key: cord-1012941-d2hsemjv
authors: Shamsi, Anas; Mohammad, Taj; Anwar, Saleha; Amani, Samreen; Khan, Mohd Shahnawaz; Husain, Fohad Mabood; Rehman, Md. Tabish; Islam, Asimul; Hassan, Md Imtaiyaz
title: Potential drug targets of SARS-CoV-2: From genomics to therapeutics
date: 2021-02-09
journal: Int J Biol Macromol
DOI: 10.1016/j.ijbiomac.2021.02.071
sha: 6ce3803840cd939769ce822c4960a5c9be2a1913
doc_id: 1012941
cord_uid: d2hsemjv

The emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) from China has become a global threat due to the continuous rise in cases of Coronavirus disease 2019 (COVID-19). The problem with COVID-19 therapeutics is due to complexity of the mechanism of the pathogenesis of this virus. In this review, an extensive analysis of genome architecture and mode of pathogenesis of SARS-CoV-2 with an emphasis on therapeutic approaches is performed. SARS-CoV-2 genome consists of a single, ~29.9 kb long RNA having significant sequence similarity to BAT-CoV, SARS-CoV and MERS-CoV genome. Two-third part of SARS-Cov-2 genome comprises of ORF (ORF1ab) resulting in the formation of 2 polyproteins, pp1a and pp1ab, later processed into 16 smaller non-structural proteins (NSPs). The four major structural proteins of SARS-CoV-2 are the spike surface glycoprotein (S), a small envelope (E), membrane (M), and nucleocapsid (N) proteins. S protein helps in receptor binding and membrane fusion and hence plays the most important role in the transmission of CoVs. Priming of S protein is done by serine 2 transmembrane protease and thus plays a key role in virus and host cell fusion. This review highlights the possible mechanism of action of SARS-CoV-2 to search for possible therapeutic options.

proteins. There is a difference in epidemiological dynamics of SARS-CoV-2 and SARS-CoV and MERS-CoV and hence former is comparatively more infectious and lethal. 

Various organs like lungs, heart, arteries, kidney, intestine, etc. possess Angiotensin-converting enzyme 2 (ACE2) attached to their cell membrane. ACE2 is a monocarboxypeptidase that plays an essential role in maintaining the balance of the renin-angiotensin system [12] . This enzyme acts as a cell receptor for SARS-CoV [13] . It is through this enzyme that SARS-CoV virion particles enter into the cell and its genome is then translated into PPs, via the host ribosome, which further gets processed by proteolysis. PP degradation is mediated by main protease (M pro ) and papain-like protease (PL pro ) which chop it into smaller fragments to support replication and helps in forming new virions [14] . The resulting PP1a and PP1ab are processed into the J o u r n a l P r e -p r o o f individual NSPs that form the viral replication and transcription complex [15] . The PPs move into endoplasmic reticulum (ER) membranes and transfer through the ER-to-Golgi intermediate compartment, where contact with N-encapsidated, newly formed genomic RNA fallouts in budding into the lumen of secretory vesicular compartments, and then virions are secreted from the infected cell by the process of exocytosis [15] . Similarly, SARS-CoV-2 also uses ACE2 as a way in the ACE2-expressing cells, thus it can be assumed that both targets a similar spectrum of cells. According to literature, macrophages and pneumocytes are the main targets of SARS-CoV [16] . The extra-pulmonary spread of SARS-CoV was also reported as ACE2 expression is not restricted to lungs only. A high transmission rate of SARS-CoV-2 in contrast to SARS-CoV can be attributed to more efficient exploitation of cellular attachment factors that mediates vigorous infections of ACE2 expressing cells in the upper respiratory tract. ACE2 occurs mainly in type II alveolar epithelial cells (pneumocytes). It is with these ACE2 molecules, the S-protein of SARS-CoV-2 interact Expression of ACE2 is slightly elevated in males in comparison to females which can be attributed to higher incidences of COVID-19 in men. CoVs have been known to modulate the affecting cells by their cytocidal activity and immune-mediated mechanisms [17] . CoVs infection results in cytopathic effects, as well as apoptosis and cell degradation.

The binding of ACE to SARS-CoV-2, as was in SARS-CoV, may lead to its increased expression, resulting in alveolar damage. Based on biophysical and structural analysis, in contrast to SARS-CoV, SARS-CoV-2 showed approximately 10-20 times higher affinity for ACE2 [18] . Finally, it can be said that SARS-CoV-2 entry in the host cell is initiated by binding to the ACE2 receptor. Apart from ACE2, there is another host cell factor that plays a key role in virion entry is the serine protease, Transmembrane protease serine 2 (TMPRSS2) [19] .

