key: cord-0729109-b9palezs
authors: Masre, Siti Fathiah; Jufri, Nurul Farhana; Ibrahim, Farah Wahida; Abdul Raub, Sayyidi Hamzi
title: Classical and alternative receptors for SARS‐CoV‐2 therapeutic strategy
date: 2020-12-26
journal: Rev Med Virol
DOI: 10.1002/rmv.2207
sha: a647a434db84f0aa8d2df7b44ecb3efbc068304e
doc_id: 729109
cord_uid: b9palezs

Understanding the molecules that are essential for severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) entry can provide insights into viral infection and dissemination. Recently, it has been identified from several studies that angiotensin‐converting enzyme 2 receptor and transmembrane serine protease 2 are the main entry molecules for the SARS‐CoV‐2, which produced the pandemic of Covid‐19. However, additional evidence showed several other viral receptors and cellular proteases that are also important in facilitating viral entry and transmission in the target cells. In this review, we summarized the types of SARS‐CoV‐2 entry molecules and discussed their crucial roles for virus binding, protein priming and fusion to the cellular membrane important for SARS‐CoV‐2 infection.

Covid-19 is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). SARS-CoV-2 is classified within the Betacoronavirus genus, which also contains SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). 1 and have shown several symptoms, including fever, dry cough, tiredness, headache, abdominal pain and diarrhoea. 2, 3 The loss of smell, or anosmia, has been reported as one of the early symptoms among persons infected with SARS-CoV-2. 4 Also, Covid-19 patients were diagnosed with pneumonia and having a ground glass opaque appearance on the lungs through a computed tomography (CT) scan. 5, 6 Progression of Covid-19 disease in infected people may eventually advance to multiple organ failure and even lead to death. 7, 8 target cell membrane. 9, 10 Proteolytic cleavage catalysed by endogenous protease is required to facilitate the viral fusion to the cellular membrane and enter the target cells. 11 This review will discuss the classical and several alternative receptors for SARS-CoV-2, together with their cellular proteases implicated in Covid-19 disease.

Angiotensin-converting enzyme 2 (ACE2) plays a primary role in the conversion of angiotensin II (Ang II) to angiotensin 1-7 (Ang 1-7). 12 ACE2 is also vital in regulating cardiac function and various organs through the renin-angiotensin system (RAS). 13 Though ACE2 shares some homology with ACE and has 61% similarity in the amino acids, ACE2 is not inhibited by ACE inhibitors. 12, 14 In Covid-19, ACE2 plays a key role in SARS-CoV-2 entry and its infection. ACE2 serves as a primary receptor for the SARS-CoV-2 spike protein (S protein) to bind and enter human cells. 15, 16 The receptor-binding domain of the virus S protein binds to ACE2 causes SARS-CoV-2 to undergo endocytosis and exposes it to endosomal proteases leading to viral infection in the host. [17] [18] [19] Zhou et al. 20 revealed that HeLa cells with ACE2 expression are susceptible to infection with SARS-CoV-2 compared to cells without ACE2 expression.

Recent sequencing data on normal human tissues by Li et al. 21 showed that ACE2 is highly expressed in the small intestine, testis, kidneys, heart and thyroid, followed by medium expression of ACE2 in the lungs, large intestine, bladder, liver and adrenal glands. ACE2

showed the lowest expression in the blood, spleen, bone marrow and brain. The findings indicate that expression of ACE2 in various organs may explain SARS-CoV-2 infection out with the lungs. 21 Notably, in the lungs, SARS-CoV-2 has been reported to infect mainly type II pneumocytes, 22 demonstrated by a post-mortem study on the lung tissue histology of Covid-19 patients, which revealed cellular fibromyxoid exudates with a bilateral distribution of alveolar damage. 23 Zhao et al. 24 also demonstrated in their RNA expression study using normal human lung samples, where 83% of the ACE2 receptor is expressed in the type II pneumocytes. Interestingly, ACE2-expressing type II pneumocytes appeared to be involved in the viral life cycle, viral process, viral assembly and viral replication via enrichment analysis indicating their roles for transmission in humans. 24 A recent study by Lukassen et al. 25 showed that apart from lung tissues, ACE2 is also expressed mainly in the subsegmental bronchial branches, particularly in the transient secretory cells.

