key: cord-1056577-xf8dq3ec
authors: Emrani, Jahangir; Ahmed, Maryam; Newman, Robert H.; Thomas, Misty D.; Mowa, Nathan; JeffersFrancis, Liesl; Teleha, John C.
title: SARS-COV-2, infection, transmission, transcription, translation, proteins, and treatment: A review
date: 2021-10-28
journal: Int J Biol Macromol
DOI: 10.1016/j.ijbiomac.2021.10.172
sha: 63dd85e72e3bacf46d7b733a6b2aa4971af344ef
doc_id: 1056577
cord_uid: xf8dq3ec

In this review, we describe the key molecular entities involved in the process of infection by SARS-CoV-2, while also detailing how those key entities influence the spread of the disease. We further introduce the molecular mechanisms of preventive and treatment strategies including drugs, antibodies, and vaccines.

. In addition, body temperature is raised, causing fever in an attempt to kill (i.e., denature) the virus while facilitating the immune response. [30] [31] In patients who develop more severe disease, SARS-CoV-2

induces an aberrant host immune response. Overproduction of proinflammatory cytokines leads to a so-called -cytokine storm‖ which, if not remedied with the help of immunomodulators that regulate cytokine production or drugs like dexamethasone or blood thinners, can lead to death. [32] [33] [34] [35] This -cytokine storm‖, can adversely affect several organs, including the liver, kidneys, and lungs. 32, 36 The latter leads to breakdown of lung epithelial cells that line the air sacs in lungs, causing the air sacs to fill with fluid. This induces pneumonia and, in severe cases, acute respiratory distress syndrome (ARDS) that can cause lung failure and death. Studies have shown that levels of certain cytokines can be correlated with the severity of COVID-19 symptoms. 32 SARS-CoV-2 has an enhanced rate of transmission compared to the 2002 SARS-CoV. This is due to several characteristics, both of the virus (i.e., SARS-CoV-2) and its associated disease (i.e., . For instance, active virus can remain viable on some surfaces for up to 9 days and in the indoor air for several hours, thus increasing the chances of exposure. 37 Likewise, differences in the severity and onset of symptoms of COVID-19 compared to SARS may lead to increased contact with infected individuals. For example, during the SARS-CoV epidemic of 2002, mortality rates were nearly twice that currently observed for COVID-19 pandemic (9.6% vs. 5.4%, respectively), 10, 12 and infected individuals exhibited clear symptoms of respiratory distress almost immediately. 38 2 is rapidly evolving mechanisms to increase contagiousness and subvert existing immune defenses. [42] [43] Clearly, additional information is needed to understand the global risks these new variants pose.

After the initial sequencing of the SARS-CoV-2 genome in December 2019, 16 the viral genome has been sequenced numerous times in order to detect mutations and identify variants. [44] [45] [46] The genome of SARS-CoV-2 is comprised of a single-stranded RNA molecule housed inside a fatty acid membrane ( Figure 2 ), known as the envelope. 47 The viral RNA, which is capped and polyadenylated, contains a 5' leader sequence of 70 It is important to note that while most living organisms possess DNA as their fundamental genetic material, using RNA as the basis of the genome is unique to viruses. 16 Steps in SARS-CoV-2 viral replication. SARS-CoV-2 spike (S) glycoprotein and ACE2 on host cell surface interact and virus enters the host cell. Viral genomic RNA is released into the cytoplasm of the host cell, and the single-stranded positivesense genome is transcribed to produce the viral papain-like protease (PLpro) and 3C-like serine protease (3CLpro), which cleave the two large polyproteins (pp1a and pp1ab) into 16 mature nonstructural proteins (NSPs), including two replicase polyproteins (RNA-dependent RNA polymerase (RdRp) and helicase (Hel)). Mature NSPs and the RdRp and Hel proteins are gathered into replication−transcription complexes (RTCs) for viral replication and transcription. RTCs synthesize negative-strand guide RNA (gRNA) and a set of subgenomic RNAs for viral replication and transcription. The newly produced subgenomic RNAs are translated into viral structural proteins such as the S, membrane (M), and envelope (E) proteins. These proteins are inserted into the membrane of the rough endoplasmic reticulum (ER) and then transported to the ER-Golgi intermediate compartment (ERGIC) to assemble with the N protein-encapsidated RNA to form viral particles. Virions are then released from the cell through exocytosis. The red boxes indicate where processes can be inhibited using named compounds in parenthesis.52 caption and figure from Ref 52.

