Targeting Angiotensin-converting Enzyme 2 (ACE2) for the Discovery of Anticoronaviral Drugs

ABSTRACT

Coronaviruses are a leading cause of emerging life-threatening diseases, as evidenced by the ongoing coronavirus disease pandemic (COVID-19). According to complete genome sequence analysis reports, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which causes COVID-19, has a sequence identity highly similar to the earlier severe acute respiratory syndrome coronavirus (SARS-CoV). The SARS-CoV-2 has the same mode of transmission, replication, and pathogenicity as SARS-CoV. The SARS-CoV-2 spike protein's receptor-binding domain (RBD) binds to host angiotensin-converting enzyme-2 (ACE2). The ACE2 is overexpressed in various cells, most prominently epithelial cells of the lung (surface of type 1 and 2 pneumocytes), intestine, liver, kidney, and nervous system. As a result, these organs are more vulnerable to SARS-CoV-2 infection. Furthermore, renin-angiotensin system (RAS) blockers, which are used to treat cardiovascular diseases, intensify ACE2 expression, leading to an increase in the risk of COVID-19. ACE2 hydrolyzes angioten-sin-II (carboxypeptidase) to heptapeptide angiotensin (1-7) and releases a C-terminal amino acid. By blocking the interaction of spike protein with ACE2, the SARS-CoV-2 entry into the host cell and inter-nalization can be avoided. The pathogenicity of SARS-CoV-2 could be reduced by preventing the RBD from attaching to ACE2-expressing cells. Therefore, inhibition or down-regulation of ACE2 in host cells represents a therapeutic strategy to fight against COVID-19. However, ACE2 plays an essential role in the physiological pathway, protecting against hypertension, heart failure, myocardial infarction, acute respiratory lung disease, and diabetes. Given the importance of ACE's homeostatic role, targeting of ACE2 should be realized with caution. Above all, focusing on the SARS-CoV-2 spike protein and the ACE2 gene in the host cell is an excellent way to avoid viral mutation and resistance. The current review summarises the sequence analysis, structure of coronavirus, ACE2, spike protein-ACE2 complex, essential structural characteristics of the spike protein RBD, and ACE2 targeted approaches for anti-coronaviral drug design and development.Copyright © 2022 Bentham Science Publishers.