Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent
of coronavirus disease 2019 (COVID-19), uses the viral spike (S) protein for host
cell attachment and entry. The host protease furin cleaves the full-length precursor
S glycoprotein into two associated polypeptides: S1 and S2. Cleavage of S generates
a polybasic Arg-Arg-Ala-Arg carboxyl-terminal sequence on S1, which conforms to a
C-end rule (CendR) motif that binds to cell surface neuropilin-1 (NRP1) and NRP2 receptors.
We used x-ray crystallography and biochemical approaches to show that the S1 CendR
motif directly bound NRP1. Blocking this interaction by RNA interference or selective
inhibitors reduced SARS-CoV-2 entry and infectivity in cell culture. NRP1 thus serves
as a host factor for SARS-CoV-2 infection and may potentially provide a therapeutic
target for COVID-19.
