Neuropilins Facilitate SARS-CoV-2 Entry into Host Cells

As cases of COVID-19 surge, researchers are learning more about the biology of SARS-CoV-2 and why it is so infectious. A central focus is to understand why the virus is significantly more transmissible than its older cousin SARS-CoV. Though both viruses use ACE2 as a receptor for their respective spike proteins, SARS-CoV-2 spike is distinguished by the addition of a polybasic furin-type cleavage site (RRAR) located at the junction of the S1 and S2 subunits that has long been suspected of increasing viral spread. In two studies published together in Science, this suspicion has been confirmed through elegant work revealing the mechanism driving the enhanced infectivity of SARS-CoV-2 (1, 2). Both groups noted the “RRAR” motif in the SARS-CoV-2 spike sequence and realized that furin cleavage generates a “C-end rule” (CendR) sequence at the C-terminus of S1. CendR peptides bind the transmembrane receptors Neuropilin-1 (NRP1) and NRP2. Using various experimental approaches, the two studies establish that neuropilins facilitate SARS-CoV-2 entry into host cells, and demonstrate that inhibition of NRP1 and CendR association decreases infection. While ACE2 and the serine protease TMPRSS2 are the key cellular factors for SARS-CoV-2 binding and uptake into cells, neuropilins greatly enhance the infectivity of SARS-CoV-2. Given that neuropilins are found on epithelia that interface with the external environment, and that NRP1 and NRP2 are upregulated in lung tissue from COVID-19 patients, the development of therapies specifically targeting the S1-neuropilin interaction appears to be worthy of further examination.

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References:

1. Science. 2020 Oct 20;eabd2985.
2. Science. 2020 Oct 20;eabd3072.