3) accessory proteins (Table 1) . Many structures of SARS-CoV-2 proteins have been described in the literature and have been compared with those of other coronaviruses. 66 The variation between these proteins accounts for the observed differences in each virus's contagiousness and infectivity in human cells. 

Structural analysis of proteins and protein complexes can provide key insights into the molecular basis for their observed function. Therefore, researchers have examined the structure of several SARS-CoV-2 proteins and related complexes. Traditionally, X-ray J o u r n a l P r e -p r o o f crystallography has been used to determine high resolution three-dimensional protein structures important for determining biological function and drug design. [67] [68] [69] Though X-ray crystallography is a very detailed and powerful method, it is often limited by difficulties associated with protein crystalization caused by size and flexibility constraints. In addition, due to their flexibility, it is difficult to observe glycosylation patterns on the surface of crystallized proteins. Finally, since crystals require static positioning within a crystal lattice, it is very difficult to observe and predict conformational changes and protein dynamics without assuming movement between crystals in different static conformational states. Therefore, as an alternative technique, many structural biologists have begun to use cryogenic electron microscopy (cryo-EM) to determine protein structure. [70] [71] During a cryo-EM experiment, the protein is deposited frozen onto a metal grid in a single molecule layer. The deposited layer is then irradiated with low energy electron beams and a 2-D image of the protein is obtained. By adding additional layers and using a computer to collect and sort the data, a 3D image of the protein is obtained. With cryo-EM, conformational changes and protein dynamics can also be recorded. In recent years, the quality of the images from cryo-EM experiments has improved to resolutions that are comparable to those obtained using crystallography. [72] [73] [74] Because of these technologies, several structures of SARS-CoV-2 S-protein in a complex with the ACE2 receptor have been solved. 8, 53, [75] [76] The S-protein The S-protein of SARS-CoV-2 is a 150 kDa transmembrane protein embedded into the surface of the viral envelope. As mentioned previously, S-protein binds to ACE2 receptors on the surface of host cells to facilitate viral entry. 8, 77 Several groups have solved the threedimensional structure of the S-protein, thus providing valuable insights into its overall shape, plasticity, and specific target interactions. 8, 53-54, 72, 75 The S-protein consists of an S1 subunit that binds the host cell receptor and an S2 subunit that is responsible for fusion of the viral envelope with host-cell membranes. In addition, S-protein has a receptor binding domain (RBD), composed of approximately 230 amino acids, that binds to specific sequences of the ACE2 receptor. The protein is fully glycosylated and forms a homotrimer made of A, B and C J o u r n a l P r e -p r o o f chains embedded within the viral envelope (in Figure 9A and 9B, glycosylation sites are shown in dark grey). Interestingly, the S1 subunit has several domains that have been shown to vary in function depending on the specific viral strain. This variation leads to its ability to use alternative host cell recognition targets.

Recently a cryo-EM structure of the SARS-CoV-2 S-protein ectodomain trimer was solved. 8, 54 The result suggests that the SARS-CoV-2 S-protein adopts conformations similar to those reported for both the SARS-CoV and MERS-CoV S-proteins. As observed in other -coronavirus S-glycoproteins, the SARS-CoV-2 S1 subunit takes on a V-shape and harbors three human ACE2-recognition motifs in its closed state (known as the receptor binding domain or RBD shown in Figure 9C ).Structural information shows that these motifs are buried, and therefore an opening of the structure is likely required for interactions with ACE2. This interaction would initiate a conformational change that would subsequently allow S2 protease cleavage, leading to membrane fusions and viral entry. In comparison to SARS-CoV, which uses S-protein residues Y422, L472, N479, D480, T487, and Y4911 for binding to ACE2, the SARS-CoV-2 Sprotein may use amino acids L455, F486, Q493, S494, N501, Y505 for binding to ACE2. [78] [79] [80] [81] The differences in the amino acids promote stronger binding interactions between the SARS-CoV-2 S1 RBD and ACE2 receptors on the host cell. While cryo-EM is a beneficial strategy to elucidate the overall protein structure of S1, it is not an optimal method to identify the structure of the sugars that are covalently linked to the surface of the protein. [82] [83] [84] The sugars play important roles in stabilizing the proteins to aid in folding. In addition, they have been shown to contribute to viral host immune evasion tactics. Because of their importance, the molecular composition and the structure of these sugars have been analyzed through mass spectrometry. 85 S-protein is heavily glycosylated, undergoing glycosylation on multiple asparagine (Asn) or . The amine functional group of asparagine (Asn) functions as a nucleophile to promote N-linked glycosylation, in which a carbohydrate chain (e.g., N-acetyl glucosamine (GlcNAc)) is added to the protein chain. In general, a carbohydrate chain is added to an Asn residue when it is flanked C-terminally by X-serine or X-threonine, where X is any amino acid other than proline. In the case of O-linked glycosylation, the hydroxyl group of threonine or serine acts as the nucleophile to promote conjugation of GlcNAc or Nacetyl galacosamine (GalNAc). See ref 79