SARS-CoV-2 infection will lead to the downregulation of ACE2 in the infected cells as the virus interacts with ACE2-expressing cells in the lung epithelium and other organ tissues. Upon SARS-CoV-2 infection, ACE2 can be shed from the lung tissue to the bronchial space, thus, reducing the ACE2 level of the infected cells. Meanwhile, the ACE2 shed in the bronchial space is still capable of converting Ang II to Ang (1-7). 7 The ACE2 remains capable of binding to the SARS-CoV-2 in the bronchial space, but it will enter the cells because the ACE2 shed is no longer attached to the epithelial cell. Also, it is reported that the ACE2 shed has an unknown physiological function. 26 The question of whether this shedding behaviour of ACE2 can prevent SARS-CoV-2 infection or can predict the prognosis of disease progression 27 is still to be answered, and further study is needed.

However, ACE2 as the entry receptor is not limited to SARS-CoV-2 since it is also the receptor for SARS-CoV infection. 28 The tendency for SARS-CoV-2 and SARS-CoV to bind the ACE2 receptor may be due to both viruses sharing 76.5% sequence homology. 23 Moreover, Xu et al. 23 also reported that the receptor-binding domain in both SARS-CoV-2 and SARS-CoV S proteins has a similar structure. Nevertheless, ACE2 has better affinity with up to 20-fold higher binding to the SARS-CoV-2 S protein than the SARS-CoV S protein. 10 A crystallography study by Shang et al. 29 reported that the SARS-CoV-2 has a broader linking interface with ACE2 as compared to the SARS-CoV. ACE2 is known to serve as a binding receptor, and although ACE2 is present in various organs, it does not indicate that the SARS-CoV-2 may enter through all different organs that have the ACE2 receptor. The entry of SARS-CoV-2 to target cells that mainly occurs via endocytosis may rely on the viral S protein binding to the ACE2 receptor and the presence of cellular proteases to cleave the viral S protein. 30 

Another receptor for SARS-CoV-2 infection has been discovered through an in-depth study. CD147, a receptor on host cells, 31 is a transmembrane glycoprotein, 32 and is commonly known as basic immunoglobulin (Basigin) or extracellular matrix metalloproteinase inducer (EMMPRIN). 33 Distinct from ACE2 expression, CD147 is highly expressed in pathological tissues such as in tumour tissues 34, 35 and inflamed tissues, 36, 37 suggesting little cross-reactivity with normal tissue. 33 Besides, in contrast to ACE2, CD147 is greatly expressed in the brain cell lines and brain tissues than in the lung cells. 38 invading Vero E6 cells upon meplazumab application, an inhibitor for CD147. Wang et al. 33 also revealed the interaction and binding between CD147 and SARS-CoV-2 S protein via surface plasmon resonance assay, ELISA test and co-immunoprecipitation assay, thus identifying an alternative receptor for the entry of SARS-CoV-2 to host cells. In accordance with this finding on CD147, a phase II clinical trial (NCT04275245) is currently ongoing in China, targeting the entry of SARS-CoV-2 by blocking the CD147 receptor with meplazumab. Hence, the CD147 receptor may act as a potential therapeutic target in Covid-19 patients.

When CD147 was initially isolated from the human lung carcinoma (LX-1 cell line), CD147 was found to induce matrix metalloproteinases (MMP) production that is responsible for fibrosis in tumour progression. 39, 40 It is reported that CD147 was also presented in non-tumour tissues such as in the alveolar macrophages and type II pneumocytes in the lungs, which indicates its role may be related to the MMP production. 41 Guillot et al. 41 described that CD147 was highly expressed in the fibrosis area of lung parenchyma compared to the normal lung area, indicating the association between CD147 and fibrosis. Moreover, it is demonstrated that the inhibition of CD147 by the anti-CD147 antibody prevented TGF-B1-induced myofibroblasts formation. 31 Indeed, recent clinical findings suggested that lung fibrosis and fibrous stripes are among the major complications from SARS-CoV-2 infection. [42] [43] [44] Hence, targeting the CD147 receptor may also be advantageous to prevent the burden of lung fibrosis in Covid-19 patients. At the same time, additional study is necessary to approve whether CD147 acts as a novel new receptor, as a co-receptor with ACE2, or as an alternative secondary receptor.

