Novel Therapeutic Target Critical for SARS-CoV-2 Infectivity and Induction of the Cytokine Release Syndrome.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101600052 Publication Model: Electronic Cited Medium: Internet ISSN: 2073-4409 (Electronic) Linking ISSN: 20734409 NLM ISO Abbreviation: Cells Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI

COVID-19*; Animals ; SARS-CoV-2/metabolism ; Peptidyl-Dipeptidase A/metabolism ; Angiotensin-Converting Enzyme 2 ; Cytokine Release Syndrome/drug therapy ; Receptors, Virus/metabolism ; Mammals/metabolism

We discovered a novel therapeutic target critical for SARS-CoV-2, cellular infectivity and the induction of the cytokine release syndrome. Here, we show that the mammalian enzyme neuraminidase-1 (Neu-1) is part of a highly conserved signaling platform that regulates the dimerization and activation of the ACE2 receptors and the Toll-like receptors (TLRs) implicated in the cytokine release syndrome (CRS). Activated Neu-1 cleaves glycosylated residues that provide a steric hindrance to both ACE2 and TLR dimerization, a process critical to both viral attachment to the receptor and entry into the cell and TLR activation. Blocking Neu-1 inhibited ACE2 receptor dimerization and internalization, TLR dimerization and activation, and the expression of several key inflammatory molecules implicated in the CRS and death from ARDS. Treatments that target Neu-1 are predicted to be highly effective against infection with SARS-CoV-2, given the central role played by this enzyme in viral cellular entry and the induction of the CRS.
Competing Interests: The authors declare no conflict of interest.

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Keywords: SARS-CoV-2; Toll-like receptors; angiotensin-converting enzyme 2; cytokine release syndrome; neuraminidase-1

EC 3.4.15.1 (Peptidyl-Dipeptidase A)
EC 3.4.17.23 (Angiotensin-Converting Enzyme 2)
0 (Receptors, Virus)

Date Created: 20230513 Date Completed: 20230515 Latest Revision: 20230515

20231215

PMC10177205

10.3390/cells12091332

37174732