The role and significance of angiotensin‐converting enzyme 2 peptides in the treatment of coronavirus disease 2019

Abstract Since the end of 2019, coronavirus disease 2019 (COVID‐19) caused by the novel coronavirus (2019‐nCoV) posed a serious threat to human health and life. Therefore, the discovery of drugs that can effectively prevent and treat COVID‐19 is urgently warranted. In this article, the role and significance of angiotensin‐converting enzyme 2 in drug development and the treatment of COVID‐19 are discussed. It was found that the binding of ACE2 to SARS‐CoV‐2‐RBD involved two core regions (31st and 353rd lysine) and 20 amino acids of the ACE2 protein. The mutation of these amino acids could lead to a great change of the binding ability of ACE2 and SARS‐CoV‐2‐RBD. This information was important for us to find more efficient ACE2 peptides to block the 2019‐nCoV infection. So during this study, we summarized the role of ACE2 in the regulation of 2019‐nCoV infection and stress, and hypothesized that the development and optimization of ACE2 peptide can effectively block 2019‐nCoV infection and reliably treat the COVID‐19.

an effective and specific pharmacological agent for the treatment of COVID-19. Hence, the battle against SARS-CoV-2 remains at the stage of continuous exploration.

| ANG IOTENS IN -CONVERTING ENZ YME ( ACE2) AND SAR S -CoV-2
Since the outbreak of SARS-CoV-2, scientists have carried out intensive research to establish a more comprehensive scientific basis for the treatment of COVID-19. Similar to the pathogenic mechanism of SARS-CoV, SARS-CoV-2 also attaches to the host cell through binding of the receptor binding domain (RBD) in the S1 subunit of S (Spike) protein to the cellular receptor ACE2 and enters the cells via endocytosis. [8][9][10][11] This leads to progression and deterioration of the disease. SARS-CoV-2 can easily invade the human body through the combination of RBD and ACE2.
Researchers determined the structure of the SARS-CoV-2 spike protein using cryo-electron microscopy, and found that the SARS-CoV-2 spike protein exhibits significantly higher ACE2-binding affinity than the SARS-CoV spike protein (10-20-fold higher). 12 This fully explains the markedly more efficient transmission of SARS-CoV-2 versus SARS-CoV, and also reveals the important role of ACE2 in the process of SARS-CoV-2 infection. Therefore, using ACE2 receptor protein as a target, we may be able to discover a specific drug for the treatment of COVID-19.

| THE B I OLOG I C AL FUN C TI ON S OF ACE2
ACE2 is a multifunctional type I transmembrane glycoprotein with a single extracellular catalytic domain. 13 It belongs to the ACE family and is the homolog of ACE. ACE and ACE2 are involved in the regulation of the renin-angiotensin system (RAS). The ACE/angiotensin II/angiotensin II type 1 receptor (ACE/Ang II/AT1R) axis regulates signaling pathways to increase blood pressure and promote inflammatory reactions. The signaling pathway regulated by the ACE2/Ang1-7/MAS axis has been associated with vasodilatory, anti-oxidative, and anti-inflammatory effects. [14][15][16] A previous study demonstrated that SARS-CoV-2 infections caused a downregulation of ACE2 expression. [17][18][19] This led to imbalance in the RAS system, promotion of inflammation, and further disease progression. In some patients with cardiovascular disease, diabetes, etc., SARS-CoV-2 infection is accelerated by overexpression of ACE2. 20,21 Consequently, elderly individuals accounted for 80% of the clinical deaths caused by SARS-CoV-2, and 75% of those patients suffered from cardiovascular disease, diabetes, and other underlying diseases.
Using single-cell analysis technology, researchers found that ACE2 is abundantly expressed in human alveolar type II epithelial cells and colonic epithelial cells. Furthermore, gene functional enrichment analysis revealed the genes that are relevant to viral infections in human alveolar type II epithelial cells and colonic epithelial cells with high expression of ACE2. These mainly include genes regulating virus invasion and release, recognizing virus nucleic acid and type I/ III interferon signaling, pro-inflammatory cytokines and chemokines, the major histocompatibility complex I (MHC I) antigen presentation pathway, and cytokine receptors. 22,23 The results of that study indicated that entry of the virus into cells through ACE2 leads to undetermined consequences.

| THE B IND ING S ITE S OF ACE2 TO S A R S -C oV-2
It has been found that the new small-molecule peptides prepared from the N-terminal 21-43 amino acid protein of ACE2 can effectively bind to SARS-CoV-2-RBD. 26 However, recent studies using the deep parsing approach for the structural investigation of SARS-CoV-2 and ACE2 binding showed that the binding of ACE2 to SARS-CoV-2-RBD involves two core regions (31st and 353rd lysine) of the ACE2 protein. 27,28 Whether the new small-molecule peptides pre-  analyzed the data and wrote the manuscript.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from the corresponding author upon reasonable request.