Neuropilin (NRP) may become another docking receptor to facilitate SARS-CoV-2 entry. It has four domains consisting of the N-terminal CUB (for complement C1r/C1s, Uegf, Bmp1) domain, coagulation factor domain, MAM (meprin, A-5 protein, and receptor proteintyrosine phosphatase mu) domain and transmembrane domain. 45 Neuropilin consists of two family members, NRP1 and NRP2. NRP1 is a transmembrane protein of relative molecular mass (Mr) 130,000 and acts as a receptor that binds to furin-cleaved substrates. It acts as a regulator of the vascular endothelial growth factor (VEGF)induced angiogenesis cellular signalling cascades, sprouting, and controlling cell migration in vessel remodelling and angiogenesis. [46] [47] [48] However, its signalling is associated with cancer as it could promote angiogenesis and increased vascular permeability, causing oedema. 49 Its overexpression is associated with poor tumour prognosis such as in the gastrointestinal (GI) tract, prostate, lung, ovary, and gliomas, osteosarcomas, and melanomas. 50 NRP1 is not only expressed in the respiratory epithelium but also the olfactory epithelium. Particularly, NRP1 is highly expressed in endothelial cells, excitatory neurons and nasal cavity epithelial cells 51, 52 . Increased expression has been identified in biological samples from Covid-19 patients and suspected to aid viral invasion. 53 Moreover, Daly et al. 54 revealed that NRP1 was capable of binding the S1 protein of SARS-CoV-2 through the mechanism of canonical C-end rule, and NRP1 was shown to be a host factor for SARS-CoV-2 in cell culture study. Positive NRP1 cells in the olfactory epithelium and endothelial cells of the olfactory bulb were infected by the virus. 53 The entry of SARS-COV-2 into the nervous system is likely via the interaction of virus S protein and the receptor located in the olfactory system. 55 Specifically, the binding occurs through the b1/b2 domain on the NRP1 receptor through a polybasic amino acid sequence (682RRAR685). 56 Currently, the potential monoclonal blocking antibody was being studied to block the extracellular b1/b2 domain of NRP1. 53 

Dipeptidyl peptidase 4 (DPP4), also known as CD26, is an ectopeptidase present on the surface membrane of different types of cells 57 such as in the immune system, kidneys, lungs, smooth muscle, liver and capillaries. 57,58 DDP4 plays a role in various physiological processes and immune-system-related diseases. 59 The expression of DDP4 and its relation to injuries in the human respiratory tract from coronavirus infection have been shown previously in MERS-CoV infection. 60 A study to determine virus infectivity in HeLa cells showed that the SARS-CoV-2 did not bind to the DPP4 receptor. 20 However, a binding conformation between DPP4/CD26 and SARS-CoV-2 spike glycoprotein has recently been reported, so it is suggested that both MERS-CoV and SARS-CoV-2 may have shared the mode of entry through DPP4. 61 Also, Qi et al. 62 showed DDP4 as a potential receptor for SARS-CoV-2 infection as it has a similar expression pattern with the ACE2 receptor. A study by Venkatakrishnan et al. 63 agreed with the data from Qi et al., 62 where they depicted that DPP4 has a high similarity of expression profiles to ACE2 receptor. A study on the inhibition of DPP4 activity using a mouse model depicted lower T-cell counts that reduced airway inflammation. 64 As some of the Covid-19 patients have developed inflammatory tissue damage in their airways, 65 future studies targeting on DPP4 activity are required that may be beneficial to reduce the burden of inflammatory reaction in Covid-19 patients.

