The chaperone GRP78 is a host auxiliary factor for SARS-CoV-2 and GRP78 depleting antibody blocks viral entry and infection

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19 global pandemic, utilizes host receptor angiotensin-converting enzyme (ACE2) for viral entry. However, other factors might also play important roles in SARS-CoV-2 infection, providing new directions antiviral treatments. GRP78 is a stress-inducible chaperone entry and infectivity many viruses. Recent molecular docking analyses revealed putative interaction between receptor-binding domain (RBD) Spike protein (SARS-2-S). Here we report that can form complex with SARS-2-S ACE2 on surface at perinuclear region typical endoplasmic reticulum VeroE6-ACE2 cells substrate-binding critical this interaction. In vitro binding studies further confirmed directly bind to RBD ACE2. To investigate role complex, knocked down cells. Loss markedly reduced cell expression led activation markers unfolded response. Treatment lung epithelial humanized monoclonal antibody (hMAb159) selected its safe clinical profile preclinical models depleted expression, as well SARS-2-S-driven infection in vitro. Our data suggest an auxiliary factor potential target combat novel pathogen viruses utilize combination therapy.