key: cord-0772608-5glhtxg8
authors: Peng, Ruchao; Wu, Lian-Ao; Wang, Qingling; Qi, Jianxun; Gao, George Fu
title: Cell entry of SARS-CoV-2
date: 2021-06-07
journal: Trends Biochem Sci
DOI: 10.1016/j.tibs.2021.06.001
sha: dca3eeef30bb1a131a20fd8e2471d49e1738463b
doc_id: 772608
cord_uid: 5glhtxg8

The severe acute respiratory syndrome virus 2 (SARS-CoV-2) invades host cells by interacting with receptors/co-receptors, as well as other co-factors, via its spike (S) protein that further mediates the fusion between viral and cellular membranes. The host membrane protein angiotensin-converting enzyme 2 (ACE2) is the major receptor for SARS-CoV-2 and a critical determinant for its cross-species transmission. Additionally, some auxiliary receptors and co-factors are also involved which would expand the host/tissue tropism of SARS-CoV-2. After receptor engagement, certain proteases are required to cleave the S protein to trigger its fusogenic activity. In this review, we discuss the recent advancement in understanding the molecular events during SARS-CoV-2 entry which would contribute to developing vaccines and therapeutics.

In late 2019, a novel coronavirus named severe acute respiratory syndrome virus 2 (SARS-CoV-2) emerged in humans, causing the coronavirus disease 2019 (COVID-19) [1] [2] [3] [4] .

This outbreak has rapidly developed into a worldwide pandemic and has resulted in more than 0.1 billion confirmed cases as of May 23 rd , 2021, including approximately 3.5 million deaths (https://www.who.int/emergencies/diseases/novel-coronavirus-2019). SARS-CoV-2 is the seventh human-infecting coronavirus (HCoV) identified so far (Box 1), and it is most similar to SARS-CoV which emerged in 2002 [4, 5] . However, SARS-CoV-2 exhibits a higher transmission efficiency (see Glossary) compared to SARS-CoV and other HCoVs [6] , while with a relatively lower mortality rate compared to SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV) [6] [7] [8] . Although several candidate vaccines are being distributed in different countries, the global pandemic situation is yet far from under control.

It is very urgent to promote vaccination among human populations and develop effective therapeutics.

SARS-CoV-2 is a positive-sense RNA virus with a large single-stranded RNA genome of approximately 30,000 nucleotides [9] . The genome encodes three classes of proteins: two large polyproteins, pp1a and pp1ab, which are cleaved into sixteen non-structural proteins (NSPs) required for viral RNA synthesis (and probably other functions); four structural proteins (the Spike, Envelope, Membrane and Nucleocapsid proteins), essential for viral entry and assembly; and nine accessory proteins, which are supposed to counteract the host immunity during infection [10, 11] . Viral entry is the first step of infection and one of the most important processes in the virus life cycle, which is also the key target for vaccines and therapeutics. This process is executed by the spike (S) protein on the envelope of SARS-CoV-2, which recognizes the host cell receptor and mediates the subsequent membrane fusion to allow the viral genome to be released into the cytoplasm [12] .

There are 30-60 S protein trimers in average protruding from the envelope of SARS-CoV-2 virion, with an average distance of 15 nm from each other [13] [14] [15] . Each trimeric spike is approximately 10 nm in length with a long hinge helix-stalk that allows the spike to adopt different orientations on the viral envelope [14, 15] . The coronavirus S protein is a typical class I viral fusion protein and is the largest viral fusion machine identified so far, containing more than 1,200 amino acid residues.