After being conjugated to Asn or Ser, N-acetyl glucosamine (GlcNAc) is further glycosylated by the enzyme GTase to produce D-galactose-GlcNAc. 87 Ser686. 92 The presence of O-glycosylation at Thr323 and Ser325 of the S1 subunit of SARS-COV-2 has been correlated with the active structure for the protein, which leads to the biological function. 93 These differences can have a bearing on vaccine production, as they can influence how the S-protein interacts with ACE2 receptor. 94-95 Figure 7 . Structures of the SARS-CoV-2 S-glycoprotein. A) Cartoon diagram of the 3D structure of the S-glycoprotein solved using cryo-EM to 3.46 Å (PDB ID: 6VSB). The S-glycoprotein forms a trimer composed of an S1-subunit (pink), an S2-subunit B (green) and an S3-subunit (blue). This structure represents the prefusion confirmation and was found to have 22 glycosylation sites (dark grey). B) 90 o rotation of A. Here, the receptor binding domain (RBD) is located at the top of the structure. The RBD of the subunit C is boxed in black. C) Cartoon diagram of the RBD of the S-glycoprotein (green) bound to the host receptor ACE2 (orange) (PDB ID: 6M0J). This structure was solved to 2.45 Å using X-ray protein crystallography. D) Cartoon diagram of the SARS-CoV-2 RBD (green) bound to a SARS-CoV-2 specific antibody (the antibody heavy and light chains are colored dark blue and light blue, respectively). This structure was solved using X-ray crystallography to 2.85 Å (PDB ID: 7BWJ). It is important to note that the antibody binding site is at the same position as the ACE2 binding site, thereby blocking interactions between the virus and the host receptor. All figures were made using PyMol. domain of SARS-CoV-2 N-protein, which is required for dimerization and oligomerization, interacts with the M-protein through the CL region. 112 The NTD binds to RNA and contains a many positively-charged amino acids residues, which aid in binding the negatively-charged RNA. The amino acid sequence of SARS-CoV-2 Nprotein is 90% similar to that of SARS -CoV. 113 Most of the differences are due to the presence of these positively-charged amino acids in the SARS-COV-2, which are absent in other CoVs.

In addition to the structural proteins, there are also 16 non-structural proteins (Nsps) in SARS-CoV-2, including polyproteins, nucleoproteins, and membrane proteins, each with varying functions (Figure 8 ). For instance, Nsp1 and Nsp2 are involved in modulating the immune response. 114 Nsp1 has 180 amino acids and binds to the small subunit of the ribosome, stopping synthesis of antiviral proteins. In addition, Nsp1 halts all host protein synthesis by cleaving host mRNA. 47, 115 As a result, production of type-1 interferons (which provide innate immunity) is halted, disabling the host defense mechanisms against the virus.

Nsp2, on the other hand, influences cell division by altering the host cell cycle (Figure 3 ). 116 Nsp3, or papain-like protease (PL pro ), is the largest of all Nsps and plays many roles. Along with Nsp5, it is responsible for cleavage of viral polyproteins into functional units. [117] [118] Nsp3 also plays a role in the onset of cytokine storm, assembly of viral particles, and, via interactions with Nsp4, in formation of double membrane vesicles. 119 Finally, Nsp3 both inhibits the host enzyme poly-[ADP-ribose] polymerase (PARP), whose role is to block viral replication, and suppresses the expression of interferon genes (required for inhibition of viral infections).

