SARS-CoV-2 receptor ACE2 and molecular pathway to enter target cells during infection : Reviews and Research in Medical Microbiology

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SARS-CoV-2 receptor ACE2 and molecular pathway to enter target cells during infection

Najafi, Khadijeha,∗; Maroufi, Parhamb,∗; Khodadadi, Ehsanehb,∗; Zeinalzadeh, Elhama,c; Ganbarov, Khudaverdid; Asgharzadeh, Mohammade; Kafil, Hossein Samadib

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Reviews and Research in Medical Microbiology 33(1):p e105-e113, January 2022. | DOI: 10.1097/MRM.0000000000000237
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Coronaviruses (CoVs) belong to the Coronaviridae family, which includes a group of enveloped, positive, single-RNA viruses [1]. Such viruses that bear the largest genome among RNA viruses were called ‘CoVs’ because of their crown morphology under an electron microscope. CoVs are structurally nongenomic and share a common organization [2]. Around two-thirds of the genome consists of two large overlapping open reading frames (ORF1a and ORF1b), which are translated into the polyproteins pp1a and pp1ab replicate [3,4]. The remainder of the genome contains structural open reading frame (ORF) proteins, including spike (S), envelope (E), membrane (M), and nucleoprotein (N). Different lineages of CoVs encode a variety of lineage-specific accessory proteins too [5]. Thus, the accurate detection of coronavirus is an important issue.

CoVs are classified into four genera (alpha-CoV, beta-CoV, gamma-CoV, and delta-CoV) based on the difference in protein sequences, of which the beta-CoV genera contain the most HCoVs [6,7]. Seven human CoVs (HCoVs) have been identified. Among them are alpha-CoVs, HCoV-229E, and HCoV-NL63. The remaining five beta-CoVs are HCoV-OC43, HCoV-HKU1, extreme acute respiratory coronavirus syndrome (SARS-CoV), Middle East coronavirus respiratory syndrome (MERS-CoV), and SARS-CoV-2 [8–11]. Conversely, SARS-CoV, MERS-CoV, and the recently identified SARS-CoV-2 are highly pathogenic, triggering a significant lower respiratory tract infection in comparatively more patients at higher risk of developing acute respiratory distress syndrome (ARDS) and extrapulmonary manifestations [12].

Spike proteins SARS-CoV-2 and SARS-CoV share a similarity of 76.5% in amino acid sequences [13], and most significantly, the spike proteins SARS-CoV-2 and SARS-CoV have a high homology degree [14,15]. Over-expression of human ACE2 increased disease severity in a mouse model of SARS-Cov infection, demonstrating that viral cell entry is a key stage [16]. Injecting SARS-CoV spike into mice exacerbated lung injury; this injury was significantly attenuated by blocking the pathway to renin--angiotensin and depended on the expression of ACE2 [17]. Consequently, ACE2 is not only the virus entry receptor for pathogenesis of SARS-CoV but also protects against lung injury. Additionally, the SARS-CoV-2 spike protein binds directly to the host cell surface of the ACE2 receptor to facilitate virus entry and replication.

Therefore, knowing how this virus affects human proteins, plays a key role in making pharmacological strategies a priority [4,18]. The COVID-19 epidemic has presented the world with major medical, technological, political, and moral challenges [19]. In this study, we will look at the comparison and contrast of the various HCoVs from a virus evolution and genome recombination perspective, which in turn will assist in the creation of new drugs that interact with SARS-CoV-2 viral N protein and viral replication, and highly related SARS-CoV virus.

Furthermore, it is attempted to highlight COVID-19's molecular mechanisms and pathogenesis to demonstrate the best ways to help medical staff diagnose infection rapidly and reliably, and survive patient life and prevent infection from spreading. Through this study, various currently available approaches to coronavirus detection will be analyzed. It is expected to help researchers develop rapid and accurate detection techniques.

Analysis of the clinical characteristics of human coronaviruses

The first strain of HCoV-229E has been isolated from the patients with upper respiratory tract infection breathing tract [20]. Patients diagnosed with HCoV-229E have typical symptoms of cold, including headache, malaise, sneezing and sore throat, cough, and fever [21]. It was isolated from the culture of the organ, and the subsequent serial passage of suckling mice in the brains [22]. HCoV-OC43 isolated from organ culture, and the clinical features of HCoV-OC43 infection appear to be close to those of HCoV-229E infection, which are symptomatically isolated from other pathogens in respiratory tract infections, such as influenza A viruses and rhinoviruses [2]. HCoV-229E and HCoV-OC43 are both widely distributed and tend to be transmitted mostly during the winter season in a temperate climate [23]. The incubation period for these two viruses usually is less than 1 week, along with an outbreak of around 2 weeks [24].