During the cell entry process, the SARS-CoV-2 S protein undergoes proteolysis by cellular proteases to be cleaved into S1 and S2 subunits which remain associated and further assemble into trimers of S1/S2 heterodimer (Figure 2 ) [16, 17] . The S1 subunit can be divided into the N-terminal domain (NTD) and the C-terminal domain (CTD), of which the latter is responsible for binding the host receptor angiotensin converting enzyme 2 (ACE2) and is thus also termed as the receptor binding domain (RBD) [17] [18] [19] [20] [21] . The S2 subunit is the fusogenic portion of the spike and consists of the upstream helix (UH) region, the fusion peptide (FP), the heptad repeat 1 (HR1), the central domain (CD), the heptad repeat 2 (HR2), the transmembrane domain (TM), and the cytoplasmic tail (CP) (Figure 2A, B) . Different from most typical class I viral fusion proteins, the FP of coronavirus S protein is not located at the immediate N-terminus of the S2 subunit. Instead, it is shielded by the UH domain which therefore requires a second cleavage event to expose the FP [22, 23] . The proteolysis at the S2' cleavage site to remove the UH domain is critical for activating the fusogenic capacity of S protein, which would trigger irreversible conformational changes of the S2 fusion machine to initiate membrane fusion [24-26]. exhibit highly similar interaction profiles with ACE2 [19-21]. However, some substitutions occur at the key interacting residues in RBD that lead to more atomic contacts between SARS-CoV-2 S and ACE2, potentially resulting in the higher binding affinity compared to SARS-CoV (~4 fold difference) (Figure 3C-D) [19]. This property may somehow contribute to the highly efficient human-to-human transmission of SARS-CoV-2 [6, 7] . In addition, the ACE2 orthologs are widely distributed in various domestic and wild mammals, such as cats, dogs, pigs, camels, horses, pangolins, and bats, implying the broad host-spectrum of SARS-CoV-2 [29] . Some closely related coronaviruses to SARS-CoV-2 have been isolated in pangolins and bats [2, 30] . Two recent studies have shown that the ACE2 orthologs of a wide range of animals can bind SARS-CoV-2 RBD and mediate the S pseudo-typed viruses to enter cells, though the S-binding interface displays significant diversity ( Figure 3E , F) [31, 32].

These findings strongly imply that SARS-CoV-2 may have experienced multiple spillover events in adaptation to the diverse molecular determinants in different animals, which enabled its host-jump across different intermediate hosts and finally made it to infect humans.

Cryo-electron microscopy (cryo-EM) studies have determined the structures of SARS-CoV-2 S protein in various conformations, both before and after membrane fusion [17, 18, 26] , as well as its complex with the receptor ACE2 [33-35]. These structural snapshots enable the deduction of a complete scenario for the conformational changes of S protein during SARS-CoV-2 entry (Figure 4) . The RBD of S protein can adopt different conformations at the prefusion state, with the receptor binding interface buried by the adjacent protomer involves a key salt bridge contributed by residue D614 [33] . The progressive interactions with ACE2 molecules will lead to dissociation of the S1 head from the fusogenic S2 stalk, which facilitates the fusion activation by further proteolysis at the S2' site ( Figure 4C ) [33] . Of note, a SARS-CoV-2 variant harboring a D614G substitution in the S protein was identified in Europe in the middle of 2020. This mutation renders the RBD with a much higher flexibility, increasing the probability of adopting the open conformation to be accessible by the receptor, and reduces the stability of the prefusion structure of S trimer, making it easier for fusion activation [33, 37, 38] . This may explain the higher transmission efficiency of the variant strain compared with the earlier isolates [39, 40] . Additionally, the S protein is extensively decorated by glycans, both in S1 and S2 subunits ( Figure 2C ). The glycan shield not only changes the antigenicity of S protein, but may also alter the conformation of specific domains.

It has been shown that the N-linked glycans at residues N165 and N234 could modulate the conformational dynamics of the RBD, thus affecting the interactions with the receptor [41, 42] . In addition, abrogating the glycans on SARS-CoV-2 S will render it more sensitive to proteolysis during biogenesis in cells and compromise its stability, which would reduce the functional spikes to be presented on the viral envelope and thus inhibit viral infectivity [43] .