There are few studies about alanyl aminopeptidase (ANPEP), glu- important role in regulating blood pressure and remodelling blood vessels via the RAS catabolic pathway. 69 Recently, Qi et al. 62 identified ENPEP as a new possible entry receptor for SARS-CoV-2 as ENPEP has no history of acting as a receptor for human coronaviruses. They showed that the expression pattern of ENPEP was similar to the ACE2 receptor expression. The real reason behind the similar expression patterns needs further investigation to confirm the role of ENPEP. However, it may be due to the same types of cells infected by different human coronaviruses, which could lead to a similar expression.

AGTR2, a G-protein coupled receptor, is postulated as another receptor for SARS-CoV-2. 70 Cui et al. 70 demonstrated high and specific expression of AGTR2 in the lung, indicating the high possibility of AGTR2 acting as an entry receptor for SARS-CoV-2 infection, mainly through the respiratory system. However, AGTR2 expression is lower in the cornea and conjunctiva. 67 Cui et al. 70 found out AGTR2 has a greater binding affinity towards SARS-CoV-2 S protein compared to ACE2 through simulation of 3D structure-based protein-protein interaction and revealed that AGTR2 was capable of interacting with ACE2. Hence, further additional studies are required to confirm the significance role of AGTR2 as an entry receptor, or as a co-receptor that acts together with ACE2 or possibly with other entry receptors for SARS-CoV-2. Table 1 summarizes the receptors for SARS-CoV-2 entry with their site of expression.

Transmembrane Serine Protease 2 (TMPRSS2) is known as the cellular protease that the SARS-CoV-2 virus utilizes to facilitate virus entry into the target host cells. 16 Apart from the cell receptor, the SARS-CoV-2 entry requires viral S protein cleavage and activation of the host cell protease, which is the TMPRSS2 to mediate viral infection. 16 The S2 subunit of the viral S protein consists of two heptad repeat (HR) regions (HR1 and HR2) and a fusion peptide region. 18, 19 Within the endosome, the S1 subunit is cleaved, exposing the fusion peptide, thus allowing the viral fusion to the cellular membrane as the S2 region folds to pull together the HR1 and HR2 regions. 18, 19 Then, proceed to membrane fusion and viral entry into the host. 25, 71 Several parts in the human respiratory system, including the lungs and subsegmental bronchial branches, show TMPRSS2 expression. 25 Analysis of single-nucleus RNA sequencing on normal human lungs revealed that TMPRSS2 expression has more affinity in the type II pneumocytes, similar to ACE2 expression in the lungs. 25, 72 Other than type II pneumocytes, several sites show co-expression of TMPRSS2 and ACE2, such as the transient secretory cells in the subsegmental bronchial branches, 25 enterocytes in the small intestine, 22 heart, liver and kidney. 73 The respiratory epithelium, olfactory epithelium, endothelial cells, excitatory neurons, and nasal cavity epithelial cells 51, 52 Angiogenesis in cancer [46] [47] [48] 

Cathepsin B and L (CatB/L) are known as main lysosomal proteases, responsible for monitoring the function of lysosomes. 80 Apart from lysosomes, cathepsins are also commonly found in endosomes. 81 Cathepsin expression and activity have been commonly associated with aging neurons. 82 A study on the expression pattern of cathepsin L in the adult heart revealed about 28.6% of the whole heart expressed cathepsin L. 74 Besides, Liu et al. 74 

Studies to identify the ultimate cellular protease to cleave SARS-CoV-2 S protein are ongoing. In vitro study by Hoffmann et al. 16 showed that SARS-CoV-2 entry was not entirely prohibited even after TMPRSS2 and CatB/L blockage. This finding indicates that there is another protease that may facilitate in SARS-CoV-2 S protein priming. A recent paper by Monkemuller et al. 88 stated that furin, an endogenous serine protease, plays a role in cleaving the virus S protein to facilitate virus attachment to the ACE2 receptor and cell membrane before viral entry into the host cell. A phylogenetic study by Xia et al. 11 reported the presence of a furin-like cleavage site (FCS) at the SARS-CoV-2 S1/S2 subunit, which was not present in other types of SARS-related viruses. The ability of furin to cleave the S protein at the FCS site is postulated to be the reason behind the higher binding affinity between SARS-CoV-2 and ACE2 receptor. 89 However, this hypothesis requires confirmation.