Patients with extreme acute respiratory coronavirus syndrome (SARS-CoV) initially have myalgia, headache, vomiting, nausea, pain, and chills, followed by late signs of dyspnea, cough, and respiratory distress [25]. The specific laboratory abnormalities of SARS are lymphopenia, deranged liver function tests, and raised creatine kinase [26,27]. SARS patients also experience diffuse alveolar damage, the proliferation of the epithelial cells, and increased macrophages [28]. In addition to the lower respiratory tract, in these severe cases, several organs, including the gastrointestinal tract, liver, and kidney, may also be compromised, generally followed by a cytokine storm, This could be lethal, especially in immunocompromised patients [29].

Coryza, conjunctivitis, fever, and bronchiolitis are normal in the HCoV-NL63 outbreak. Their peak occurrence is in early summer, spring, and winter [30].

HCoV-NL63 triggers obstructive laryngitis also referred to as croup [31]. The acute asthmatic exacerbation of HCoV-HKU1 has been reported, in addition to community-acquired pneumonia and bronchiolitis [32]. HCoV-HKU1 has been found worldwide, causing mild respiratory diseases, similar to HCoV-NL63, HCoV-229E, and HCoV-OC43 [33]. All four of these community-acquired HCoVs were well suited to humans, and are therefore, less likely and mutating and developing highly pathogenic diseases [34]. In general, they often become less virulent or pathogenic as these HCoVs learn the ability to transmit efficiently and to sustain themselves continuously inside humans [35]. MERS symptoms are similar to those of SARS, distinguished by recurrent severe pneumonia [36]. Like SARS, most MERS patients have had acute renal failure, which has so far been exceptional among HCoV-induced MERS diseases [37].

SARS-CoV-2 causes severe respiratory infections, such as SARS-CoV and MERS-CoV, which are described as dyspnea, cough, and fever [38]. Moreover, some patients also suffer from diarrhea [39]. Pneumonia is one of the most serious signs and may progress quickly into the condition of acute respiratory distress [40]. Although SARS-CoV and SARS-CoV-2 are very similar because of homology of 82% high nucleotide sequence, they cluster into various branches of the phylogenetic tree [5]. Compared with SARS-CoV and MERS-CoV, SARS-CoV-2 is potentially less pathogenic but more conveyable [41]. Comparing the SARS-CoV-2 to the other six HCoVs demonstrate similarities and very interesting variations [42]. Firstly, the period of incubation and the duration of the HCoV disease course are quite similar [43]. SARS-CoV-2 is following the general pattern of the six other HCoVs in this regard. Second, the intensity of symptoms of COVID-19 lies between SARS-CoV and the four community-acquired HCoVs (i.e. HCoV-229E, HCoV-HKU1, HCoV-OC43, and HCoV-NL63) [37]. On one hand, SARS-CoV-2 infection exhibits features that are most often seen during community-acquired HCoV infection, including the presentation of nonspecific, moderate, or even no symptoms. Second, SARS-CoV-2 transmission often demonstrates interesting characteristic patterns in community-acquired SARS-CoVs and HCoVs (Table 1).

Table 1 - Comparison of clinical features of the seven human coronaviruses.
HCoVs Classification Clinical symptoms Representative References
HCoV-229E Alpha-CoV Malaise, headache, nasal discharge, sneezing, sore throat, fever and cough [20]
HCoV-OC43 Beta-CoV, lineage A Malaise, headache, nasal discharge, sneezing, sore throat [2]
SARS-CoV Beta-CoV, lineage B Malaise, headache, myalgia, dyspnea, diarrhea, fever and dry cough [25]
HCoV-NL63 Alpha-CoV Cough, rhinorrhea, tachypnea, fever, hypoxia, croup [31]
HCoV-HKU1 Beta-CoV, lineage A fever, running nose, cough, dyspnea [32]
MERS-CoV Beta-CoV, lineage C fever, chills, cough, myalgia, pneumonia, arthralgia, diarrhea and vomiting [36]
SARS-CoV-2 Beta-CoV, lineage B Myalgia, dyspnea, fever, headache, diarrhea, dry cough [5]

