early/2020/10/01/2020.09.30.317818.abstract AB SARS-CoV-2 infection causes an inflammatory cytokine storm and acute lung injury. Currently there are no effective antiviral and/or anti-inflammatory therapies. Here we demonstrate that 2019 SARS-CoV-2 spike protein subunit 1 (CoV2-S1) induces high levels of NF-κB activations, production of pro-inflammatory cytokines and mild epithelial damage, in human bronchial epithelial cells. CoV2-S1-induced NF-κB activation requires S1 interaction with human ACE2 receptor and early activation of endoplasmic reticulum (ER) stress, and associated unfolded protein response (UPR), and MAP kinase signalling pathways. We developed an antagonistic peptide that inhibits S1-ACE2 interaction and CoV2-S1-induced productions of pro-inflammatory cytokines. The existing FDA-approved ER stress inhibitor, 4-phenylburic acid (4-PBA), and MAP kinase inhibitors, trametinib and ulixertinib, ameliorated CoV2-S1-induced inflammation and epithelial damage. These novel data highlight the potentials of peptide-based antivirals for novel ACE2-utilising CoVs, while repurposing existing drugs may be used as treatments to dampen elevated inflammation and lung injury mediated by SARS-CoV-2.Competing Interest StatementThe authors have declared no competing interest.