TMPRSS2 plays a key role in pathogenesis by cleaving S protein at S1/S2 and the S2' site and J o u r n a l P r e -p r o o f Journal Pre-proof helps in S protein priming that allows virion entry into the host cell and ultimately viral and cellular membrane fusion. Thus, TMPRSS2 can also serve as a potential drug target. Post binding, ss RNA of SARS-CoV-2 gets attached to the host cell ribosomes which lead to the translation of two co terminals large PPs. Figure 2 shows a brief outline of various factors performing different responsibilities in the life cycle of SARS-CoV-2. The PPs thus formed are further processed into 16 distinct NSPs by the action of two main proteolytic enzymes namely SARS-CoV-2 M pro and PL pro [14] . These smaller components further play different roles such as viral assembly, immune response modulation, and others. M pro can be considered as an important drug target among CoVs owing to its function in the processing of PPs that result from the translation of viral RNA. CoVs Like all pathogens, the mechanism of SARS-CoV-2 pathogenesis follows innate and the adaptive immune system as well [20] . 

The envelope spike (S) protein plays a crucial role in CoVs infection and pathogenesis [21, 22] .

SARS-CoV-2 has a highly glycosylated S protein that belongs to trimeric class I viral fusion glycoprotein. S protein has 1273 amino acid residues forming three subunits namely, S1, S2, and S2'. They undergo structural changes during the process of viral and host membrane fusion (Li, 2016) . S1 and S2 domains are responsible for receptor binding and membrane fusion respectively, while S2', a cleaved subunit of S protein, acts as a fusion peptide [23] . The process of viral infection is initiated when the virus binds to the human ACE2 cell surface receptor with its S1 subunit [19] .

The head region of S1 is known as receptor binding domain (RBD) which recognizes ACE2, with Glu394 of RBD and Lys31 of ACE2 playing a crucial role in receptor and S protein interaction [24] . This binding destabilizes the pre-fusion trimer that leads to the release of the S1 subunit and ultimately the transition of the S2 subunit to a more stable post-fusion conformation [25] . For attachment to host cell receptor, RBD of S1 endures hinge-like conformational changes that can conceal or reveal determinants of receptor binding transiently. These two states are known as -down‖ and -up‖ conformation with down conformation being referred to as stable and receptor unapproachable while up conformation as less stable receptor approachable state [26] . The function of the S2 subunit is to cause membrane fusion between the virions and the host cell. For this, S2 exists in three different conformations namely; pre-fusion native state, hairpin intermediate state, and post-fusion hairpin state viz. RBD is the most unpredictable feature of SARS-CoV-2 with maximum variation in the receptor-binding motif. This variation can be directly linked to variation in the mechanism of pathogenesis among different CoVs. An understanding of changing conformations of S protein that results in the entry of the virion into the mammalian cell can provide a breakthrough in COVID-19 therapeutics. Our recent study suggested that out of six residues of RBD of S1 subunit of SARS-CoV-2 (Leu455, Phe486, Gln493, Ser494, Asn501, and Tyr505) that are crucial for binding to ACE2, five differ from SARS-CoV [27] . The similarity between S protein of SARS-CoV-2, SARS CoV, and MERS

CoV is that in all these it exists in homologous trimeric conformation having three chains viz. A, B and C [28, 29] . Chain A and C show a high degree of a structural anomaly in the N terminal domain (NTDs) and RBDs as compared to chain B when they were aligned and visualized in PyMOL ( Figure 3 ). These deviations can provide a platform to develop different approaches that can be implicated in COVID-19 therapeutics. The trimeric spike glycoprotein (S) of SARS-CoV-2 is a key target for virus neutralising antibodies6 and the prime candidate for vaccine development [30] . Recent research reported the preclinical development of two BNT162b vaccine candidates, which contain lipid-nanoparticle (LNP) formulated nucleoside-modified mRNA encoding SARS-CoV-2 spike glycoprotein-derived immunogens [30] .