Specific features of SARS CoV 2 genome

Analysis of phylogenetic of SARS-CoV-2 illustrated that this virus belonged to lineage B of the betacoronavirus genus. SARS-CoV-2 includes a high percentage of similarity with SARS-CoV as well as, the genomic analogy of viruses identified of two particular characteristics of SARS CoV 2, I: based on structural studies and biochemical tests, SARS CoV 2 has been optimized for binding to the human receptor ACE2, II: SARS CoV 2 spike protein has a functional polybasic (Furine) cleavage site in the S1-S2 region, which results in the further prediction of three O-linked glycans around the site by the addition of 12 nucleotides [5,44,45].

Mutation in the domain SARS CoV 2 receptor binding

The most variable component of the coronavirus genome is the receptor-binding domain (RBD) in the spike protein [46,47]. Six RBD amino acids are essential for binding to ACE2 receptors and for deciding host receptor binding to SARS CoV, whose coordinates are based on (SARS CoV) Y442, L472, N479, D480, T487, and Y4911, which correspond to L455, F486, Q493, S494, N501, and Y505 in (SARS CoV 2), in which five of the six cases vary between SARS CoV 2 and SARS CoV [15,48].

Polybasic furin cleavage site and O-linked glycans

The next noticeable characteristic of SARS CoV 2 is a polybasic cleavage site (RRAR) in the spike protein at the junction between S1 and S2. This allows it to be effective through furin and other proteases, and play a role in identifying viral infection and binding to the host cell [43]. In addition, in this site, SARS-CoV-2 can insert a precursor proline by inserted sequence RRAR. Thus, it is anticipated that proline will add O glycans linked to S673, T678, and S686 that fill the gap portion and are specific to SARS CoV 2 [44].

SARS-CoV-2 and the severe coronavirus acute respiratory syndrome

The sequence of hundreds of SARS-CoV-2 virus isolates has shown that there is a near relationship between two bats-derived SARS-like coronaviruses as well as, RBD of SARS-CoV-2 is similar to the SARS-CoV RBD, suggesting a probable common receptor of the host cell [49]. In-vitro and in-vivo investigations have shown that these strains of coronavirus have an analogous receptor-binding domain structure in the spike (S) protein for host angiotensin-converting enzyme (ACE2) proteins [50,51]. In mice infected with SARS-CoV, human ACE2 over-expression increased the severity of the disease, demonstrated that the ACE2-dependent entrance of the virus into cells is a critical step [52]. Injection of SARS-CoV spike into mice has been reported to decrease levels of ACE2 expression, thus aggravating lung injury [50,51]. In addition, studies have shown that ACE2 acts both as the SARS-CoV entry receptor and to defend the lung against injury [17].

Using the angiotensin-converting enzyme 2 receptor (SARS-CoV) to facilitate the viral entry into target cells

Cryo-EM is a type of transmission electron microscope (TEM) in which the sample studied in refrigeration (liquid nitrogen temperature) is examined [53]. In line with this, there are three recent cryo-EM studies, which demonstrated that the new coronavirus enters human cells using a glycoprotein called ‘SARS-CoV-2 Spike’ or ‘S’ that binds to the protein of cell membrane, ‘angiotensin-converting enzyme 2’ (ACE2), as well as they, discovered that the ability of (SARS-CoV-2) to bind receptors 10 up to 20 times more efficient than another coronavirus [15,48,54]. The prerequisite for a coronavirus attack on the host cell is bound to the receptor [55]. After that, viral spike protein through cathepsin acid-dependent proteolysis, TMPRRS2 or furin protease breaks down and then integrates with the viral envelope to cell membranes [56]. The spike is a big clover-shaped trimmer that can be broken down by proteases into an RBD receptor-binding domain-containing ns1 subunit and a region of C terminal S2 [57].

Unlike other coronavirus proteins, the spike protein contains the most complex sequence of amino acids, which is the best way to conform to their hosts [15,58,59]. The glycoprotein, or SARS-CoV-2 spike, is a combination of protein and carbohydrate that it has been glycosylated with small chains of oligosaccharides (sugars) but does not contain phosphoric acid, purine or pyrimidine. On the other hand, ‘ACE2’, is an exopeptidase that converts angiotensin-1 to 9 (Ang 1–9) or it is led to converting angiotensin-II (Ang-II) to angiotensin 1–7 (Ang 1–7) [15,58,59]. This enzyme has a direct effect on heart function and is mostly expressed in the inner layer of blood vessels, heart, and kidneys [10,60,61]. When coronavirus infects a human cell, the ‘S’ protein is subdivided into ‘S1’ and ‘S2’ subunits. ‘S1’ encompasses the RBD, thus ‘COVID-19’ can bind to the peptidase domain directly in ‘ACE2’ [62–64]. It is assumed that the ‘S2’ subunit has a role in cell fusion (Fig. 1).

