key: cord-0947771-ccau1qwc authors: Zehra, Zainy; Luthra, Manav; Siddiqui, Sobia Manaal; Shamsi, Anas; Gaur, Naseem; Islam, Asimul title: Corona virus versus existence of human on the earth: A computational and biophysical approach date: 2020-06-05 journal: Int J Biol Macromol DOI: 10.1016/j.ijbiomac.2020.06.007 sha: 53cf34591152157c179356172800d7b4fe1d7b70 doc_id: 947771 cord_uid: ccau1qwc SARS-CoV-2 has a positive sense RNA genome of 29.9 kb in size, showing high sequence similarity to the BAT-CoV, SARS-CoV, MERS-CoV. SARS-CoV-2 is composed of 14 open reading frames (ORFs), which encodes for a total of 27 proteins divided into structural and non-structural proteins (NSPs). The fundamental structural protein-encoding genes are a spike protein (S) gene, envelope protein (E) gene, a membrane protein (M) gene, and a nucleocapsid protein (N) gene. They make about 33% of the entire genome and are vital for the viral life cycle. Rest 67% is distributed among different NSPs (such as M(pro), helicase, and RNA-dependent RNA polymerase) encoding genes across the ORFs, which are involved in virus-cell receptor interactions during viral entry. Researchers are trying to formulate vaccines, therapeutic antibodies or protein-targeted antiviral drugs to control the spread. This review proceeds stepwise through the COVID-19 outbreak, structural and genomic organization, entry mechanism, pathogenesis, and finally highlighting the essential proteins involved at each step that might be potential targets for drug discovery. Currently, approved treatment modalities consist of only supportive care and oxygen supplementation. This review is established on the current knowledge that has expanded on structural motifs and topology of proteins and their functions. CoV was more epidemic in Saudi Arabia. Similar manifestations were detected as acute lung injury often followed by pulmonary and renal failure. Dromedary camels were involved in the infection, which were thought to be the most common source of transmission from animal to human. Nevertheless, its risk factors in human remained unclear [9, 10] . The infection of MERS-CoV further virus spread to France, UK, Spain, Italy and Tunisia. The fatality rate of MERS-CoV infected persons was about 35% [11] . High fatality rates of 9.5% and 34.4% were reported for SARS-CoV and MERS-CoV respectively. Fortunately, the fatality rate of SARS-CoV-2 is only 2.4% reported which is significantly low [12] . All of these three pathogenic viruses belong to the genus betacoronavirus. Other previously known coronaviruses that can infect human includes human coronavirus 229E (HCoV-229E), OC43 (HCoV-OC43), NL63 (HCoV-NL63), HKU1 (HCoV-HKU1) [13] . The metagenomics next-generation sequencing technology identified that the genetic material J o u r n a l P r e -p r o o f is highly conserved between the two with an overall identity of 96%. In fact, according to , the homology between the SARS-CoV-2 and RaTG13 (SARS-like coronavirus in bats) is 96% at the whole-genome level [18] , depicting bat as the zoonotic source of newly evolved SARS-CoV-2 [19] . SARS-CoV-2 found to be an enveloped virus with particle size of 100-160 nm in diameter and as the name suggests "corona" (means crown), it has crowned like projections when seen under electron microscopy [20] . It has a positive sense RNA as genetic material having size of 29.9 kb (Fig. 1 ) roughly distributed among adenosines (30%), cytosines (18%), guanines (20%), and rest thymines (32 %) [21] . The genome is compacted into a helical nucleocapsid often enclosed by a lipid bilayer. Also, the RNA genome of CoVs is largest among all the RNA viruses [22] . non-structural open reading frames are also present [23] . The orf1ab is the largest gene in SARS-CoV-2, encoding a polyprotein (PP1ab). Another gene orf1a encodes for a polyprotein (PP1a). Two-thirds of viral RNA situated in the first ORF (ORF1ab) encodes a 7096 residues long polyprotein. Thus, both orf1a and orf1ab are translated to produce PP1a and PP1ab polyproteins, which are cleaved by the proteases that are encoded by ORF1a to yield 15 non-structural proteins (NSPs). Sequence studies have noted variations between SARS-CoV-2 and SARS-CoV such as the lack of 8a gene or in variation in the number of base pairs in 8b and 3c genes in SARS-CoV-2 [24] . In addition, around 380 substitutions are recognized within the