A recent investigation by Hoffmann et al. 16 implicated furin in the SARS-CoV-2 S proteolytic process at the S1/S2 site by using furin inhibitor, decanoyl-RVKR-CMK. Interestingly, the proteolytic process of SARS-CoV-2 S was also inhibited, indicating the need for furin to cleave the S protein at the S1/S2 site. It is reported that furin is commonly distributed in the small intestine, and can enhance the pathogenicity of some bacteria and viruses. 88 Since some papers have described gastrointestinal symptoms such as diarrhoea, nausea and vomiting in patients with Covid-19 89, 90 , the small intestine may serve as one of the viral entry sites for SARS-CoV-2, facilitated by furin.

Moreover, the increase of transmission rates from humans to humans is postulated due to the role of furin, which can be secreted and act to cleave the S protein even in the target cells that do not express furin. 25 Again, this hypothesis requires further investigation.

Shang et al. 91 revealed a remarkable role of furin preactivation towards facilitating SARS-COV-2 entry to some target cells that have lower TMPRSS2 and/or cathepsin proteases expression. Since protease activation is essential to allow viral structural conformation for membrane fusion, Shang et al. 91 showed that by furin preactivation, the SARS-COV-2 might no longer be dependent on target cells, especially the cells that have low proteases such as TMPRSS2 and/or cathepsin, increasing viral entry to the human body.

Trypsin has been reported as one of the proteases that may act as the SARS-CoV-2 entry molecule. 30 Trypsin, a serine endopeptidase, is highly expressed in respiratory cells and gastrointestinal cells, particularly in the small intestine. 81 A study by Bertram et al. 92 showed that human airway trypsin-like protease is capable of cleaving and activating SARS-CoV S protein, which might be responsible for viral spread in humans. Recently, Ou et al. 30 showed the role of trypsin in activating SARS-CoV-2 S protein to allow viral fusion to HEK293T cell lines. Nevertheless, the SARS-CoV-2 S protein is still capable of being activated even with the blockage of MASRE ET AL. 71 showed that camostat mesylate, a serine protease inhibitor of TMPRSS2, can partly prevent the entry of SARS-CoV-2-S. However, they revealed the combination of E64d, a cathepsin B/L protease inhibitor, and camostat mesylate appeared to completely block SARS-CoV-2 Smediated viral entry into 293T cells. 71 Nevertheless, the SARS-CoV-2 has been reported to bind to other receptors and is not limited to ACE2. Moreover, the availability of several cellular proteases to aid in membrane fusion for viral entry is another crucial factor to be considered in a therapeutic approach for Covid-19. This therapeutic strategy targeting the entry molecules may help prevent SARS-CoV-2 infection in the early phase. However, the strategy may not be entirely effective in the late phase of the disease due to the possibility of cytokine storm-induced acute respiratory distress syndrome, which in some cases may contribute to patient mortality. Therefore, a better pharmacological approach that may consider the classical and alternative viral receptors and proteases are suggested to be developed as a countermeasure for SARS-CoV-2 infection.

The reason for the immense human-to-human transmission of SARS-COV-2 cases compared to SARS-COV or MERS-COV remains to be answered. Hence, possible factors related to viral entry could be due to varieties of potential receptors on the cell surface, diverse cellular proteases and the host factor itself that may influence the virus to enter the human body. While the development of effective treatment targeted to viral entry molecules is still ongoing and urgently needed, current efforts to reduce viral transmission such as physical distancing and wearing masks should be consistently practised in our daily lives.