Fig. 1:
Schematic illustration of therapeutic mechanism against corona virus disease-2019 in the context of host pathways and viral entry mechanism.

Cleavage of SARS-COV-2 S proteins by host furin

As mentioned, The S protein of SARS-CoV-2 binds with a stronger affinity to human ACE2 receptors than that of the SARS-CoV virus [54,65], it can be because of a furin-like cleavage site (682RRAR/S686) implanted in the S1/S2 SARS-CoV-2 virus protease cleavage site. The spike protein (S1 region) is in charge of binding to the host cell receptor ACE2, where the S2 region is responsible for viral RNA fusion and cellular membranes [54,66]. Such polybasic furin sites in hemagglutinin proteins have most also been observed in highly virulent influenza viruses. Therefore, the addition of the furin site can increase the ability of this new SARS-CoV-2 to bind and invade human ACE2-expressed cells [67].

SARS-CoV-2 invades host cells via a CD147-spike protein

CD147 is a transmembrane glycoprotein that belongs to the superfamily of immunoglobulins, which is implicated in the development of cancers, plasmodium invasions, and virus infections [68–71]. CD147 express in by various sorts of cells, including epithelial cells, endothelial cells, and leukocytes [72]. Previously, studies have been shown that CD147 plays a working role in promoting SARS-CoV invasion of host cells, and that CD147-antagonistic peptide-9 has a high binding capacity to HEK293 cells and a SARS-CoV inhibitory effect [71]. Nowadays, scientist reported that SARS-CoV-2 invades host cells through a new way of CD147-spike protein. The host-cell-expressed basigin (CD147) may bind SARS-CoV-2 spike protein and possibly be involved in the invasion of host cells [73,74]. Consequently, Meplazumab has been studied in patients with SARS-CoV-2 pneumonia as a humanized anti-CD147 antibody [74].

Human angiotensin-converting enzyme 2 in complex with B0AT1 and pathogenesis of coronavirus disease-2019

Recent studies show that ACE2 moonlights as the chaperone for the membrane trafficking of an amino acid transporter. B0AT1, also known as (SLC6A19) mediates the absorption of neutral amino acids into the intestinal cells using a sodium-related method as well as whose surface expression in intestinal cells requires ACE2 [75–78]. Newly, scientists presented modeling of the 2.9 Å resolution cryo-EM configuration of full-length human ACE2 in complex with B0AT1. The investigations indicating that human ACE2 in complex with B0AT1 can bind two spike proteins simultaneously so, this data can be an important clue to the molecular basis for coronavirus detection and infection [60].

Molecular pathways and therapeutic target

The lung seems to be the most vulnerable goal organ as the lung's vast surface area makes it particularly susceptible to inhaled viruses [79]. Gene ontology enrichment research revealed that ACE2-expressing AECII has high rates of several viral process-related genes including viral process regulatory genes, viral life cycle, viral assembly, and replication of viral genomes, indicating that the ACE2-expressing AECII facilitates the replication of coronavirus in the lungs [80]. ACE2 receptor expression can also be observed in multiple extrapulmonary tissues, such as the heart, intestine, endothelium, and kidney. Significantly, ACE2 is expressed so much on the luminal surface of intestinal epithelial cells, acting as a co-receptor for the absorption of nutrients, especially for the resorption of amino acid from food [17]. Therefore, it is predicted that the intestine may also be an essential SARS-CoV-2 entry site.

Potential pathways to corona virus disease-2019, mediated by angiotensin-converting enzyme 2

Spike protein vaccine

The creation of a vaccine based on a spike 1 subunit of protein could be contingent on the reality that ACE2 is the receptor for SARS-CoV-2 [81]. Cell lines, which promote viral replication in the presence of ACE2 can be the most effective in the large-scale production of vaccines [48].

