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\def\RunningAuthor{Shiva Prasad Kollur et al.}
\firstPage{442}
\articleType{Original Article}
\receivedDate{25 Apr 2020}
\acceptedDate{19 Jun 2020}
\revisedDate{05 May 2020}
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\title{Understanding the pathogen evolution and transmission prevention measures: Recent findings on molecular interventions towards COVID-19 therapeutics \textit{via }hints from the past}
\author{Vinusha~H~M\textsuperscript{1},  
            Chandan~Shivamallu\textsuperscript{2},  
            Shashanka~K~Prasad\textsuperscript{2},  
            Muneera~Begum\textsuperscript{1},  
            Gopinath~S~M\textsuperscript{3},  
            Chandrashekar~Srinivasa\textsuperscript{4},  
            Latha~K~Chennabasappa\textsuperscript{5},  
            Navya~Shree~B\textsuperscript{6},  
            Shiva~Prasad~Kollur\textsuperscript{*}\textsuperscript{7},  
            Veena~Malligere~Ankegowda\textsuperscript{8}, 
            Balasubramanian~S\textsuperscript{9}~\\[5pt]{\textsuperscript{1}Department of Chemistry, JSS Science and Technology University, Mysuru, Karnataka{\textendash}570006, India}~\\{\textsuperscript{2}Department of Biotechnology and Bioinformatics, JSS Academy of Higher Education \& Research, Mysuru{\textendash}570015, Karnataka, India}~\\{\textsuperscript{3}Department of Biotechnology, Davangere University, Shivagangotri, Davanagere{\textendash}577007, Karnataka, India}~\\{\textsuperscript{4}Department of Chemistry, Sarada Vilas College, Mysuru, Karnataka{\textendash}570004, India}~\\{\textsuperscript{5}Department of Education, University Grants Commission, Bangalore, Karnataka-56009, India}~\\{\textsuperscript{6}Department of Zoology, JSS College of Arts, Commerce and Science (Autonomous), Mysuru, Karnataka{\textendash}570015, India}~\\{\textsuperscript{7}Department of Sciences, Amrita School of Arts and Sciences, Mysuru, Karnataka{\textendash}570026, India}~\\{\textsuperscript{8}Department of Chemistry, Bangalore Institute of Technology, K.R. Road, Bangalore-560004, Karnataka, India}~\\{\textsuperscript{9}Department of Research, JSS Academy of Higher Education \& Research, Mysuru-570015, Karnataka, India}}

\begin{abstract}
The novel coronavirus pandemic has spread over in 150 countries as of March 2020. Approximately 900,000 people have been infected so far (WHO).  Preventive measures are been taken globally to contain the rapid spread of virus. Compared to 2002 SARS epidemic, COVID-19 is apparently less lethal but far more contagious as it spreads more easily among individuals. This review highlights ongoing progress in figuring out the structure of major proteins designing vaccines and therapeutics to combat COVID-19 while also concentrating on developing preventive steps to avoid the emerging infection of viruses.
\end{abstract}\def\keywordstitle{Keywords}

\begin{keywords}COVID-19,\newline SARS-CoV-2,\newline Phylogeny
\end{keywords}
\twocolumn[ \maketitle {\printKwdAbsBox}]
\makeatletter{\raggedright\textsuperscript{*}Corresponding Author\par Name:\ Shiva~Prasad~Kollur~\\ Phone:\ 8861676145~\\  Email:\ shivachemist@gmail.com 
        \par}\vspace*{-11pt}\hrulefill\par{\fontsize{12}{14}\selectfont ISSN: 0975-7538}\par% 
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\section{Introduction}
Coronaviruses, belonging to the Subfamily \textit{Coronavirinae } of the Family \textit{Coronaviridae, } are enveloped, positive sense, single-stranded RNA viruses (Figure~\ref{f-228a06663b5f}) that infect a broad host variety to produce diseases ranging from ordinary flu to life threatening illnesses such as the SARS, MERS and in the recent context, the COVID-19.


