DMBT1 promotes SARS-CoV-2 infection and its SRCR-derived peptide inhibits SARS-CoV-2 infection

DMBT1 is a large scavenger receptor cysteine rich (SRCR) B protein that has been reported as a tumor suppressor gene and a co-receptor for HIV-1 infection. Here, we found DMBT1 is a major mucosal protein bound to SARS-CoV-2. Overexpression of DMBT1 in 293T cells may enhanced infection by SARS-CoV-2 in ACE2 dependent manner. Blocking experiments using overlapping peptide library of SRCR domain of DMBT1 showed that peptide 7 (CQGRVEVLYRGSWGTV), which contains bacteria-binding VEVLXXXXW motif, could inhibit SARS-CoV-2 infection. High concentration of peptide 7 can significantly inhibit the replication of SARS-CoV-2 in hamsters. Peptide 7 inhibits SARS-CoV-2 infection by aggregating the spike protein, thereby reducing its binding to and internalization by host cells. The cysteine residue at the N-terminus of peptide 7 is critical for dimerization and antiviral activity. These results indicate that DMBT1 can serve as a candidate target for the development of antiviral drugs.