Many phylogenetically distant animal viruses, including the new coronavirus SARS-CoV-2, have surface proteins with polybasic sites that are cleaved by host furin and furin-like proteases. Other than priming certain viral surface proteins for fusion, cleavage generates a carboxy-terminal RXXR sequence. This C-end Rule (CendR) motif is known to bind to neuropilin (NRP) receptors on the cell surface. NRPs are ubiquitously expressed, pleiotropic cell surface receptors with important roles in growth factor signaling, vascular biology, and neurobiology, as well as immune homeostasis and activation.
The CendR–NRP receptor interaction promotes endocytic internalization and tissue spreading of different cargo, including viral particles. We hypothesize that the interaction between viral surface proteins and NRPs plays an underappreciated and prevalent role in the transmission and pathogenesis of diverse viruses. It could, therefore, represent a promising broad-spectrum antiviral target that we are currently testing in epithelial cells, blood and lymphatic vessels, and in neurons.