The binding of ACE2 to S protein will induce the endocytosis of the virion, after which the viral envelope would fuse with the endosomal membrane to enable the release of viral genome into the cytoplasm [44] [45] [46] . Alternatively, the membrane fusion event can also occur at the plasma membrane after receptor engagement. Both entry mechanisms have been indicated for SARS-CoV-2, probably with a preference for the endosomal pathway (Figure 1 )

A remarkable feature of SARS-CoV-2 S protein is the insertion of a polybasic residue motif at the boundary between S1 and S2 subunits, which renders it prone to be cleaved by furin/furin-like proteases during biogenesis and cell entry [17, 47] . The trimeric spikes on the viral envelope are thus mostly cleaved S1/S2 complexes, in contrast to the uncleaved S0 form observed in SARS-CoV and other SARS-CoV-related viruses [17, 25] . This property suggests the SARS-CoV-2 S may be easier primed for membrane fusion than SARS-CoV S as the latter requires two proteolysis events after receptor binding. Since the furin-like proteases are almost ubiquitously distributed in different tissues and organs, the presence of furin-type cleavage sites in viral fusion proteins has been implicated to be related to broad cell tropism, and even high pathogenicity of related viruses [48, 49] . This may partially explain the highly efficient transmissibility of SARS-CoV-2 among human populations that has resulted in the unprecedented global pandemic of coronavirus so far. In line with this hypothesis, a recent study reported that mutations of this furin cleavage site in SARS-CoV-2 S led to reduced viral replication in a human respiratory cell line and attenuated its pathogenesis in both hamster and mouse models [50] .

After the receptor engagement, the second step of proteolysis of SARS-CoV-2 S is supposed to be executed mainly by the transmembrane serine protease 2 (TMPRSS2), which cleaves the S2 fusion machine at the S2' site to expose the FP [51] . The TMPRSS2 is a primary serine protease expressed in many epithelial cells, which has also been shown as an ideal antiviral target for inhibiting SARS-CoV-2 entry [25]. In addition to furin/furin-like proteases and TMPRSS2, other proteases may also be involved in the entry process of SARS-CoV-2, such as serine endoprotease proprotein convertase 1 (PC1), trypsin, matriptase (trypsin-like integral-membrane serine peptidase) and cathepsins [52] [53] [54] (Figure 1) . The broad-spectrum of protease usage by SARS-CoV-2 may significantly facilitate its infectivity and transmissibility among humans and other hosts, and may lead to systematic multi-organ infections in infected patients [55] .

The alternative receptors AXL, KREMEN-1, and ASGR-1 J o u r n a l P r e -p r o o f

Although both SARS-CoV and SARS-CoV-2 utilize ACE2 as the main receptor for cell entry, the cells in main target organs, e.g. the lungs and bronchi, display low levels of ACE2 expression as revealed by single-cell sequencing analyses [56, 57] . Moreover, SARS-CoV-2 was also found to be able to efficiently infect the upper respiratory tract and other tissues/organs, including the pharynx, heart, liver, brain, kidneys, and the gastrointestinal tract [55, 58] . This evidence suggests other molecules are involved in the entry process of SARS-CoV-2 ( Table 1) [59] . On the other hand, overexpression of KREMEN-1 or ASGR-1 in ACE2 knock-out cells only partially restored the infectivity of SARS-CoV-2, with a lower efficiency as compared to ACE2 expressing cells [60] . Therefore, the contribution of these three candidate receptors in SARS-CoV-2 entry into human cells is yet to be further determined. Biochemical data reveals that AXL binds to the NTD of S protein, whereas the KREMEN-1 and ASGR-1 interact with both the NTD and RBD [59, 60] . These observations 

Two additional studies reported that the membrane protein neuropilin-1 (NRP1) promotes SARS-CoV-2 entry [70, 71] (Figure 1 ). Neuropilins are a family of membrane-anchored co-receptors for a panel of molecules, such as vascular endothelial growth factors (VEGFs) and semaphorins [72] . Both NRP1 and NRP2 can bind the furin-cleaved C-terminal peptides of VEGFs, which are accommodated within a pocket in the b1 domain of the NRPs [73] . This C-terminal motif generally follows the rule of Arg/ Lys-X-X-Arg/Lys (R/K-XX-R/K, where X can be any amino acid) [74] . Interestingly, the proteolysis of SARS-CoV-2 S by the furin/furin-like proteases would generate a polybasic Arg-Arg-Ala-Arg motif at the C-terminus of S1 subunit, which conforms the rule for interactions with NRPs [17, 53] . Both structural and biochemical evidence have demonstrated that the S1 C-terminal motif of SARS-CoV-2 directly binds to NRP1 [70, 71] . Down-regulating the expression of NRP1 by J o u r n a l P r e -p r o o f Journal Pre-proof RNA interference or intercepting the NRP1-S interactions by inhibitors can effectively reduce the cell entry and infectivity of SARS-CoV-2 [70, 71] . Therefore, NRP1 serves as a co-receptor for SARS-CoV-2 infection that may complement the low expression level of ACE2 in certain target cells.