genome of SARS-CoV-2 when compared to previously known coronaviruses in a systemic study, which may have affected the functionality and pathogenicity of this novel virus [24] . These said proteins are extensively studied for devising new antiviral agents against COVID-19 because the genome, as well as 3D structures, indicate that main drug-binding pockets are probably conserved across SARS-CoV-2, SARS, and MERS [23] . For coronaviruses, entry is found to be often biphasic in nature, which means it can enter the cell when near the cell surface or in the late endosomal phase [8] . In addition, a characteristic coronavirus fusion peptide (fragment of the fusion protein) that works in a calciumdependent manner is employed during membrane fusion. Different receptors are identified NSP1,2,3,4,5,6,7, 8, 9, 10, 12, 13, 14, 15, 16 receptor for MERS-CoV [9] and receptor of HCoV-229E is found to be aminopeptidase N (aka CD13). Lung epithelial cells are the primary targets for SARS-CoV-2, and binding takes place between receptor binding domain of class I viral fusion protein called spike (S) glycoprotein and ACE-2 receptor of lung epithelial cells [10] (Fig. 3) . Molecular interactions studies and crystal structure analysis, also confirms that spike protein of SARS-CoV-2 binds to human angiotensin-converting enzyme 2 (ACE2) receptor and readily infects ciliated bronchial cells and type II pneumocytes found in lungs. Unfortunately, SARS-CoV-2 has more affinity for ACE2 receptors than SARS-CoV due to a single N501T mutation in the S protein of SARS-CoV-2 [25] , which aids in their transmission from host to host. It is noteworthy that the expression level as well as allele frequency of ACE2 receptors varies among populations. These factors may correlate the disease susceptibility and sequence polymorphism. The binding of the viral S protein to ACE2 induces a negative feedback loop. As the level of ACE2 drops, its counterpart enzyme ACE picks up its role of converting substrate angiotensin I to angiotensin II. Elevated levels of angiotensin II results in the profound binding to its receptor, AGTR1A resulting in the increased pulmonary vascular permeability [26] . A study of 99 patients infected with SARS-CoV-2 showed that females were less susceptible to infection than males, and older males with comorbidities J o u r n a l P r e -p r o o f were more likely to be infected with SARS-CoV-2, and highlighted insights into the role of ACE2 in the SARS-CoV-2 pandemic [27, 28] . Advance research in the field of structural and molecular biology shall reveal the complexities of the molecular mechanism that prompts coronavirus S-mediated membrane fusion. SARS-CoV-2, the seventh member of the coronavirus family has the characteristic manifestation of both lower and upper respiratory tracts with symptoms like dry or productive cough, sore throat, lassitude followed by fever. [29] . The sterility of a C-section coupled with isolation measures immediately after, rule out the possibility of infection during or after birth, strongly raising the suspicion of in utero transmission of the virus. The neonate needed external ventilator support for twelve hours, then, he was extubated and put on CPAP. The outcome was favourable and he did not require antibiotic support. Lab tests and imaging were found to be normal throughout [30] . Infected patients have shown high leukocyte counts, abnormal respiratory functioning, or boosted pro-inflammatory cytokines such as TNF-α, MIP1α, Interleukin-2, 7, and 10. Additionally, C-reactive protein, erythrocyte sedimentation rate, and D-dimer formation also peaks with infection [31] . Journal Pre-proof J o u r n a l P r e -p r o o f COVID-19 showed some unique clinical features that include the targeting of the lower airway as is evident by symptoms like rhinitis, sneezing, and sore throat (Fig. 4) . Also, patients infected with COVID-19 were found to have developed intestinal symptoms like diarrhoea [32] , while only a few of MERS or SARS patients had diarrhoea [31] . Upon entering the host, SARS-CoV-2 has been reported to stay in the respiratory tract for a few days, which is the asymptomatic period. It has been found that the virus persists for up to 14 days in severe cases and 8 days in non-severe cases. The viral load profile is found to peak at the time of onset of symptoms, and so is transmissible easily at an