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ACE2 Protein in COVID-19: The Guardian and Gateway Zipporah Mariebelle R. Enriquez - S3999907 Xiunan(Yana) Ouyang - S3993600 Khyati Viren Shah - S4028107 Vijeta - S4032016 College of Science, Master of Biotechnology, Protein Technologies RMIT University

ABSTRACT The pandemic COVID-19 caused by SARS-CoV-2 virus, has created a demand for a comprehensive understanding of the virus's mode of human cell invasion. The human ACE2 receptor protein has been identified as central to this process. This paper delves into the structure, function, and significance of the ACE2 protein, highlighting its roles in regulation of blood pressure, immune system modulation, and cardiovascular protection. Interaction of SARS-CoV-2 with ACE2 in molecular dynamics, which facilitates viral entry and spread is also discussed. Notably, post-infection ACE2 expression patterns differ among adults, children, and genders. Given the role of ACE2 in multi-organ damage during COVID-19, potential therapeutic interventions like Orientin and Direct Blue 53 are discussed. Recognizing the ACE2 receptor's core role in COVID-19 emphasizes the importance of targeted research to combat this global health crisis. 1

Introduction The emergence of pandemic COVID-19 from the novel coronavirus SARS-CoV-2, has profoundly impacted global health, economy, and societal structures. The World Health Organization (WHO) (2020), has warned of potential spikes in extreme poverty rates due to the pandemic. This calls for urgency in global initiatives to halt virus transmission and to manage the disease. As researchers aim to understand the virus and its pathogenesis, the human ACE2 receptor protein has emerged as a significant molecule. According to Oudit et al. (2023), the ACE2 receptor has been implicated in COVID-19 as a major invasion site for SARS-CoV-2.. This receptor, which serves dual roles as an enzyme and a chaperone, is distributed across various human tissues. Given the pivotal role of ACE2 in the COVID-19 disease pathway, it becomes imperative to dissect its protein structure and function, aiming ultimately at therapeutic interventions against both SARS-CoV-2 and other potential zoonotic coronaviruses that may utilize the human ACE2 receptor. 2

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The ACE2 receptor protein and its structure The angiotensin-converting enzyme (ACE)-related carboxypeptidase, ACE2, is present across different species, especially in vertebrates. The ACE2 plays a crucial role in a number of physiological processes which includes blood pressure regulation, cardiovascular functions, and fluid balance. According to Peka and Balatsky (2023), the ACE2 receptor is generally conserved across different species as can be inferred from the results of Multiple Sequence Alignments (MSAs) in Figure 1. Furthermore, interactions between humans and animals, particularly livestock, has served as opportunities for pathogens to adapt to human hosts. Figure 1 Comparison of the coding sequence of ACE2 across different species Note. Multiple Sequence Alignment results of human ACE2 with different species. The Donkey ACE2 may be considered to be the closest to the human ACE2 with an alignment score of 9756 and percent identity of 89.4 with the human ACE2. From “Analysis of RBD-ACE2 interactions in livestock species as a factor in the spread of SARS-CoV-2 among animals” by Peka, M., & 3

Viktor Balatsky, 2023, Veterinary and Animal Science , 21 , 100303–100303. https://doi.org/10.1016/j.vas.2023.100303. According to Felipe Pantoja Mesquita et al. (2023), the ACE2 receptor is implicated in the infection and spread of the severe acute respiratory syndrome (SARS) in humans and animals. This is most likely attributed to the conserved regions in the protein across species and the frequent interactions of humans with livestock animals. To gain a better understanding of the role of ACE2 in SARS in humans, its structure is analyzed. The human ACE2, has 805 amino acid sequences and is classified as a type I integral membrane. This receptor also contains a catalytic domain that functions in blood pressure homeostasis (Towler et al., 2004). Studies have also identified ACE2 as a functional receptor for coronaviruses which cause SARS. The native human ACE2 protein structure was obtained via X-ray crystallography, shown in figure 2. 4

Figure 2 Structure of the Native Human Angiotensin Converting Enzyme-Related Carboxypeptidase (ACE2) Note. The human ACE2 protein structure (Entry ID: 1R42) was retrieved from the Protein Data Bank (PDB). The protein is 76.77 kDa, obtained via X-ray crystallography with a resolution of 2.20 Å . The protein was then viewed using the Visual Molecular Dynamics (VMD) program. In the figure, alpha helices are colored purple, beta-sheets are colored yellow, beta turns are colored blue, while white and cyan are random coils in the protein. The overall structure of human ACE2 is classified under zinc metallopeptidases, where uniquely, ACE2 has two catalytic sites (Warner et al., 2004). These active sites hydrolyses or functions as a carboxypeptidase to process other proteins for various cellular processes. In a study by Geng et al. (2022b), binding between SARS-CoV-2 and human ACE2 was enhanced because of new mutations in the viral binding structural domain and conformational changes in the viral spike protein.. Much of the human ACE2 structure is conserved and can possibly be studied for inhibitors of the ACE2-coronavirus interactions. 5

