Research Spotlight | Science: New infection co-factor of SARS-CoV-2: NRP1


Background of Researching

Despite these differences, uptake of both viruses is mediated by the identical cellular receptor, angiotensin-converting enzyme 2 (ACE2) (1-3). One attractive hypothesis to explain the enhanced spreading of SARS-CoV-2 is the presence of a polybasic furin-type cleavage site, RRAR^S, at the S1/S2 junction in the SARS-CoV-2 spike (S) protein that is absent in SARS-CoV (4). Similar sequences are found in the S proteins of many other pathogenic human viruses, including Ebola, HIV-1 and highly virulent strains of avian influenza (4, 5). The presence of the polybasic cleavage site in SARS-CoV-2 results in enhanced pathogenicity by priming the fusion activity (6) and could potentially create additional cell surface receptor binding sites. Proteolytic cleavage of RRAR^S by furin exposes a conserved carboxyterminal (C-terminal) motif RXXROH in the S protein. Such C-terminal sequences that conform to the “C-end rule” (CendR) are known to bind to and activate neuropilin (NRP1 and NRP2) receptors at the cell surface (7). Recent cryo-electron microscopy structures of the SARS-CoV-2 S protein demonstrated that the S1/S2 junction is part of a solvent-exposed loop and therefore accessible for receptor interactions (8, 9).

Research Findings

NRP1 facilitates the cellular entry of SARS-CoV-2 pseudotyped particles

  • 1. NRP1 co-expression with ACE2 and TMPRSS2 markedly enhanced infection.
  • 2. NRP1 can potentiate infection in the presence of other host factors, such as endogenously express ACE2.
  • 3. Antibodies functionally block the extracellular b1b2 domain of NRP1, mediated the binding to CendR peptides and make wild-type significantly reduce infection.

Blocking antibody against the b1b2 domain of NRP1 can't reduce infection by a mutant with deletion at the furin-cleavage site

  • 1. Exogenous NRP1 expression caused HEK-293T cells lower levels of infection, which were only detectable with increasing virus titer.
  • 2. NRP1 requires a furin-cleaved substrate for its effects.
  • 3. NRP1-blocking antibody had no effect on the infection by the mutated virus.

NRP1 mediates entry of nanoparticles coated with SARS-CoV-2 S derived CendR peptides into cultured cells, olfactory epithelium and CNS (Central Nervous System) of mice

  • 1. Cleavage of SARS-CoV-2 S protein at the S1/S2 site generates the specific C-terminal end.
  • 2. AgNP-TQTNSPRRAROH are efficiently taken up by HEK-293T cells expressing NRP1.
  • 3. AgNP-TQTNSPRRAROH particles are also internalized into cells in vivo.

SARS-CoV-2 infects the olfactory epithelium

The infected olfactory epithelial cells showed high expression of NRP1.


The reason why a number of viruses use NRP1 as entry factors could be because of their high expression on epithelia facing the external environment, and their function in enabling cell, vascular, and tissue penetration.

NRP1 antibody functionally block the extracellular b1b2 domain of NRP1, which mediated the binding to CendR peptides.

NRP1 raises the possibility that co-factors are required to facilitate virus-host cell interactions in cells with low ACE2 expression.

Elabscience® NRP1 related products accelerate your research

As a new infection co-factor of SARS-CoV-2,Not only ACE2, but NRP1 can also mediate SARS-CoV-2 infection in vivo.

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Recombinant Human ACE2 Protein (Fc Tag)

Recombinant Human ACE2 Protein (His Tag)


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  • 3. 3.N. J. Matheson, P. J. Lehner, How does SARS-CoV-2 cause COVID-19? Science. 2020; 369, 510–511.
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  • 5. L. V. Tse, A. M. Hamilton, T. Friling, G. R. Whittaker, A novel activation mechanism of avian influenza virus H9N2 by furin. J. Virol. 2014; 88, 1673–1683.
  • 6. 6.M. Hoffmann, H. Kleine-Weber, S. Pöhlmann, A Multibasic Cleavage site in the spike protein of SARS-CoV-2 is essential for infection of human lung cells. Mol. Cell. 2020; 78, 779–784.e5.
  • 7. T. Teesalu, K. N. Sugahara, V. R. Kotamraju, E. Ruoslahti, C-end rule peptides mediate neuropilin-1-dependent cell, vascular, and tissue penetration. Proc. Natl. Acad. Sci. U.S.A. 2009; 106, 16157–16162.
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