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

Nsp9 is a single-stranded RNA-binding protein that plays a role in viral replication. Nsp12

is an RNA-dependent RNA polymerase (RdRp) and nsp13 is a helicase. 80, 118 Both are essential for RNA replication. Nsp12, along with Nsp7 and Nsp8, recognize the RNA template and facilitate processivity. 120 ( Figure 8A 121 In SARS-CoV-2, it has been shown that the heterodimer Nsp7-Nsp8 and individual Nsp8 can bind with the RdRp. 82 The nsp13 helicase contributes to RNA synthesis and 5'-RNA capping by unwinding double stranded RNA in a 5'-3' direction to enable elongation by the RdRp. The RdRp (Nsp12) from SARS-COV-2 has the structure of a typical polymerase, which resembles a right hand with finger, thumb, and palm domains. 122 When overlayed with the RdRp of SARS-CoV, there is only a root mean squared distance (rmsd) of 0.82 for 1,078 of the C-alpha for SARS-COV-2,

indicating that there are very few structural differences between the two proteins. 82 Despite these small differences, the amino acid sequence and the active sites of the RdRps from the two viruses are nearly identical. 123 This has enabled the rapid development of inhibitors against SARS-CoV-2 using the lessons learned from the previous inhibition studies on SARS-CoV.

Nsp14 is an exoribonuclease protein that acts as methyl transferase for N7 guanine in mRNA cap synthesis. For activation, Nsp14 requires Nsp10 to form a heterodimer. 124 Nsp15 is a nidoviral RNA uridylate specific endoribonuclease (NendoU) that protects from attacks by host immune system. 125 Meanwhile, Nsp16 is a 2'-O-methyltransferase, which uses SAM for its methyl source. It complexes with nsp10 but has two S-adenosyl-L-methionine (SAM) binding sites of its own. Binding between SAM and nsp16 is mediated by both hydrophobic and ionic interactions. 126 The TMPRSS2 protein, which is also expressed in prostate, salivary gland, colon, and stomach, is a chymotrypsin family serine protease (492 aa) composed of three domains. 64, [139] [140] It mediates the cleavage of S-protein within the S1-S2 linker (R685) and at S2ʹ (R815). The S1-S2 cleavage site is facilitated by the presence of several repeated basic arginine residues. 64, 137, 141 Additional help is provided to the virus by Furin, a host cell protease that cleaves at the polybasic furin cleavage site (e.g., with the PQRESRRKK/GLF sequence of amino acids) in Sprotein, promoting cell fusion and entry of the virus into human cells. 64, 79, [135] [136] 141 After cleavage at the S2ʹ site, the fusion peptide is then inserted into the host membrane. The two HR regions, HR1 and HR2, in S2 domain form antiparallel six-helix bundles (6-HB). Once inside the host cell, the virus can effectively replicate and initiate the process of infection and disease development. 136, 142 The RBD from SARS-CoV-2 S-protein has higher binding affinity (~5 kcal/mol) towards human ACE2 than the corresponding RBD from SARS-CoV S-protein, which is higher than its affinity for ACE2 from other animals. 64, 143 This higher affinity, according to contact map analysis, is due to greater electrostatic interactions between the virus's S-protein and ACE2 receptor. 144 Computational alanine scanning analysis has identified key residues responsible for binding of the three RBDs of SARS-COV-2 with ACE2. 145 Accordingly, SARS-CoV-2 uses almost all (90%) of the tyrosine (Tyr) and glycine (Gly) residues that are present at its ACE2 interface for binding. Molecular dynamics simulation on membrane-bound ACE2 supports the presence of about seven additional hydrogen-bonded contacts between the SARS-CoV-2 RBD and ACE2. 146 Type II alveolar cells of lungs, myocardial cells, esophagus upper and stratified epithelial cells, and digestive tract and kidneys. 53, [150] [151] [152] The initial contact may also occur on the skin, throat, or in the gastrointestinal (GI) tract.