early stage of infection. A high viral load is found in severe cases and can be potentially used as a marker of case severity and prognosis. The viral RNA particle is found in the faeces for 5 days after the onset of the symptom and persists up to 4 to 5 weeks, as well as in total blood, urine, serum, and saliva [32] . The main mode of transmission is through fomites and respiratory droplets. Rates of transmission appear to be similar for asymptomatic and symptomatic patients. According to the data revealed by European Centre for Disease Prevention and Control, the environmental sustainability of active SARS-CoV-2 is up to 3 hours in the air after aerosolization, around 24 hours on chipboard, and almost 3 days on stainless steel or plastic. Based on the assessment made by the Chinese government, the WHO indicated that about 80 J o u r n a l P r e -p r o o f C-terminal together comprise the ED [39] , both are crucial for the successful entry of coronavirus into a host cell. S1 initiates the first step of viral entry, as it contains the receptorbinding domain. S2 later mediate the fusion of the cell and viral membranes. The critical step of cleavage of S protein is generally mediated by host protein convertase that allows for the fusion sequences to be exposed as required for the fusion. Cleavage of S protein at S1/S2 site mediates cell-cell fusion and is an essential step for the entry of S protein into human lung cells. This vital step is governed by cellular protease furin that performs this cleavage. SARS-CoV-2, like MERS-CoV depends on this furin-mediated pre-cleavage of S proteins at the S1/S2 site for the activation of S protein by TMPRSS2 in lung cells, which fail to express robust levels of cathepsin L. Inhibitors of furin and TMPRSS2 can serve as possible therapeutic options in COVID-19. A recent study reported that the inhibitor of TMPRSS2 blocks SARS-CoV-2 infection [40] . However, an interesting point that should be noted is that furin is needed for normal development unlike TMPRSS2 and hence, obstructing furin for longer periods can be associated with unwanted toxic effects [40] . Genomic analysis of the novel coronavirus revealed that its spike protein differs from those of close bat CoV relatives, in the sense that it has a specific site, which gets activated by an J o u r n a l P r e -p r o o f cleavage site can be expressed as 'gain of function' that allowed a bat CoV to infect humans [41] . It can also transmit between different hosts through gene recombination or mutations in the receptor-binding domain, leading to a higher mortality rate. The SARS-CoV-2 virus can enter human bronchial epithelia through contact with the ACE2 receptors on them, making this virus highly host-specific. Recently, the crystal structure of the spike protein's receptor-binding domain of SARS-CoV-2, in complex with human ACE2, was released by Wang and Zhang's group [25] . Interestingly, a study conducted revealed that ACE2 expression is higher in males than females. Supporting this notion 61.8% deaths were reported in males in a sample study carried out in New York. Additional findings suggest that the binding of SARS-CoV-2 to ACE2 is synergistic to the expression of ACE2 [44] . The main components of the S1 domain are the N-terminal domain (NTD) and the C-terminal domain (CTD). This S1 domain is marked as a major antigen on the surface of the coronavirus. Receptor binding domain (RBD) at the head region of S1 recognizes the host cell receptor (ACE2). It is reported that the glutamine 394 and lysine 31 are the key residues of RBD and ACE2 respectively that are involved in this interaction [25] initiating the membrane fusion between viral particles and the host's receptor. There are 18 residues of ACE-2 that interact with the RBD (contain 14 amino acids) of spike protein and for this contact, K341 of ACE-2 and R453 residue of RBD play the most important role (38) . A small section of the S1 region formed between 318 to 510 amino acid residues are plenty for strong attachment to the peptidase domain of ACE2 [25] . According to another report six RBD residues: L455, F486, Q493, S494, N501 and Y505 are actively involved in ACE2 receptor binding and determining host range of SARS-CoV-2 [45] . S2 contains basic elements like hydrophobic fusion peptide needed for membrane fusion (Fig. 6 ). X-ray crystallographic analysis