ACE-2: The Receptor for SARS-CoV-2

CoVs are a large family of enveloped, positive-sense, single-stranded RNA viruses that infect a broad range of vertebrates. They are extensive in bats but can be found in many other birds and mammals including humans. CoVs can cause a variety of diseases such as enteritis in pigs and cows and upper respiratory disease in chickens.¹ In humans, CoVs tend to cause mild to moderate upper respiratory tract infections such as the common cold.^2,3 However, in the past couple of decades, there have been outbreaks of severe, and sometimes fatal, respiratory illnesses that were later found to be caused by novel, human pathogenic CoVs. These CoV strains, which were determined to be phylogenetically distinct from the common human CoVs, had originated in bats and were transmitted to humans, typically through an intermediate host.^1,4,5 These strains exhibited stronger virulence and quickly passed from human to human. While infection with these CoVs typically produced mild symptoms, for certain individuals, responses were more severe. In extreme cases, death occurred due to gradual respiratory failure as the result of alveolar damage.^3,4,6

Identification and sequencing of the virus responsible for COVID-19 (view SARS-CoV-2 protein sequence) determined that it was a novel CoV that shared 88% sequence identity with two bat-derived SARS-like CoV, suggesting it had originated in bats.¹⁰ Additionally, it was shown that this CoV, which was termed 2019-nCoV or SARS-CoV-2, shared 79.5% sequence identity with SARS-CoV.^5,10 The coronaviral genome encodes four major structural proteins: the spike (S) protein, nucleocapsid (N) protein, membrane (M) protein, and the envelope (E) protein.⁶ The spike protein is responsible for facilitating entry of the CoV into the target cell. It is composed of a short intracellular tail, a transmembrane anchor, and a large ectodomain that consists of a receptor binding spike S1 subunit and a membrane-fusing spike S2 subunit.¹¹ Sequence analysis of the SARS-CoV-2 spike protein genome showed that it was only 75% identical with the SARS-CoV spike protein.^5,10 However, analysis of the receptor binding motif (RBM) in the spike protein showed that most of the amino acid residues essential for receptor binding were conserved between SARS-CoV and SARS-CoV-2, suggesting that the 2 CoV strains use the same host receptor for cell entry.¹² The entry receptor utilized by SARS-CoV is Angiotensin-Converting Enzyme 2 (ACE-2).¹³

Based on the sequence similarities of the RBM between SARS-CoV-2 and SARS-CoV, several independent research groups investigated if SARS-CoV-2 also utilizes ACE-2 as a cellular entry receptor. Zhou et al. showed that SARS-CoV-2 could use ACE-2 from humans, Chinese horseshoe bats, civet cats, and pigs to gain entry into ACE-2-expressing HeLa cells.⁵ Hoffmann et al. reported similar findings for human and bat ACE-2.²¹ Additionally, Hoffmann et al. showed that treating Vero-E6 cells, a monkey kidney cell line known to permit SARS-CoV replication, with an Anti-ACE-2 Antibody (R&D Systems, Catalog # AF933) blocked entry of VSV pseudotypes expressing the SARS-CoV-2 spike protein.²¹

These new findings could greatly impact the development of effective therapies for COVID-19. For instance, anti-ACE-2 antibodies could be used to block SARS-CoV-2 binding to the receptor. Additionally, TMPRSS2 inhibitors could be used to prevent SARS-CoV-2 entry into host cells. Camostat has been used to treat chronic pancreatitis in Japan and is currently undergoing Phase 1/2 trial testing in the United States.²⁶ If deemed safe, camostat could be a potential treatment option of CoV infections.²⁷ It is also possible that antibodies developed during SARS-CoV infection could help prevent or treat COVID-19. Hoffmann et al. showed that sera from recovering SARS patients reduced SARS-CoV-2 spike protein-driven entry into Vero-E6 cells.²¹ However, future studies are needed to determine whether any of these options are effective in disrupting the interaction between virus and receptor in vivo.