Journal Pre-proof 

The E protein plays a key part in the virion life cycle, particularly during viral morphogenesis and assembly [31, 32] . It is another structural protein that can serve as a potential drug target in COVID-19 therapeutics because it can form a pentamer and function as an ion channel, thus J o u r n a l P r e -p r o o f named as E channel or viroporin. Moreover, there are regions of high similarity in E proteins of BAT-CoV, SARS-CoV, and SARS-CoV-2. Interestingly, there is a subtle disparity amongst SARS-CoV-2 and MERS-CoV E proteins. These proteins can form ion channels, an important function in virus-host interaction [33] . Ion conductivity is considered a beneficial feature for viruses and thus in its pathogenesis [34] . E protein ion channel activity is also required for inflammasome activation [35] . E protein also plays an important role in intracellular protein trafficking as well as regulation and hence this is another aspect of E protein that can be used in COVID-19 therapeutics.

Another example of transmembrane glycoprotein is M protein which has three transmembrane domains, a characteristic trait of the membrane proteins. These are the structural blocks made up of 222 amino acids that provide a framework to the virion particle and aids in the structural assembly of the virus. This structural protein functions in harmony with E, N, and S proteins and aids in RNA packaging [36] . Another role played by M protein is intracellular homeostasis. M protein also helps in viral-specific humoral response and can elicit efficient neutralizing antibodies in SARS patients [37] . therapeutics. There is a high sequence similarity amongst N protein of BAT-CoV, SARS-CoV, and SARS-CoV-2 which implicates that Abs recognizing N proteins of SARS-CoV will be successful against SARS-CoV-2 also and thus, N proteins can be retorted as a diagnostic tool.

Apart from the above discussed structural proteins, Replicase proteins also play a key part in SARS-CoV-2 pathogenesis. The major part of the replicase genome is covered by the ORF1ab gene which encodes two major PPs i.e., pp1a and pp1ab. The replicase PP is made up of mainly three domains; the macro domain, the papain-like domain, and the main protease. These multifunctional proteins guide the degradation of host RNA and replication of viral RNA [38] .

These PPs are subsequently processed into 16 smaller NSPs through proteolytic enzymes, mainly the M pro and PL pro [14] , which cleaves the C and N terminal ends of these PPs respectively [39] . 

M pro is a vital cog of SARS-CoV-2 that can be an attractive drug target in COVID-19

therapeutics [14] . It is a crucial enzyme that works in cooperation with other components and helps in the replication and transcription of viral RNA M pro is also the most studied target for CoVs drugs as it is responsible for the processing of polyproteins required for the assembly of virus drugs. of the polyprotein replicase 1ab [42] . A recent study reported the crystal structure of SARS-CoV-2 providing a platform to develop COVID-19 therapeutics targeting M pro [14] . Design and development of safe and potential for SARS-CoV-2 can be achieved via targeting conserved enzymes residues of M pro [43] [44] [45] .

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

These refer to proteins that are not included in viral particles but function inside the infected cell playing several important roles viz. viral replication, controlling early transcription and modulates immune response [9] . NSPs are also found to be associated with helicase activity. Table 1 lists all the NSPs along with their proposed functions.

SARS CoV enters into the host cell with the help of its S protein whose S1 subunit binds to the receptor on the cell surface. In the cell line, other key players involved in this entry were found to be endosomal cysteine proteases cathepsin B and L (CatB/L) [48] and the serine protease TMPRSS2 [49] which are involved in the priming of S protein. The important fact is that only the activity of TMPRSS2 is crucial for viral spread and pathogenesis unlike the dispensable activity of CatB/L activity [50] (Figure 2) . Another study suggested that TMPRSS2 is a critical host cell SARS-CoV-2 also playing a role in its spread and pathogenesis [50] . A TMPRSS2

inhibitor approved for clinical use, camostat mesylate, blocked the entry and can provide a new avenue in COVID-19 therapeutics.

At present, SARS-CoV-2 is offering a major risk across the globe and there is no specific drug available to treat COVID-19. In the past, antiviral drugs have been used to treat other human J o u r n a l P r e -p r o o f

CoVs, but these have been rendered ineffective due to structural differences in SARS-CoV-2 as compared to other human CoVs. SARS-CoV-2 is far more pathogenic in contrast to other human

CoVs. The SARS-CoV-2 vaccine is still under development, and there is no specific drug at present and all other trial drugs have also been unsuccessful. A comparative genomics-based approach with earlier known human CoVs can provide a breakthrough in COVID-19

therapeutics. Figure 5 shows the SARS-CoV-2 life cycle with the depiction of different target sites that can be retorted in COVID-19 therapeutics. Thus, the need of the hour is to perform an extensive analysis of its genomics and its comparison with other pathogenic human CoVs as this detailed insight will provide a platform to understand the molecular basis of SARS-COV-2

pathogenesis. This review article provides an extensive investigation of the genome of SARS-COV-2 and its comparison with other human CoVs that enable us to identify the molecular way of pathogenesis. It also provides a brief insight into important proteins of SARS-CoV-2 that can act as possible drug targets and enlightened the differences in the structure of these proteins in comparison to other human CoVs. Table 2 

Protein Function

The exact function is biologically unique and unknown. Forms a previously unknown complex βbarrel fold with several unique structural features and contributes to the degradation of mRNA [51] . It is also involved in innate immune response antagonism [52] .