\bgroup
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\centering \makeatletter\IfFileExists{images/7e5fcffb-c9ee-4277-9a65-721222a90ae6-upicture1.png}{\includegraphics{images/7e5fcffb-c9ee-4277-9a65-721222a90ae6-upicture1.png}}{}
\makeatother 
\caption{\boldmath {3D medical animation of the structure and cross-sectional view of Human Coronavirus}}
\label{f-c8acbcb97e0d}
\end{figure*}
\egroup
\textit{Coronavirinae }subfamily is classified into four genera of \textit{a}, \textit{}, \textit{g}, and \textit{d}, based on their genome structures and phylogenetic relationships. While the \textit{a}- and \textit{\space }- coronavirus infections are restricted to mammals, the \textit{g}- and \textit{d}-coronaviruses have been reported to additionally infect the aves \unskip~\citep{818884:19569032}. The former genera of coronaviruses are found to cause the human respiratory complications termed as the Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome. Thereby gaining the alternate names of SARS- coronavirus (SARS-CoV) and MERS-coronavirus (MERS-CoV), respectively.

As enveloped viruses, the coronaviruses possess large, trimeric spike glycoproteins (S) as manifested in the Figure~\ref{f-228a06663b5f}. These S-glycoproteins or S-proteins are essential aids for infection due to their prominence in host receptor identification, mixture of viral and host cell membranes and the subsequent provision of viral entry into the host cell (Figure~\ref{f-c8acbcb97e0d}), \unskip~\citep{818884:19569055}.


\bgroup
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\makeatother 
\caption{\boldmath {Exhibiting Structure of Spike Protein 1SSK visualized using Chimera visualization tool}}
\label{f-228a06663b5f}
\end{figure}
\egroup
Viral diseases are considered a serious public health concern by the World Health Organization. In the past two decades, several viral outbreaks, such as the SARS in 2002, the Swine flu (caused by the Influenza A virus; subtype {\textendash} H11) in 2009, the MERS in 2012, and most recently the devastating pandemic of COVID-19 (caused by the SARS-CoV-2 a.k.a 2019-nCoV).


\bgroup
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\centering \makeatletter\IfFileExists{images/ffdb2b29-80cb-4de1-9227-f1a7212d4c9d-upicture3.png}{\includegraphics{images/ffdb2b29-80cb-4de1-9227-f1a7212d4c9d-upicture3.png}}{}
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\caption{\boldmath {Structure of 2019-nCoV}}
\label{f-768521028479}
\end{figure}
\egroup
The\textbf{\space }schematic of 2019-nCoV S primary structure 


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\makeatother 
\caption{\boldmath {Phylogeny of 2019-nCoV}}
\label{f-aac699b731e5}
\end{figure*}
\egroup
colored by domain. SARS Spike Glycoprotein, Trypsin-cleaved, Stabilized variant, C3 symmetry and the crystal structure of COVID-19 main protease in complex with an inhibitor N3 (Figure~\ref{f-768521028479}). 

The day's pandemic COVID-19, characterized by impenetrable respiratory complications, was first reported on 31 December 2019 at the Wuhan metropolitan area of the Hubei Province in the Republic of China. However, regional publications point out the start of infections classified as ``pneumonia of unknown etiology'' to the early December 2019. The Chinese national and local Centers for Disease Control and Prevention (CDCs) were reported to have organized outbreak investigation programs to detect and curb the infection. Constant global efforts have now assisted in recognizing the COVID-19 etiology to a novel coronavirus. The identified novel coronavirus was initially called the 2019-nCoV and subsequently renamed SARS-CoV-2 by the International Committee on Taxonomy of Viruses (ICTV) taking into regard the genetic similarities it shared with the severe acute respiratory syndrome causing SARS-CoV \unskip~\citep{818884:19569050}. The continuing SARS-CoV-2 threat has rapidly transpired into a pandemic, of unprecedented magnitude in the recent years, to be declared a ``public health emergency of international concern'' by the WHO, on 30 January 2020.