Global patterns in coronavirus diversity

Characteristics of COVID-19 infection in Beijing

Clinical characteristics of coronavirus disease 2019 in China

Olfactory dysfunction in COVID-19 diagnosis and management

COVID-19 and the nervous system

Time course of lung changes on chest CT during recovery from 2019 novel coronavirus (COVID-19) pneumonia

SARS-CoV-2 pandemic and research gaps: understanding SARS-CoV-2 interaction with the ACE2 receptor and implications for therapy

COVID-19: towards understanding of pathogenesis

Structural basis for the recognition of the SARSCoV-2 by full-length human ACE2

Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation

The role of furin cleavage site in SARS-CoV-2 spike protein-mediated membrane fusion in the presence or absence of trypsin

Angiotensin-converting enzyme 2 (ACE2) is a key modulator of the renin angiotensin system in Health and disease

Role of the ACE2/angiotensin 1-7 Axis of the renin-angiotensin system in heart failure

SARS-coronavirus modulation of myocardial ACE2 expression and inflammation in patients with SARS

Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses

A multibasic cleavage site in the spike protein of SARS-CoV-2 is essential for infection of human lung cells

Inhibitors of cathepsin L prevent severe acute respiratory syndrome coronavirus entry

The trinity of COVID-19: immunity, inflammation and intervention

The complexity of respiratory disease associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: from immunopathogenesis to respiratory therapy

A pneumonia outbreak associated with a new coronavirus of probable bat origin

Expression of the SARS-CoV-2 cell receptor gene ACE2 in a wide variety of human tissues

SARS-CoV-2 receptor ACE2 is an Interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues

Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its Spike protein for risk of human transmission

Single-cell RNA expression profiling of ACE2, the receptor of SARS-CoV-2

SARS-CoV-2 receptor ACE2 and TMPRSS2 are primarily expressed in bronchial transient secretory cells

Angiotensin-converting enzyme 2: the first decade

CT quantification of pneumonia lesions in early days predicts progression to severe illness in a cohort of COVID-19 patients

Angiotensin-converting enzyme 2: a functional receptor for SARS coronavirus

Structural basis of receptor recognition by SARS-CoV-2

Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV

CD147 as a target for COVID-19 treatment: suggested effects of azithromycin and stem cell engagement

Function of HAb18G/CD147 in invasion of host cells by severe acute respiratory syndrome coronavirus

CD147-spike protein is a novel route for SARS-CoV-2 infection to host cells

HAb18G (CD147) a cancer-associated biomarker and its role in cancer detection

EMMPRIN regulates the canonical Wnt/β-catenin signaling pathway, a potential role in accelerating lung tumorigenesis

CD147 (EMMPRIN/Basigin) in kidney diseases: from an inflammation and immune system viewpoint

The roles of CyPA and CD147 in cardiac remodelling

The expression of SARS-CoV-2 receptor ACE2 and CD147, and protease TMPRSS2 in human and mouse brain cells and mouse brain tissues

The human tumor cell-derived collagenase stimulatory factor (renamed EMMPRIN) is a member of the immunoglobulin superfamily

EMMPRIN-CD147, an MMP modulator in cancer, development and tissue repair

Increased extracellular matrix metalloproteinase inducer (EMMPRIN) expression in pulmonary fibrosis

Pulmonary fibrosis and COVID-19: the potential role for antifibrotic therapy

Research advances in the mechanism of pulmonary fibrosis induced by coronavirus disease 2019 and the corresponding therapeutic measures

Chest CT manifestations of new coronavirus disease 2019 (COVID-19): a pictorial review

Structural and functional relation of neuropilins

Large-scale multi-omic analysis of COVID-19 severity

NRP1 acts cell autonomously in endothelium to promote tip cell function during sprouting angiogenesis

Neuropilin functions as an essential cell surface receptor

Neuropilin regulation of angiogenesis, arteriogenesis, and vascular permeability

Neuropilins: expression and roles in the epithelium

Effects of COVID-19 on the nervous system

Devilishly radical NETwork in COVID-19: oxidative stress, neutrophil extracellular traps (NETs), and T cell suppression

Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity

Neuropilin-1 is a host factor for SARS-CoV-2 infection

Deciphering SARS-CoV-2 virologic and Immunologic features

SARS-CoV-2 spike protein coopts VEGF-A/neuropilin-1 receptor signaling to induce analgesia

Dipeptidyl-peptidase IV from bench to bedside: an update on structural properties, functions, and clinical aspects of the enzyme DPP IV

Dipeptidyl peptidase-IV inhibition for the treatment of cardiovascular disease -recent insights focusing on angiogenesis and neovascularization