The SARS-CoV-2 genome is different from all previously identified coronaviruses, including SARS-CoV and MERS-CoV. These differences likely account for differences in cellular targets, as SARS-COV-2 targets host nasal epithelium in addition to many other organs, in contrast SARS-CoV, which does not target the nasal epithelium but targets lung, trachea/bronchus, stomach, small intestine, distal convoluted renal tubule, sweat gland, parathyroid, pituitary, pancreas, adrenal gland, liver and cerebrum. 158 The SARS-CoV-2 S-protein exhibits even less homology with the MERS-CoV S-protein, which recognizes dipeptidyl peptidase-4 (DPP-4) as a specific receptor for host cell entry (as opposed to ACE2). 79, 141, [159] [160] Aside from molecular factors, other factors such as age, smoking, and gender may also The SARS-CoV-2 genome sequence was first published in January 2020 and is 79.5% similar to the genome of SARS-CoV. 66, 80, [164] [165] Both SARS-CoV and SARS-CoV-2 have Sproteins that are nearly 80% identical in composition. [166] [167] [168] [169] Interestingly, the relatively small number of differences between the two S-proteins can greatly influence parameters such as affinity between the S-protein and its receptor (ACE2). [170] [171] The increased affinity of S-protein for ACE2 allows SARS-CoV-2 to attach to human cells much more strongly than the SARS-CoV. This characteristic of SARS-CoV-2 enhances both the contagiousness and infectivity of the virus. RdRp, are also targeted by small molecule inhibitors, which binding to the enzyme active site.

In some cases, these drugs are already available. For instance, several in silico screening efforts have shown similarities between SARS-CoV-2 and other non-coronaviruses, enabling the use of a number of available antivirals and drugs that are currently on the market. [177] [178] [179] [180] 

Much of the current efforts in combating SARS-CoV-2 is focused on finding ways to block the interactions between ACE2 and the viral S-protein, sometimes through specialized maneuvering that stabilizes the spike. 181 The difficulty in doing this is that ACE2 is also present on the cells in other parts of the body that are not targets of the virus. Therefore, nontissue specific inhibition of ACE2 could lead to unwanted side effects. 182-183 ACE2's physiological role in the cell is in the maturation of angiotensin, which is a hormone that controls blood pressure by regulating blood vessel constriction. Consequently, the inhibition of ACE2 can lead to several complications, including cardiovascular disease and hypertension. 53 As a result, alternative strategies are being explored to block the interaction between the SARS-

CoV-2 S-protein and ACE2 directly using therapeutic antibodies. The ideal therapeutic antibody would specifically bind the S-protein and prevent it from interacting with the ACE2 receptor, achieving a similar result as blocking ACE2 directly without the negative side effects. 77 Alternatively, designing small peptides or small molecules that bind to different subunits of the SARS-CoV-2 S-protein will prevent the subunits from interacting with ACE2 and entry of virus into the cell. As previously stated, the S-protein is initially cleaved into S1

and S2 subunits by the host cell protease, furin. S1 facilitates receptor binding by engaging with the host cell membrane while S2 provides structural support and regulates the fusion with the host's epithelial cell membrane. For this reason, blocking the cleavage of the S-protein could also be a potential strategy for inhibiting viral entry. 8, 54, 77, [184] [185] [186] Using knowledge gained from HKU1, a common cold virus, and MERS virus, scientists found two small loops of amino acids that held two -helices in the spike together. When the Sprotein binds to human cells, the coil-like structure is released and the two helices and one loop are elongated to bring the human cell and the virus close together for fusion. By adding up to six proline residues to the SARS-CoV-2 S-protein, scientists believe that they can prevent the -spring‖ from being released, which would prevent the fusion of SARS-CoV-2 with human cells. 181

Due to the relatively small size of the SARS-CoV-2 genome and recent rapid advances in whole genome sequencing technologies, scientists were able to sequence the genome of the SARS-CoV-2 rather quickly once it was isolated. 80, 165 As a result, the sequence has been used to determine the primary structure (i.e., linear amino acid sequence) of the viral proteins. Once a protein's primary sequence has been determined, computational modeling programs can be 

At the onset of the COVID-19 pandemic, a list of 50,000 compounds with potential antiviral properties was provided by the American Chemical Society (ACS) Central Science. The compounds were extracted from the CAS registry, which contains 160 million compounds. 188 The identified compounds were anti-infective, enzyme inhibitors, or have shown an effect on the respiratory system. 189 Recently, the cryo-EM structure of the RdRP was determined (Figure 8) . 74, 82, 190 The structural information led to computational simulations (in silico) of the interactions between RdRp and potential drug candidates. Similarly, knowledge of the structure of the S-protein and main protease (M-protein or M pro ) has allowed for similar studies. 82, 170, [191] [192] To make these studies possible, computational resources around the world have been made readily available to COVID-19 researchers by major international computer centers inside and outside the U.S.