demonstrates that HR1 and HR2 domains combinedly form the 6-HB fusion core in the S2 subunit of SARS-CoV-2. The structure is crucial for membrane fusion in SARS-CoV- M pro also called chymotrypsin-like protease (3CL pro ) and the presence of cys-his dyad on the active site is responsible for its protease activity (47) . The most commonly found recognition sequence of M pro is Leu,Gln♦Ser,Ala,Gly (where ♦ denotes the cleavage site) [58] . M pro is majorly involved in the cleavage of PPs to generate (NSPs) which later compile into the replicase-transcriptase complex (RTC) [59] . M pro exists as a homodimer having a molecular mass of 33.797 KDa, as determined by mass spectroscopy [59] . The 2.1 Å high-resolution crystal structure reveals the two-fold symmetry of the M pro molecule where the two subunits are held together by a salt-bridge interaction between Glu290 of one protomer and Arg4 of the other [59] (Fig. 7) . Each monomer has three distinct domains: Domains Ⅰ and Ⅱ display antiparallel β-barrel structures whereas domain III is a large antiparallel globular structure made up of 5 α-helices arranged. Domains II and III, are connected using a long loop like segment of domain III. The substrate binds to a pocket created between Domains I and II. It is highly conserved among all the CoVs. On the other hand, the most variable regions were α-helices and surface loops domain III [59] . The two monomers are arranged in a perpendicular orientation such that the domain II of one is in contact with the NH2-terminal residues aka 'N-finger' of others. This dimerization is essential for the formation of substrate binding sites, thus also affect catalytic efficiency of the protease, and thereby maintain the shape of the substrate-binding pocket of S1 protein [59] . SARS-CoV-2 Mpro is made up of 306 amino acid residues. Crystal structure analysis suggests that Thr25, Thr26, Leu27, His41, Ser46, Met49, Tyr54, Phe140, Leu141, Asn142, Gly143, Cys145, His163, Met165, Glu166, Leu167, Pro168, Phe185, Asp187, Gln189, Thr190, Ala191, and Gln192 are found in the active site pocket [60] . PL pro cleaves at the borderlines of NSP1/2, NSP2/3, and NSP3/4. It works in association with M pro to cleave the poly protein into NSPs [56] . PL pro at its catalytic core domain contains 316 amino acids, which is responsible for cleaving replicase substrates, and a consensus sequence at cleavage sites usually found to be LXGG [59] (Fig. 8) . Major antiviral drugs are designed against M pro and PL pro proteases. Inhibiting the activity of these enzymes could hamper viral replication. Many studies have recently reported that drugs targeting the main protease can be possible therapeutics in COVID-19. A recent literature used repurposing of FDA approved drugs to identify potential leads that inhibited the SARS-CoV-2 M pro and can play a key role in COVID-19 therapeutics [60] . The absence of any similar human protease makes M pro an easy target for antiviral drug development [59] . Nonetheless, care should be taken to avoid the chances of host toxicity by ensuring that the cleavage sequence for the host protease should be different [59] . Another approach could be to mutate Ser139 and phe140 positions, which are crucial sites involved in the dimerization of 3CLpro [58] . J o u r n a l P r e -p r o o f The helicase unwinds the double-stranded RNA segment into single strands by hydrolysing NTPs. This enzyme prefers ATP, dATP, and dCTP as substrates. Due to its sequence conservation in all coronaviruses, this helicase is an easy target to develop antiviral drugs [61]. The ADP binding site and the nucleic acid binding site of NSP 13 are considered in molecular docking studies while designing inhibitors but a serious limitation is the nonspecificity of inhibitors that may cause host toxicity. RdRP is the structurally conserved RNA polymerase that executes RNA replication and transcription with the help of its cofactors NSP7 and NSP8 (Fig. 9 ). This complex forms the largest (160 kDa) unit involved in RNA synthesis. It also possesses the characteristic nidovirus NSP12 N-terminal domain having kinase-like structural fold [62] . J o u r n a l P r e -p r o o f It is involved in the various steps of the central dogma of novel coronavirus. It has two main domains: The N-terminal exoribonuclease (ExoN) domain has an important part to play in proofreading and preventing