De Meester I. The dipeptidyl peptidase family, prolyl oligopeptidase, and prolyl carboxypeptidase in the immune system and inflammatory disease, including atherosclerosis

Dipeptidyl peptidase 4 distribution in the human respiratory tract: implications for the Middle East respiratory syndrome

Emerging WuHan (COVID-19) coronavirus: glycan shield and structure prediction of spike glycoprotein and its interaction with human CD26

Single cell RNA sequencing of 13 human tissues identify cell types and receptors of human coronaviruses

Knowledge synthesis of 100 million biomedical documents augments the deep expression profiling of coronavirus receptors

CD26 (dipeptidylpeptidase IV)-dependent recruitment of T cells in a rat asthma model

COVID-19 severity correlates with airway epithelium-immune cell interactions identified by singlecell analysis

Human aminopeptidase N is a receptor for human coronavirus 229E

Ocular surface expression of SARS-CoV-2 receptors

COVID-19 hyperinflammation: what about neutrophils? mSphere

Mammalian glutamyl aminopeptidase genes (ENPEP) and proteins: comparative studies of a major contributor to arterial hypertension

AGTR2, one possible novel key gene for the entry of SARS-CoV-2 into human cells

SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor

HCA Lung Biological Network. SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes

Influenza and SARS-coronavirus activating proteases TMPRSS2 and HAT are expressed at multiple sites in human respiratory and gastrointestinal tracts

Single-cell analysis of SARS-CoV-2 receptor ACE2 and spike protein priming expression of proteases in the human heart

Pathological findings of COVID-19 associated with acute respiratory distress syndrome

Myocardial localization of coronavirus in COVID-19 cardiogenic shock

TMPRSS2 contributes to virus spread and immunopathology in the airways of murine models after coronavirus infection

SARS-CoV-2 receptor ACE2 gene expressions and RAAS inhibitors

Air pollution and COVID-19 mortality in the United States: strengths and limitations of an ecological regression analysis

Loss of cathepsin B and L leads to lysosomal dysfunction, NPC-like cholesterol sequestration and accumulation of the key Alzheimer's proteins

Host cell proteases: critical determinants of coronavirus tropism and pathogenesis

Neuronal and microglial cathepsins in aging and agerelated diseases

Cardiac involvement in a patient with coronavirus disease 2019 (COVID-19)

Life-threatening cardiac tamponade complicating myo-pericarditis in COVID-19

Evidence that TMPRSS2 activates the severe acute respiratory syndrome coronavirus spike protein for membrane fusion and reduces viral control by the humoral immune response

Wild-type human coronaviruses prefer cell-surface TMPRSS2 to endosomal cathepsins for cell entry

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COVID-19, coronavirus, SARS-CoV-2 and the small bowel

Effect of gastrointestinal symptoms in patients with COVID-19

COVID-19 and gastrointestinal symptoms

Cell entry mechanisms of SARS-CoV-2

Cleavage and activation of the severe acute respiratory syndrome coronavirus spike protein by human airway trypsin-like protease

Dexamethasone in hospitalized patients with Covid-19 -preliminary report

Remdesivir for the treatment of Covid-19 -final report

Angiotensin-converting enzyme 2 protects from severe acute lung failure

Classical and alternative receptors for SARS-CoV-2 therapeutic strategy

The authors would like to thank all the staff in the Centre for Toxicology and Health Risk Studies, Faculty of Health Sciences, Universiti Kebangsaan Malaysia.

The authors declare that there is no conflict of interest.

All authors scoped and constructed the literature search. Nurul 

Data sharing is not applicable as there is no new data were analysed in this study.

Site of expression Reference

Type II pneumocytes, subsegmental bronchial branches, enterocytes in the small intestine, heart, liver, kidney, and neurons. 22, 25, 73 CatB/L High expression in the heart 74 Furin Small intestine 88 Trypsin Respiratory cells and gastrointestinal cells, particularly in the small intestine. 81 Abbreviations: CatB/L, Cathepsin B and L; TMPRSS2, transmembrane serine protease 2.6 of 9 -MASRE ET AL.

Siti Fathiah Masre https://orcid.org/0000-0002-4202-2289