In the sequence of SARS-CoV-2 S protein, some putative cholesterol recognition consensus motifs were identified in both the NTD and CTD of S1 subunit. Biochemical studies confirmed that SARS-CoV-2 S protein and RBD can directly bind cholesterol, and potentially the high-density lipoprotein (HDL) components [75] . These interactions would promote the endocytosis of SARS-CoV-2 virion via scavenger receptor B type 1 (SR-B1) mediated cholesterol uptake (Figure 1) . Thus, the expression of SR-B1 can enhance the internalization of SARS-CoV-2, which further increases the efficiency of viral entry in an ACE2-dependent mechanism [75] . Since the binding of HDL to SARS-CoV-2 S involves both the NTD and RBD, the NTD-targeting monoclonal antibodies that block the cholesterol-binding site on SARS-CoV-2 S can significantly inhibit HDL-enhanced SARS-CoV-2 infection. Similar inhibitory effect can also be observed by treatment with SR-B1 antagonists which impairs cholesterol uptake [75] . As SR-B1 is co-expressed with ACE2 in human pulmonary tissue and several extrapulmonary tissues, SR-B1 may play an important role in the multi-organ damage resulting from SARS-CoV-2 infection [76, 77] .

In addition to visceral organs, SARS-CoV-2 has also been shown to invade the immune cells and neurons [78, 79] . Some of these cells do not express ACE2, and thus might be infected via other alternative receptors. Two recent studies reported that the SARS-CoV-2 S protein may also bind CD147 [80] and CD4 [81] (preprint) molecules (Figure 1) . The CD147 is a type I transmembrane protein that interacts with several extracellular and intracellular molecules, and plays critical roles in the infection of Plasmodium falciparum and SARS-CoV [82, 83] . It is expressed in many cells including epithelial, neuronal, lymphoid, and myeloid cells, which may facilitate SARS-CoV-2 to invade the immune and nervous systems. Indeed, J o u r n a l P r e -p r o o f Journal Pre-proof Wang et al. showed that the CD147 directly binds to the RBD of SARS-CoV-2 S protein with high affinity [80] . The expression of human CD147 allows SARS-CoV-2 to infect the non-permissive BHK-21 cells, and the loss of CD147 or treatment with anti-CD147 antibody or soluble CD147 extracellular domain inhibits SARS-CoV-2 replication [80] . These 

Given the critical role of S protein for virus entry, it is a very important target for antiviral intervention and also the major antigen for developing vaccines. Many neutralizing antibodies (nAbs) targeting different epitopes of SARS-CoV-2 S protein have been reported, and some of them have shown promising efficacies in clinical trials [61, [89] [90] [91] [92] . Most of the potent nAbs target the RBD of S protein, making it a hotspot for eliciting antibodies and an ideal molecular entity for developing subunit vaccines [91, 93, 94] . Some antibodies targeting the NTD can also achieve effective neutralization by different mechanisms [61, 75] , such as posing steric hinderance for receptor engagement by RBD or impairing the interactions with potential (co-)receptors/co-factors that bind the NTD. Additionally, some antibodies may target the S2 subunit or the S1/S2 interface to prevent the conformational changes of S protein for membrane fusion [93] . As more alternative or auxiliary mechanisms for SARS-CoV-2 J o u r n a l P r e -p r o o f entry are being discovered, the candidate nAbs intercepting different steps of SARS-CoV-2 entry will continue to increase, which offer more chances to identify highly potent therapeutic antibodies for clinical usage.