during the COVID-19 pandemic. 193 In addition to in silico analysis, animal models have been used to model infection, including mice that express the necessary receptors and succumb to similar symptoms as humans. 189, 194 SARS-CoV-2 receptor ACE2 and TMPRSS2 are primarily expressed in bronchial transient secretory cells. This affords the opportunity to devise appropriate treatments through docking studies. 83, 135 J o u r n a l P r e -p r o o f

Researchers at Novartis had quickly discovered that the M pro from SARS-CoV-2 (cysteinemain protease) was very similar to the protease from the previous corona viruses. This includes the actives site cysteine, which serves as a target for identifying inhibitors. As a result, sixteen potential inhibitors were identified using computational methods. [195] [196] [197] A select number of identified inhibitors were synthesized and tested in models. Chemical structures were then further refined based on the results of the inhibition studies. A new smaller set of inhibitors were then obtained and some of the final compounds have entered randomized clinical trials. [198] [199] Computational studies have suggested that lopinavir, oseltamivir, and ritonavir may bind to SARS-CoV-2 M pro . [198] [199] A similar approach could be used to develop inhibitors for all other viral proteins, including RdRp and the S-protein. More recently, it was discovered that drug repurposing studies for COVID-19 provided compounds that were harmful to the body as their mechanism of action was misunderstood in the initial studies. 200 As a result, some of such drugs like hydroxychloroquine, Amiodarone, and Sertraline, cause phospholipidosis in the infected host cells which mistakenly in the studies was correlated with antiviral efficacy.

As previously discussed, RdRp is responsible for replication of the viral RNA ( Figure 8 ). 201 Remdesivir (See Table 2 )( an inhibitor of this enzyme, was originally developed as anti-Ebola drug, [202] [203] [204] [205] and soon entered the Phase I clinical trial against COVID-19. [205] [206] In addition, remdesivir was tested in combination with chloroquine and the combination compared with chloroquine alone. 194, [207] [208] Remdesivir in combination with interferon beta was also shown to be effective against SARS-CoV-2. [208] [209] Based on clinical trial results, and the compassionate use of this drug, 18, 203, 210 remdesivir received Emergency Use Authorization by the FDA. 205, [211] [212] [213] [214] However, similar studies conducted in China suggested that remdesivir did not offer any benefit compared to placebo. 205, [215] [216] [217] Considering all the results, clinicians think of remdesivir as a helpful treatment for shortening recovery time but not a cure. 215, 218 Phase III Clinical trials of RdRp inhibitors, are currently underway. Remdesivir was recently approved by FDA. [205] [206] 213 Two other inhibitors of viral RdRp's, favipiravir and the ribonucleoside analog, EIDD-2801 (See Table 2 ), were originally developed against HIV and hepatitis B. [219] [220] [221] In animals infected J o u r n a l P r e -p r o o f with SARS-CoV and MERS-CoV, EIDD significantly reduced viral titer and loss of body weight.

Also, in vitro, in primary human airway epithelial cells (HAECs), EIDD reduced SARS-CoV-2 reproduction in a dose-dependent manner. 189, 222 Remdesivir (administered through IV) and