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Functions of ACE2 Protein Renin-Angiotensin System (RAS), the protective axis, has many crucial roles in maintaining the physiological functions through the ACE component which is vital. In a regular RAS pathway, Angiotensin is converted into Angiotensin 1 by renin. This is catalyzed by ACE enzymes promoting inflammation and increase in blood pressure. The distinctive function of ACE2 in RAS is the conversion of Angiotensin 2 into Angiotensin 1-7. This prevents inflammatory actions of Angiotensin 2 helping to protect cardiovascular health (Medina-Enríquez et al., 2021). ACE2's role in the kidney is still to be uncovered but it is involved in the pathogenesis of renal damage. It is also involved in mother-fetus interaction, which has probable function in pregnancy and fetal programming. When there is deficiency of ACE2 it leads to hypertension and even if there is increase in blood pressure ACE2 might protect against it. It has been noticed that slight change in the balance of ACE2 can affect the blood pressure control ( Hamming I, 2007). There are three major functions which includes regulation of blood pressure, immune system, and cardiovascular protection highlighted below: Regulation of Blood Pressure. ACE2 has various mediated factors for lowering blood pressure, consequence of angiotensin 1-7 which is the outcome of ACE2 activity is one amongst them, in which catabolism of angiotensin 2 is likely to be important. Infusion of Angiotensin 1-7 has vasodilatory effects to control normal pressure and hypertension in individuals. Acute angiotensin 1-7 infusion impacts on blood pressure in individuals with normal blood pressure remains indecisive (Jiang et al., 2021). Immunological Homeostasis Regulation by ACE2 protein. Expression of key receptors for SARS-CoV-2, such as ACE2, TMPRSS2, CTSB, and CTSL, in immune cells has been known from the research done in the molecular mechanism of viral entry and effects of organs, tissues, etc. These help us to understand that viruses could affect the immune system, possibly leading to depletion, activation or other mechanisms. Uncontrolled innate immune system as well as production of inflammatory cytokines is the core factor in developing COVID-19 through disturbance in the immune system (Medina-Enríquez et al., 2021). 6

Cardiovascular stability with the help of ACE2 protein. ACE2 protein has beneficial effects in dysfunction and cardiac remodeling of cardiac hypertrophy, myocardial infarction and diabetic cardiomyopathy. If not ACE2 proteins it can further worsens the cardiac problems including heart failure. Catabolism of Angiotensin II, which is a cardioprotective mechanism which reduces oxidative strain, fibrotic changes and inflammation. One of the recent studies has been identified that a patient with heart failure originating through ACE2 has compound roles in cardiac functions, but its implication in the heart failure is unresolved (Jiang et al., 2021). 7

Connection Between COVID-19 and ACE2 The viruses of SARS-CoV-2 mainly utilize the receptor ACE2 to infiltrate host cells (Ning et al., 2021; Yan et al., 2020). When the virus first encounters this receptor, it attaches itself to the ACE2 on the cell surface, interfering with the renin-angiotensin system (RAS) (Ning et al., 2021). SARS-CoV-2's affinity for ACE2, especially within its receptor-binding domain (RBD), is stronger than the previous SARS-CoV, making it more transmissible (Ning et al., 2021). After this attachment, there's a noted decrease in immune cell numbers and a spike in IL-1 levels, leading to weakened immunity (Ning et al., 2021). Specific enzymes, like TMPRSS2, enhance the virus's entry by splitting a vital part of ACE2, facilitating the viral S protein's entry into the cell (Yan et al., 2020). The presence of the protein B0AT1 may hinder TMPRSS2 from accessing the ACE2 cleavage site (Yan et al., 2020). Furthermore, the collaborative function of ACE2 and B0AT1 plays a role in cell membrane transport processes, possibly revealing ACE2's full structure when B0AT1 is around (Yan et al., 2020). Given that ACE2 is widely present in organs such as the kidneys, lungs, intestines, and heart, and B0AT1's involvement in some coronavirus infections in the gut (Yan et al., 2020), ACE2 interaction with SARS-CoV-2 is critical to understanding the disease (Ning et al., 2021; Yan et al., 2020). The trimeric spike glycoprotein (S) in SARS-CoV-2 facilitates conjugation to the host cell ACE2 receptor, this interaction results in the membrane fusion of the cell, which allows the virus to enter the cell (Ju et al., 2020; Ku et al., 2021).By structure, the spike protein was a homotrimer whose N-terminal S1 subunit was involved in attachment to the receptor and whose C-terminal S2 subunit assisted in fusion of the membranes (Ku et al., 2021). It was shown that attachment of the SARS-CoV-2 RBD to the ACE2 N-terminal peptidase structural domain was similar to that of the SARS-CoV (Ju et al., 2020). There is a core structure and a receptor binding motif (RBM) in the RBD that binds directly to ACE2 (Ju et al., 2020). This essential interaction between RBD and ACE2 involves specific molecular forces, such as hydrogen bonds and van der Waals forces (Ju et al., 2020). It's worth noting that the RBM in the RBD, which contains key antigenic regions, plays a significant role in eliciting strong neutralizing antibody reactions (Ku et al., 2021). 8

