SARS-CoV-2 strategically mimics proteolytic activation of human ENaC

March 26,2021

May 26, 2020

Abstract: Molecular mimicry of host proteins is an evolutionary strategy adopted by viruses to evade immune surveillance and exploit host cell systems. We report that SARS-CoV-2 has evolved a unique S1/S2 cleavage site (RRARSVAS), absent in any previous coronavirus sequenced, that results in mimicry of an identical FURIN-cleavable peptide on the human epithelial sodium channel α-subunit (ENaC-α). Genetic truncation at this ENaC-α cleavage site causes aldosterone dysregulation in patients, highlighting the functional importance of the mimicked SARS-CoV-2 peptide. Single cell RNA-seq from 65 studies shows significant overlap between the expression of ENaC-α and ACE2, the putative receptor for the virus, in cell types linked to the cardiovascular-renal-pulmonary pathophysiology of COVID-19. Triangulating this cellular fingerprint with amino acid cleavage signatures of 178 human proteases shows the potential for tissue-specific proteolytic degeneracy wired into the SARS-CoV-2 lifecycle. We extrapolate that the evolution of SARS-CoV-2 into a global coronavirus pandemic may be in part due to its targeted mimicry of human ENaC and hijack of the associated host proteolytic network.

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Praveen Anand1Arjun Puranik2Murali Aravamudan2AJ Venkatakrishnan2Venky Soundararajan2
1nference Labs, Bengaluru, KA 560047, India 
2nference, Cambridge, MA 02142, USA
Correspondence: AJ Venkatakrishnan (
Correspondence: Venky Soundararajan (


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