EIDD-2801 (administered orally) both hamper viral replication by targeting RdRp. 223 Interestingly, EIDD, unlike other antiviral compounds, cannot be overcome by resistance through mutations in the virus. EIDD-2801 has a pyrimidine as its base structure altered with a N-hydroxycytidine. The drug EIDD-1931 has two tautomers, one tautomer is an oxime that mimics uridine and base pairs with adenosine, the other tautomer mimics cytidine, and forms hydrogen bonds with guanosine. 224 to be given to patients as soon as infection is detected. Because of its mechanism of action, this drug will work against many RNA viruses, including MERS-CoV, HIV, Ebola, H1N1, and SARS-CoV. However, since other compounds that are similar to EIDD-2801 have been linked to birth defects in animals, expecting mothers or those who intend to become pregnant should avoid this drug. 226 Mechanism of incorporation of these drugs into RNA is shown in Figure 11 . 227 Figure 11 . Comparison of the mechanism of actions of antivirus Remdesivir, favipiravir, EIDD-2801, and EIDD-1931 through incorporation into DNA. 227 Other potential drugs under study against COVID-19 include interferon, ribavirin, tocilizumab, sarilumab, lopinavir, and chloroquine.To date, no benefit has been observed with lopinavir-ritonavir treatment of patients. 118, [228] [229] As additional potentially useful drug target, protein kinases also have a crucial role in entry, spread, and replication of the virus. AK-1 inhibitors, caffeic acid and its ester, propolis, ketorolac, and triptolide may help patients by inhibition of these crucial stages of virus life J o u r n a l P r e -p r o o f cycle. However, these compounds are not easily available to the body due to their solubility problems. 176, 230 Cathepsin C inhibition has also been pursued as an option to save overburdened lungs in serious cases. 231 Structures of three such inhibitors, Brensocatib, Abu-Bip-CN, IcatCxpz41 are included in Table 2 . In terms of mechanism, in the inhibitor compound containing nitrile group, the nitrile group is said to interact with the cysteine 234 of Cathepsin C, resulting in a thioimidate complex and inhibition ( Figure 12 ). 231 Thioimidate complex 

Blood pressure drugs are thought to increase the expression of ACE2 receptors (though this idea has been disputed by more recent studies). [244] [245] [246] Therefore, initially, it was thought that people taking these drugs would have an increased number of ACE2 receptors on their cell surfaces, thus providing more sites for the virus to attach and making the patient more susceptible to infection. However, more recent evidence suggests that blood pressure drugs actually protect patients against the induced lung injury, as described in more detail below. 18, 244, [247] [248] Since COVID-19 is more serious disease in older patients, they are also more likely to take ACE inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) for hypertension, heart disease, and cardiovascular disease. These drugs regulate the renin-angiotensin equilibrium.

ACEIs prevent ACE1 from converting angiotensin I to angiotensin II. Angiotensin II controls lung injury and severe inflammation preventing angiotensin II from binding to its receptors. To J o u r n a l P r e -p r o o f lower blood pressure, these drugs keep the level of angiotensin II at a desired level by effecting the renin-angiotensin equilibrium ( Figure 13 ). 244, 247 In the lungs, heart, kidneys, nose, and GI tract, ACE2 helps regulate the angiotensin II levels by shifting this equilibrium to the right or the left, as needed. For instance, when angiotensin II levels are too high, ACE2 converts angiotensin II to angiotensin 1-7, which is inactive. When angiotensin II levels are too low, more angiotensin II is produced. 53 If the level of angiotensin II gets too high, fibrous tissue will form in the heart, kidney, and lungs, which can lead to severe fibrosis in these organs.

Antihypertensive drugs like captopril, Lisinopril, and losartan either stop the production of angiotensin II or make it inactive. Towards the beginning of COVID-19 pandemic, many scientists warned against using ACEIs and ARBs in COVID-19 patients, 249 [even though a prolonged absence of these drugs could kill the patients by increasing their hypertension.

Subsequently, it was discovered that using these drugs does not, in fact, harm COVID-19 patients). 244 In fact, they may actually help. This is because, during COVID-19 infection, the virus binds to host ACE2 and occupies host ACE2 sites. As a result, the ACE2 needed to convert angiotensin II to angiotensin 1-7 is no longer available, causing angiotensin II levels to go up. The increase in angiotensin II levels causes cell death and injury in lung and heart. The injury in lung causes the release of cytokines (small proteins), which enhance the inflammation reaction and leads to more cell death. 33 