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ACE2 level changes after COVID-19 infection play a key role in determining disease progression and final outcome (Cantuti-Castelvetri et al., 2020; Gutiérrez-Chamorro et al., 2021; Horowitz et al., 2022; Sahu et al., 2021). The interaction of SARS-CoV-2 with the ACE2 receptor causes significant variations in ACE2 levels (Cantuti-Castelvetri et al., 2020; Gutiérrez-Chamorro et al., 2021; Sahu et al., 2021). Initially, ACE2 expression in the respiratory system spikes, facilitating the virus's entry into host cells (Gutiérrez-Chamorro et al., 2021; Sahu et al., 2021). However, as the virus binds with ACE2, there's a rapid decrease in its expression (Gutiérrez-Chamorro et al., 2021; Sahu et al., 2021). This change could unbalance the renin-angiotensin system, increasing the potential for lung damage (Sahu et al., 2021; Ni et al., 2020). Importantly, ACE2 is not only present in the respiratory system but also in organs like the heart, kidneys, and digestive tract (Sahu et al., 2021). 1. Children: Research by Patel & Verma (2020) notes that kids aged 4-9 exhibit lower ACE2 levels in their nasal lining compared to older individuals. This reduced level might explain why younger children tend to have a lower risk and milder symptoms of COVID-19. 2. Adults: Older people face a greater risk of severe pneumonia, characterized by lymphocyte reduction and unusual inflammation. The ACE2 is a conduit for SARS-CoV-2 to enter cells, but it appears to be less prevalent in the elderly. Cells with ACE2 are primarily found in the alveolar zones of seniors, particularly in SFTPC-positive cells, but are rarely seen in bronchial areas (Zhang et al., 2021). 3. Sex Differences: Lung ACE2 expression levels in males and females are largely similar. In terms of COVID-19 infection, there isn't a significant difference in pulmonary ACE2 expression between genders (Asselta et al., 2020; Zhang et al., 2021). 9

Possible Treatments and Areas of Research Focus Using the EasyVS Docking Program, there are 26 pockets identified in the ACE2 protein. According to Holien (2023) in the Week 10 lecture for Bioinformatics, a druggable pocket should have a volume greater than 140 Å 2 . In Figure 3, there are eight pockets greater than 140 Å 2 and can therefore be considered as druggable. Figure 3 EasyVS Docking Program results for pockets in the ACE2 protein Orientin, a C-glycosyl bioactive compound, has a high binding affinity to the ACE2 receptor and can be a potential inhibitor to prevent COVID-19 infection (Alagu Lakshmi, et al., 2020). Another compound, Direct blue 53 which is a biological dye, is observed to block the ACE2 receptor and spike interaction in SARS-CoV-2 in vivo and in vitro (Xiao et al., 2023) . Further analysis was done and the pharmacokinetic properties of these drugs were obtained via the pkCSM program. Table 1 shows the pharmacokinetic properties that are 10

acceptable under Astex’s Rule (RO3) and the corresponding properties of Orientin and Direct blue 53. Table 1 Pharmacokinetic properties of Orientin and Direct blue 53 in comparison with acceptable values under Astex’s Rule (RO3) Molecular Weight XlogP H-bond donors H-bond acceptors Rotatable bonds PSA (polar surface area) Astex’s Rule < 300 Da ≤ 3 ≤ 3 ≤ 3 ≤ 3 ≤ 60 Å 2 Orientin 448.38 -0.2 8 11 3 178.78 Direct blue 53 895.88 3.67 8 16 9 356.79 Note. Under Astex’s Rule, both Orientin and Direct blue 53 do not have ideal pharmacokinetic properties. Based on these findings, more research has yet to be done for other potential inhibitors of the SARS-CoV-2 and ACE2 interaction. Although several breakthroughs have been made in understanding these interactions and mechanisms of binding, there is a need for more extensive research to come up with ideal and highly effective treatments. Liu and Huang (2022) also mentioned that extreme caution is also needed in targeting ACE2 due to the crucial role it plays in cardiovascular functions. This opens other areas of research considering potential inhibitors and potential receptors that are at play in the pathogenesis of COVID-19. 11

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Conclusion The role of the ACE2 receptor protein in the COVID-19 pandemic is critical. As the main entry point of the virus into human cells, its involvement in physiological processes and the variations in its expression post-infection have been enlightening. These insights into ACE2's function and interaction with the virus are crucial for developing potential therapeutic interventions. Orientin and Direct blue 53 have been investigated for their potential inhibitory roles in COVID-19 disease development. However, pharmacokinetic analysis of these treatments show unfavorable results. There is a need to explore deeper into the potential treatments and targets involved in development of COVID-19 infections. As we navigate this global health challenge, a deeper understanding of ACE2 will be instrumental in devising strategies to combat not only the current pandemic but also future zoonotic threats. 12

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