Nsp2 A replicase product, has no special known function but fund to involved in modulation of host cell survival signalling pathway by interacting with host PHB and PHB2 [53] 3.

Nsp3

Binds to viral RNA, nucleocapsid protein, as well as other viral proteins, and contributes in polyprotein processing [54] . It has also an important role in innate immune response antagonism. 4.

Nsp4

Plays a role in membrane rearrangement in association with Nsp3 thereby affecting viral replication.

Nsp5 3C-like proteinase and main proteinase involved in viral polyprotein processing during replication [55] . 6.

Nsp6

Transmembrane domain, plays a role in the initial induction of autophagosomes from the host endoplasmic reticulum. 7.

Nsp7

An RNA-dependent RNA polymerase works in association with Nsp8 [55] . Also stimulates the polymerase activity of Nsp12. The stoichiometric ratio of nsp7 and nsp8 is found to less than nsp12 [56] . Nsp7 and nsp8 increase nsp12 binding to the template-primer RNA [56] . 8.

Nsp8

Replicase capable of de novo initiation and has been proposed to operate as a primase in complex with nsp7. Crystallized together with the 10-kDa nsp7, forming a hexadecameric, dsRNAencircling ring structure [i.e. Nsp (7+8), consisting of 8 copies of both Nsps] [57] . The nsp12-nsp7-nsp8 complex also showed RNA polymerization activity on a poly-U template upon addition of ATP [56] .

Single-stranded RNA-binding protein mediate both viral replication and virulence [58] .

Acts as a stimulatory factor along with Nsp16 to execute its MTase activity, therefore plays an essential role in viral mRNAs cap methylation [59] . It also forms complex with Nsp14 and stimulates MTase activity. 11. Nsp11 Unknown

Nsp12 RNA-dependent RNA polymerase and also has nucleotidyltransferase activity [46] 13. Nsp13

The helicase unwinds the double-stranded RNA segment into single strands by hydrolyzing NTPs, involved in replication and transcription. 14.

Nsp14

Nsp14 has two enzymatic activities, an N7 methyltransferase activity and an exonuclease activity, involved in the unique proofreading system of CoVs [60] 15.

Nsp15 Mn(2+)-dependent Endoribonuclease activity [61] . A highly conserved nidovirus component with endoribonuclease activity acts in conjunction with the viral replication complex to limit the exposure of viral dsRNA to host dsRNA sensors [62] . 16 .

Nsp16 2′-O-ribose methyltransferase involved in MTase activity [63] .

J o u r n a l P r e -p r o o f [83] J o u r n a l P r e -p r o o f causing a reduction in viral replication; Can also work by binding and destabilizing celltransport proteins used to enter the nucleus. 14. Teicoplanin

Gram-positive bacterial infection

Not known Inhibit the activity of cathepsin L which potentially plays an important role in blocking viral entry in the cells - [84] 15. Tocilizumab/ sarilumab (mAb)

Rheumatoid arthritis

Inhibition of IL-6 may attenuate pulmonary inflammation and fibrosis Phase 3 and Phase 2/3: NCT04315298 [84] 16. Anti TNF-α agents Rheumatoid arthritis TNF-α TNF-α blockage leads to downregulation of proinflammatory mediators, including IL-1, IL-6, and granulocytemacrophage colonystimulating factor as well as cytokines and acute-phase proteins - [84] Conflicts of interest: None 

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Anas Shamsi: Conceptualization; Data curation; Formal analysis Validation; Visualization

Roles/Writing -original draft; Writing -review & editing, Taj Mohammad: Resources

Software; Validation; Visualization

Roles/Writing -original draft; Writing -review & editing, Saleha Anwar: Methodology; Writing -original draft; Investigation, Samreen Amani: Writing -review & editing, Mohd Shahnawaz Khan: Funding acquisition; Resources, Fohad Mabood Husain: Funding acquisition; Validation, Md. Tabish Rehman: Funding acquisition, Visualization, Asimul Islam: Investigation; Methodology