Abstract
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.
Highlights
Cleavage of S generates a polybasic Arg-Arg-Ala-Arg C-terminal sequence on S1, which conforms to a C-end rule (CendR) motif that binds to cell surface Neuropilin-1 (NRP1) and Neuropilin2 (NRP2) receptors
We used X-ray crystallography and biochemical approaches to show that the S1 CendR motif directly bound NRP1
NRP1 serves as a host factor for SARS-CoV-2 infection and may potentially provide a therapeutic target for COVID-19
Summary
Cleavage of S generates a polybasic Arg-Arg-Ala-Arg C-terminal sequence on S1, which conforms to a C-end rule (CendR) motif that binds to cell surface Neuropilin-1 (NRP1) and Neuropilin2 (NRP2) receptors. Blocking this interaction using RNAi or selective inhibitors reduced SARS-CoV-2 entry and infectivity in cell culture. Furin-mediated processing increases infectivity and affects the tropism of SARS-CoV-2, while furin inhibition diminishes SARS-CoV-2 entry, and deletion of the polybasic site in the S protein reduces syncytia formation in cell culture [3,4,5, 7].
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