Targeting neuropilins as a viable SARS-CoV-2 treatment

Abstract

The SARS-CoV-2 pandemic has significantly impacted global health. Research on viral mechanisms, highly effective vaccines, and other therapies is in progress. Neuropilins have recently been identified as host cell receptors enabling viral fusion. Here, we provide context to neuropilin's tissue-specific role in infection and the potential impact of NRP-based therapeutics. We conclude that the central roles of neuropilins in vascular, neural, and other pathways may render it a less suitable target for treating SARS-CoV-2 than agents that target its binding partner, the viral spike protein.

Keywords: SARS-CoV-2; antibodies; neuropilin; side effects; treatment.

Fig. 1

Female organ and tissue‐specific protein (in red) and mRNA (in blue) expression patterns for human angiotensin‐converting enzyme 2 (ACE2), neuropilin1 (NRP1), neuropilin2 (NRP2), transmembrane protease serine 2 (TMPRSS2), heparan sulfate proteoglycan 2 (HSPG2) and syndecan 2 (SDC2), transmembrane protein 106B (TMEM106B), ADAM metallopeptidase domain 17 (ADAM17), HDL‐scavenger receptor B type 1 (SCARB1), angiotensin II receptor type 1 (AT1R), vasopressin V1b receptor (AVPR1B), and basigin (CD147). Genes/proteins are ordered by the number of organs or tissues expressing the mRNA. NRP1 and NRP2 are expressed in a large number of organs in both protein and mRNA forms. Tissues not shown lack detectable mRNA or protein expression. The anatograms were created in r using gganatogram [32]. RNA expression summary shows the consensus RNA‐data based on normalized expression (NX) data from three different sources: internally generated Human Protein Atlas (HPA) RNA‐seq data, RNA‐seq data from the Genotype‐Tissue Expression (GTEx) project, and CAGE data from FANTOM5 project. Protein expression scores are based on a best estimate of the ‘true’ protein expression from a knowledge‐based annotation. Data source: https://www.proteinatlas.org/ [33]. The expression levels of a number of these genes may be further elevated in COVID‐19 patients [20] and in individuals with other morbidities [21, 34].

Fig. 2

Male organ and tissue‐specific protein (in red) and mRNA (in blue) expression patterns for human angiotensin‐converting enzyme 2 (ACE2), neuropilin1 (NRP1), neuropilin2 (NRP2), transmembrane protease serine 2 (TMPRSS2), heparan sulfate proteoglycan 2 (HSPG2) and syndecan 2 (SDC2), transmembrane protein 106B (TMEM106B), ADAM metallopeptidase domain 17 (ADAM17), HDL‐scavenger receptor B type 1 (SCARB1), angiotensin II receptor type 1 (AT1R), vasopressin V1b receptor (AVPR1B), and basigin (CD147). NRP1 and NRP2 are expressed in a large number of organs in both protein and mRNA forms. Tissues not shown lack detectable mRNA or protein expression. See Fig. 1 caption for more details.

Fig. 3

Multiple host‐expressed receptors interact with the SARS‐CoV‐2 S1 protein. Therapeutics targeting these interactions could include anti‐S1 or anti‐receptor antibodies, and soluble proteins, and may prevent or diminish early infection. However, we must also consider the potential other effects of targeting endogenously expressed receptors, whether ubiquitous or tissue‐specific. Figure was created in BioRender.