On the other hand, some small molecule inhibitors are also promising drug candidates for blocking SARS-CoV-2 entry. For example, an anti-influenza drug Arbidol could neutralize SARS-CoV-2 by interfering with viral attachment to host cells, and has been used for clinical treatment of COVID-19 in China [95] . Molecular dynamics simulation analyses revealed that Arbidol may bind to both RBD and ACE2 at the contacting interface, with a higher affinity for RBD. The presence of Arbidol would impair the interactions between S and ACE2 to prevent viral entry [96] . Moreover, several fusion inhibitory peptides have been developed with potent antiviral efficacies in vitro, which bind to the HR1 domain of S2 subunit and prevent the conformational changes required for membrane fusion [97] [98] [99] [100] [101] [102] . In addition, developing inhibitors for the host proteases that proteolytically activate the S protein, such as furin and TMPRSS2 inhibitors, is also a promising strategy to block SARS-CoV-2 infection in various susceptible cells [25, 103-105].

The entry of SARS-CoV-2 into host cells is a complicated process and involves a panel of 

Antigen: a molecule presented on the outside of a pathogen that can induce host immunity. It can be any forms of molecules that derive from the pathogen, and can be recognized by host immune cells to induce the production of antibodies or specific T-cells.

Efficacy: the capacity of therapeutics to treat a certain disease. It is an evaluation of the effectiveness of therapeutics or drugs.

Epitope: a portion of the antigen that can be recognize by the immune system, either antibodies or T-cells. For an antibody, the epitope is the region it directly interacts with in the antigen.

Mortality rate: a measure of ratio of death cases within the infected populations. It is an indicative parameter for the virulence of a specific pathogen.

Neutralizing antibody (nAbs): a group of antibodies that can protect the host cell from invasion by pathogens. The neutralizing antibodies can bind to the pathogen to inactivate its infectivity.

Pathogenicity: the potential capacity of a pathogen to cause a disease in its host. It is a similar term to virulence for viral pathogens, both of them are indicators of potential harms to hosts.

Positive-sense RNA virus: a group of viruses with a single-strand RNA genome whose sequence is consistent with the mRNA that encodes the viral proteins.

Small molecule inhibitor: a group of inhibitory molecules with small molecular weight, in contrast the other large molecule inhibitors (such as antibodies). They can bind to certain specific targets to block their activities or functions. in Netherlands [109] . A year later, the HKU1 coronavirus was identified in Hong Kong, China from an elderly patient with pneumonia [110] . Since then, this virus has been found in human populations around the world. The first case of SARS-CoV infection was found in Guangdong, China in late 2002 [5] . The epidemic spread to over 30 countries and ended in compared to SARS-CoV and MERS-CoV, but it seems to be more efficient in transmission among human populations. All of the three highly-pathogenic HCoVs are thought to originate from wild animals, potentially with a common naturally host, bats [2, 112] .

J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f

How many alternative receptors or co-receptors, beyond the major receptor ACE2, exist for SARS-CoV-2 entry?

Are ACE2/TMPSS2 alone sufficient to mediate SARS-CoV-2 infection? Whether other co-receptors/co-factors are necessary to facilitate the ACE2-dependent viral entry?

What is the role of CD4 for mediating SARS-CoV-2 entry into T helper cells in cooperation with ACE2? How does CD4 interact with the S protein?

How is CD147 involved in SARS-CoV-2 entry and what is its specific function?

How many copies of ACE2 actually bind to a S trimer during the authentic viral entry process?

Are the different ACE2 molecules in sufficient close proximity to allow simultaneous interactions with a trimeric spike?

How many trimeric spikes are required for producing the fusion pore, and further triggering a productive fusion event?

What is the trigger signal for S1 head dissociation, the binding of multiple ACE2 molecules, or proteolysis at the S2' site, or both of them?

How do the NTD-interacting receptors, e.g. AXL, modulate the conformation of S protein and induce membrane fusion?

What is the host spectrum of SARS-CoV-2 in various domestic and wild animals?

How many SARS-CoV-2 related coronaviruses are there in animal reservoir and what are their potential capacity to infect humans?

What are the key determinants for the host-jump of SARS-CoV-2, and potentially related viruses, to enable human infection?

How can we design antibodies and vaccines to counteract the emerging SARS-CoV-2 variants?

How can we develop broad-spectrum coronavirus inhibitors or vaccines based on the S proteins?

