Interaction of SARS-CoV-2 and Other Coronavirus With ACE (Angiotensin-Converting Enzyme)-2 as Their Main Receptor: Therapeutic Implications

Abstract

Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 originated from Wuhan, China, in December 2019 and rapidly spread to other areas worldwide. Since then, coronavirus disease 2019 (COVID-19) has reached pandemic proportions with >570 000 deaths globally by mid-July 2020. The magnitude of the outbreak and the potentially severe clinical course of COVID-19 has led to a burst of scientific research on this novel coronavirus and its host receptor ACE (angiotensin-converting enzyme)-2. ACE2 is a homolog of the ACE that acts on several substrates in the renin-Ang (angiotensin) system. With unprecedented speed, scientific research has solved the structure of SARS-CoV-2 and imaged its binding with the ACE2 receptor. In SARS-CoV-2 infection, the viral S (spike) protein receptor-binding domain binds to ACE2 to enter the host cell. ACE2 expression in the lungs is relatively low, but it is present in type II pneumocytes-a cell type also endowed with TMPRSS2 (transmembrane protease serine 2). This protease is critical for priming the SARS-CoV-2 S protein to complex with ACE2 and enter the cells. Herein, we review the current understanding of the interaction of SARS-CoV-2 with ACE2 as it has rapidly unfolded over the last months. While it should not be assumed that we have a complete picture of SARS-CoV-2 mechanism of infection and its interaction with ACE2, much has been learned with clear therapeutic implications. Potential therapies aimed at intercepting SARS-CoV-2 from reaching the full-length membrane-bound ACE2 receptor using soluble ACE2 protein and other potential approaches are briefly discussed as well.

Keywords: China; coronavirus; coronavirus infections; renin-angiotensin system; serine.

Figure 1.

ACE (angiotensin-converting enzyme)-2 is shown in green, the severe acute respiratory syndrome coronavirus (SARS-CoV-2) receptor-binding domain (RBD) core is shown in cyan, and receptor-binding motif (RBM) in red. Disulfide bonds in the SARS-CoV-2 RBD are shown as sticks and indicated by arrows. The N-terminal helix of ACE2 responsible for binding is labeled. Reprinted from Lan et al with permission. Copyright © 2020.

Figure 2.

ACE (angiotensin-converting enzyme)-2 in its full-length is a cell membrane-bound enzyme consisting of 805 amino acids (aa). It is anchored in the cell membrane by a short transmembrane domain (red). The main part of ACE2 is on the outer surface of the cell (ectoenzyme) with only a small C-terminal tail being in the intracellular space. On the N terminus, there is a signal peptide (green) that directs the protein from the cell organelles to the plasma membrane. The catalytic domain (egg-shaped sphere) renders the protein enzymatically active. The extracellular part of ACE2 that is devoid of the transmembrane region and the intracellular tail is referred as soluble (maximally 740 aa long) because it is not membrane/tissue bound and is able to float in body fluids. Similar to full-length ACE2, the soluble ACE2 contains a fully functional catalytic domain.

Figure 3.

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) enters cells through receptor-mediated endocytosis. Top, Severe acute respiratory syndrome coronavirus (SARS-CoV-2) binds to ACE (angiotensin-converting enzyme)-2 and after priming by serine protease TMPRSS2 (transmembrane protease serine 2) is activated and then internalized. In the process, ACE2 protein decreases from the membrane. ACE2 receptor, blue; spike protein, green; TMPRSS2, red. Bottom, ACE2 (blue) converts Ang (angiotensin) II to Ang-(1–7), Ang I to Ang-(1–9), and des-arg⁹ BK (bradykinin) 1–8 to BK 1–7. ACE (red) converts Ang I to Ang II. AT₁R indicates angiotensin II type 1 receptor.

Figure 4.

Administering soluble ACE (angiotensin-converting enzyme)-2 administration could intercept the coronavirus from binding to membrane-bound full-length ACE2 and entering the cell. Full-length membrane-bound ACE2, blue; soluble ACE2, red; TMPRSS2 (transmembrane protease serine 2), gray. SARS-CoV-2 indicates severe acute respiratory syndrome coronavirus. Adapted from Batlle et al with permission. Copyright © 2020.