any fatal mutations, and the other is the C-terminal domain act as a guanine-N7 methyltransferase (N7-MTase) required for mRNA capping [63] . It is one of the RNA-processing enzymes encoded by the coronavirus genome. It forms a sixunit endoribonuclease that cleaves 3' end of uridines [64] . J o u r n a l P r e -p r o o f It acts as a cofactor and forms an assembly with NSP14 and NSP16. In the heterodimer conformation NSP16 is positioned over the NSP10 monomer. NSP 10 has an overall conserved structure comprising of a N-terminus made up of two α-helices, a central β-sheet domain, and a C-terminus domain having various loops and helices [65] . This HE enzyme when present is localized in the envelope of CoV. Usually, in [40, 65] . Camostat mesylate (serine protease inhibitor) is well known for its action against TMPRSS2 activity, which makes it a potential drug candidate to test for SARS-CoV-2 [65] . As per Centres for diseases control and prevention CDC, two types of tests are available for scan are also employed in the testing of COVID-19 [26] . Currently approved treatment modalities consist of supportive care teamed with oxygen supplementation performed via non-invasive ventilation, or through mechanical ventilation. Severe cases may also be treated with antibiotics against bacterial infection and vasopressor support. Clinicians from the USA and Italy have reported several other complications such as acute myocardial damage, thromboembolic phenomena such as PE, and sudden death. Around 12 trials are in progress to test possible treatments against COVID-19. Wang et. al from Wuhan Institute of Virology screened some of the FDA approved anti-virus or antiinfection drugs and found that remdesivir and chloroquine could effectively prevent the viral growth in cell-based assay with EC50 of 0.77 and 1.13 μM, respectively [67] . Repurposing these drugs happens to be the most practical approach in response to rapidly increasing positive cases. Other antiviral drugs, monoclonal antibodies, and antibody-rich plasma from recovered patients are also under trials. On-going therapies can be broadly classified into two on the basis of their targets; first approach targets the virus entity by blocking the key enzyme responsible for viral life processes (replication, translation etc.) or by preventing the entry of virus particle into human cells. The other approach stress on immune system functioning J o u r n a l P r e -p r o o f either by boosting innate/humoral immunity or by inhibiting inflammatory response that led to pulmonary failure [26] . On 20 March, WHO announced the launch of SOLIDARITY, a coordinated effort to collect scientific data rapidly. The study design has been kept simple so that even hospitals with an overwhelming number of patients can participate. The physician simply records the date the patient left the hospital or died, the duration of the entire stay, and whether the patient required ventilation or oxygen. The design is not blinded, and the WHO website randomizes the patient to one out of four drug regimes, or local standard care. For this study WHO has chosen an experimental antiviral remdesivir; the antimalarial drughydroxychloroquine, a combination of antiretroviral drugs lopinavir and ritonavir; and this combination plus IFNβ. Kong et al., recently introduced a docking server for docking small molecules, peptides and antibodies against potential targets of COVID-19. This can be very useful for researchers across the world for predicting target-ligand interactions for COVID-19 [68] . The evolution of novel coronavirus and the eventual outbreak of COVID-19 has put the burden on the medical fraternity and the scientific community to identify the components of this viral entity including its genome, replication cycle, proteome as well as modes of transmission. This can only be achieved with collaborative efforts backed up by advances in molecular and structural virology. Viral proteins are identified as potential targets since they are involved in each phase of the viral life cycle. In the present review, we discussed the structure, function, and host-virus interactions of various SARS-CoV-2 proteins based on a thorough review of the latest literature available. We hope our review will give a useful groundwork for the devising new drugs against COVID-19. 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