J o u r n a l P r e -p r o o f

The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2

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

A novel coronavirus from patients with pneumonia in China

A new coronavirus associated with human respiratory disease in China

Epidemiology and cause of severe acute respiratory syndrome (SARS) in

People's Republic of China

Household transmission of SARS-CoV-2: a systematic review and meta-analysis

The assessment of transmission efficiency and latent infection period in asymptomatic carriers of SARS-CoV-2 infection

Middle East respiratory syndrome

Coronaviruses: an overview of their replication and pathogenesis

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

SARS-CoV-2 infects cells following viral entry via clathrin-mediated endocytosis

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

Host cell proteases controlling virus pathogenicity

Role of hemagglutinin cleavage for the pathogenicity of influenza virus

Loss of furin cleavage site attenuates SARS-CoV-2 pathogenesis

TMPRSS2 and furin are both essential for proteolytic activation of SARS-CoV-2 in human airway cells

SARS-CoV-2 entry into human airway organoids is serine protease-mediated and facilitated by the multibasic cleavage site

Proteolytic activation of SARS-CoV-2 spike at the S1/S2 boundary: potential role of proteases beyond furin

Proteolytic cleavage of the SARS-CoV-2 spike protein and the role of the novel S1/S2 site

Multiorgan and renal tropism of SARS-CoV-2

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

SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes

Mechanisms of SARS-CoV-2 Transmission and Pathogenesis

AXL is a candidate receptor for SARS-CoV-2 that promotes infection of pulmonary and bronchial epithelial cells

Interaction network of SARS-CoV-2 with host receptome through spike protein

Identification of sialic acid-binding function for the Middle East respiratory syndrome coronavirus spike glycoprotein

Structures of MERS-CoV spike glycoprotein in complex with sialoside attachment receptors

Canine respiratory coronavirus, bovine coronavirus, and human coronavirus OC43: receptors and attachment factors

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

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

Neuropilins: role in signalling, angiogenesis and disease

Structural basis for selective vascular endothelial growth factor-A (VEGF-A) binding to neuropilin-1

Sequence dependence of C-end rule peptides in binding and activation of neuropilin-1 receptor

HDL-scavenger receptor B type 1 facilitates SARS-CoV-2 entry

Specific ACE2 expression in small intestinal enterocytes may cause gastrointestinal symptoms and injury after 2019-nCoV infection

ACE2 expression in pancreas may cause pancreatic damage after SARS-CoV-2 infection

Neuroinvasion of SARS-CoV-2 in human and mouse brain

Infection of human lymphomononuclear cells by SARS-CoV-2

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

SARS-CoV-2 uses CD4 to infect T helper lymphocytes

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

A noncompeting pair of human neutralizing antibodies block COVID-19 virus binding to its receptor ACE2

A human neutralizing antibody targets the receptor-binding site of SARS-CoV-2

Human neutralizing antibodies elicited by SARS-CoV-2 infection

Structural basis for neutralization of SARS-CoV-2 and SARS-CoV by a potent therapeutic antibody

Potent neutralizing antibodies against SARS-CoV-2 identified by high-throughput single-cell sequencing of convalescent patients' B cells

Structurally resolved SARS-CoV-2 antibody shows high efficacy in severely infected hamsters and provides a potent cocktail pairing strategy

The anti-influenza virus drug, arbidol is an efficient inhibitor of SARS-CoV-2 in vitro

Unraveling the mechanism of arbidol binding and inhibition of SARS-CoV-2: Insights from atomistic simulations

Intranasal fusion inhibitory lipopeptide prevents direct contact SARS-CoV-2 transmission in ferrets

Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion

Structural basis of HCoV-19 fusion core and an effective inhibition peptide against virus entry

The anti-HIV drug nelfinavir mesylate (Viracept) is a potent inhibitor of cell fusion caused by the SARS-CoV-2 spike (S) glycoprotein warranting further evaluation as an antiviral against COVID-19 infections

Design of potent membrane fusion inhibitors against SARS-CoV-2, an emerging coronavirus with high fusogenic activity

In silico design of antiviral peptides targeting the spike protein of SARS-CoV

Identification of a new human coronavirus

Characterization and complete genome sequence of a novel coronavirus, coronavirus HKU1, from patients with pneumonia

Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia

Bat origin of human coronaviruses

J o u r n a l P r e -p r o o f