Inhibition of transmembrane protease serine 2 activity

Many experiments have described that the SARS spike protein engages ACE2 as an input receptor and then uses the TMPRSS2 cell serine protease for S protein priming by host cell proteases [56,63,64,82]. Recently, researchers have demonstrated that the serum form a convalescent SARS patient neutralized 2019-nCoV32 S-driven entry [56,63,64,82]. Therefore, A TMPRSS2 inhibitor has then blocked entry and may represent a therapeutic choice. In addition, initial spike protein priming by transmembrane protease serine 2 (TMPRSS2) is needed for SARS-input and viral dissemination via interaction with the ACE2 receptor [64]. A serine protease inhibitor, camostat mesylate, approved for the treatment of unknown diseases in Japan, has been shown to counteract the activity of TMPRSS2, and is thus a well tolerated alternative [83,84].

Blocking the angiotensin-converting enzyme 2 receptor

The interaction sites between ACE2 and SARS-CoV have been identified at the atomic level, and the associations between ACE2 and SARS-CoV-2 should also be true from the studies to date [85]. Therefore, one may target this site of interaction with antibodies or small molecules.

Delivering excessively soluble form of angiotensin-converting enzyme 2

In mice, it is proved that SARS-CoV downregulates ACE2 protein (but not ACE) via binding its spike protein, which leads to serious lung damage [51]. This indicates that excessive ACE2 can compete with SARS-CoV-2 not only to neutralize the virus but also to rescue cellular ACE2 function that adversely regulates the system of renin--angiotensin (RAS) to protect the lung against injury [86]. In addition, increased activity of the ACE and reduced availability of ACE2 lead to lung injury during lung injury caused by acid and ventilator. Therefore, the treatment of ACE2 in a soluble form may have dual functions: slowing the entry of the virus into cells, and thus viral distribution, and shielding the lung from damage [87] (Fig. 2).

Fig. 2:
Pathogenesis and transmission mechanism of Sars and Sars-CoV-2 by angiotensin-converting enzyme 2 receptor.

New treatment strategies for corona virus disease-2019

The ACE2 enzyme is a transgenic protein and the main entry point for the Coronavirus disease 2019 (COVID-19) into the host cell [88]. Decreased levels of the ACE2 enzyme in the cell are thought to help fight the infection. On the other hand, the presence of the ACE2 enzyme protects lung cells from damage caused by the virus by increasing the level of the angiotensin-1–7 dilating agent [89]. Thought to be an ACE2 human recombinant enzyme (rhACE2) is a new treatment for acute respiratory damage [90]. In this regard, scientists used a human recombinant solution (ACE2) to prevent the growth of SARS-CoV-2, investigation shows that recombinant human angiotensin-converting enzyme 2 (hrsACE2) has an inhibitory effect on the growth of the SARS-CoV-2 virus and was able to decrease the virus by 1000 to 5000 times compared with normal cell culture [91]. Moreover, blood and kidney arteries were used to display that SARS-CoV-2 could infect these tissues directly and multiply, which could be a potential cause of any organ failure and cardiovascular damage in serious COVID-19 cases [92]. These findings showed that hrsACE2 is also able to reduce SARS-CoV-2 infection in these organoids.


Many studies showed that ‘ACE2’ must undergo a molecular process in which it binds to another identical molecule so that it can become active or infectious or contagious. The resulting molecule can simultaneously bind two molecules of (COVID-19) S protein. The scientists also studied different binding models of ‘SARS-CoV-2 RBD’ than other related viruses and showing how subtle changes in the molecular binding sequence make the coronavirus structure stronger. The scientists concluded that their research could help global efforts to design new customized antibodies to target ‘ACE2’ or other coronavirus proteins that prevent coronavirus infection. The scientists also figured out that ‘COVID-19’ could be linked to another complex structure called ‘ACE2-B0AT1’. Previously, none of these molecular structures have been identified and now likely to be contributing to the production of antiviral drugs or even a vaccine that will be capable of inhibiting coronavirus targeting cells (ACE2).


This study was supported by the Drug Applied Research Center, Tabriz University of Medical Sciences.

Transparency document: The Transparency document associated with this article can be found, in the online version.

Funding: This study was supported by Tabriz University of Medical Sciences with grant number 65174.

Conflicts of interest

There are no conflicts of interest.


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Khadijeh Najafi, Parham Maroufi and Ehsaneh Khodadadi equally participated as co-first authors.


2019-nCoV; angiotensin-converting enzyme 2; coronavirus disease-2019; molecular; pathways; SARS-CoV-2

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