Antibodies are proteins of the immune system that bind to a specific antigen (such as virus before it infects a host cell). The process involves both the innate and adaptive immune responses. 171 Antibodies bind to the antigens on the surface of infected cells (see Figure 14) and Due to similarity of viruses, the antibody raised against the SARS-CoV S-protein can also prevent infection by binding S-proteins from SARS-CoV-2 and MERS-CoV. 254-257 251 However, because the S-protein in SARS-CoV has fewer sugar moieties on its surface, antibody binding is weaker to the SARS-CoV-2 S-protein. As a result, for treatment purposes, antibodies are isolated from convalescent plasma collected from patients who recently recovered from COVID-19. Currently, scientists are working to identify the gene in the B cells that code for the SARS-CoV-2 antibody to then recombinantly express those genes as therapeutics. This approach has already worked in the case of SARS. 26, 188 In another approach used by Regeneron, genetically modified mice were injected with the Sprotein. B cells were then isolated from the mouse and among the B cells, those that produced J o u r n a l P r e -p r o o f the best monoclonal antibody were isolated, compared with best antibody from patients, and then mass produced through cell culture. 251 Palivizumab, a monoclonal antibody produced in this manner, is effective against respiratory syncytial virus. With financial support from the U.S. government, using VelociMouse technology, a mouse genetically modified to have human immune system, Regeneron developed monoclonal antibody against the S-protein of SARS-CoV-2, which received EUP from FDA approval. 74, 258 Tychan, a company from Singapore, started its clinical trial in China. Working with AbCellera, Eli Lilly also developed its monoclonal antibody (Ly-CoV555), a neutralizing antibody, designed to prevent the SARS-CoV-2 from entering the cells. The antibody targets the S-protein of the virus and thus prevents infection by clearing the virus from the body. One out of three doses were given to people with mild symptoms of COVID-19 or placebo. In these studies, the rate of hospitalization in those patients who received the real dose was reduced to 1.7% compared to 6% for the placebo. 259 Another antibody against S-protein (JS016) is a human monoclonal neutralizing antibody developed by Junshi Biosciences. When combined with Ly-CoV555, this product makes a strong antibody. 260 Some of the difficulty for these techniques lies in scaling production. As a result, with the immediate threat of this viruses, it is important to note that these companies have been able to cut the time of the development and evaluation of these therapies from 10-12 months possibly to 5-6 months. 261

Vaccines trick our bodies to perceive it as an antigen and cause our immune system to mount an attack to destroy the antigen. 262 

The fight against SARS-CoV-2 has been a major challenge for our best scientists, massive investments of pharmaceutical companies and governments, and our available technology. In a very short window of time, significant advances were made in finding ways to lessen the spread of the virus and prevent and treat the viral infection through therapeutics and vaccines.

Understanding the mechanism of interaction between the viral S-protein and ACE2 along with the structure and function of the RdRp, M pro , viral RNA, and various proteases have been instrumental in discovering novel treatment methods. 171, 265 We have seen that biochemically,

SARS-CoV-2 shows higher affinity towards the ACE2 receptor compared to SAR-CoV. Despite this small difference, fortunately there are many similarity between these two viruses, which has facilitated the discovery and development of antibody therapies, and vaccines to tame the COVID-19 Pandemic. 256 Vaccine development used many different techniques, some very new, but all focused on inducing the production of neutralizing antibodies against the spike protein in the body. [266] [267] [268] [269] In addition to developing vaccines, scientists also explored other potential strategies that have not been discussed here. They include targeting the viral proteases, therapies based on cytokines, and nucleic acids. Knowledge of these and other relevant technologies is essential, not only for fighting the SARS-CoV-2 of today, but also to combat future viruses and pathogens.

Despite development of so many prevention and treatment tools in a short time period, mutation in SARS-COV-2 virus RNA may lead to drastic changes in the viral genome and render all or some of these strategies useless. 5, 16 Fighting a mutating virus is possible, but as experience has shown, may be challenging. Thus, the most effective way of combating the virus is to vaccinate the whole population and follow safety guidelines such as social distancing, wearing masks, sanitization, and contact tracing. However, experience has shown that for political or other reasons, these are not fully achivable.

Just as in the case of the Spanish flu of 1918, SARS-COV-2 will continue to dominate the news for years to come. In fact, it is expected that this virus, like other viruses such as flu virus remain within the human population for the foreseeable future. As younger people acquire immunity, older adults will remain susceptible until heard immunity is established within the population. The potential for childhood vaccines for long-term protection as in the case of other childhood vaccines is still uncertain as we continue to understand the immune response of all segments of the population including children. In the meantime, new experimental treatments, along with social distancing and proper hygiene will be necessary in conjunction vaccines to protect the susceptible population. In the process, cooperation of national and international leaders is important for fighting the current pandemic.

Corresponding Author *E-mail: emrani@ncat.edu

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. ‡These authors contributed equally.

Any funds used to support the research of the manuscript should be placed here (per journal style). 

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