The phylogenetic tree was constructed by molecular evolutionary genetic analysis (MEGA) software based on the spike gene sequences, showing the evolutionary relationship of 2019-nCoV with predecessors strains of SARS-coronaviruses (Figure~\ref{f-aac699b731e5}). 

The SARS-CoV-2 is highly infectious has been found to be primarily occurring via human-to- human transmission through droplets of different size. The droplet particles which are {\textgreater}5-10 \ensuremath{\mu }m in diameter referred to as respiratory droplets. Whereas, the diameter {\textless}5\ensuremath{\mu }m are referred to as droplet nuclei. Considering the current evidence, COVID-19 virus is primarily transmitted between people through respiratory droplets and contact routes \unskip~\citep{818884:19569045}. However, evidences recommend a possible viral origin by the means of wild animals and birds. Additionally, the coronaviruses have evolved to become the major pathogens of growing pulmonary disease incidence \unskip~\citep{818884:19569030}. These viruses characterized by their positive-sense single- stranded RNA (+ssRNA) are of diverse distributions to an extent where they can actually be isolated from different animal species and can infect cross-species via infection mechanisms that are yet to be elucidated.

The term ``COVID-19'', in short for ``coronavirus disease 2019'', was declared on 11 February 2020 by Dr. Tedros Adhanom Ghebreyesus, Director-General WHO, for the new disease caused by the novel SARS-CoV-2. Over the last twenty years, two coronavirus outbreaks of SARS and MERS have been reported. Historically, several mild coronavirus infections in humans, caused by hCoV-OC43, HKU, 229E5, \textit{etc}. have been mentioned. Notwithstanding, high pathogenicity in human coronaviruses have been observed only in the recent times starting with SARS in 2002. It may be noteworthy that the coronavirus infections occurring post 2002 have also been reported to be of higher death rates, for SARS at {\texttildeapprox}10\% and MERS {\texttildeapprox}36.6\%. The infections of these new generation coronaviruses attribute to the causing of Acute Respiratory Distress Syndrome (ARDS) {\textendash} linked loss of pulmonary functioning, arrhythmia and even death. In comparison, the SARS-CoV-2 has emerged to be more infectious, spreading more efficiently and thereby indicating a difficult containment and increased epidemic potential.


\bgroup
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\makeatother 
\caption{\boldmath {Structural comparison between 2019-nCoV S (A) and SARS-CoV S (B)}}
\label{f-3aea7c43c669}
\end{figure}
\egroup
The coronaviruses comprise of a positive-sense 26-32 kilobases large RNA genome which encodes up to four structural proteins, the spike (S), nucleocapsid (N), membrane (M) and envelope (E) to give form a complete virus particle (Figure~\ref{f-3aea7c43c669}), \unskip~\citep{818884:19569042}. The viral genome, once inside the host cell, translate into two large precursor polyproteins, pp1a and pp1ab. These proteins are eventually processed by the ORF 1a-encoded viral proteinases namely the 3C-like proteinase (3CLpro) and the papain-like proteinase (PLpro), to give rise to 16 mature nonstructural proteins, nsp's 1-16. These nsp's industriously carry out the replication and transcription of the viral RNA genome \unskip~\citep{818884:19569044}. The frequently observed mutations and thereby the evolution of coronaviruses into novel varieties is facilitated by the viral RNA recombination occurring without a proof-reading mechanism.


\bgroup
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\makeatother 
\caption{\boldmath {Genome organization and mRNA mapping of SARS-CoV }}
\label{f-543d9fc8ffe7}
\end{figure*}
\egroup
The Figure~\ref{f-543d9fc8ffe7} is the expanded view of the structural protein coding region and predicted mRNA transcripts. The Expanded view of the structural protein coding region and predicted mRNA transcripts. The Known structural protein coding regions and reading frames X1 to X5, encoding potential nonstructural proteins longer than 50 amino acids are indicated. Lengths and map locations of the 3-coterminal mRNAs, as predicted by identification of conserved transcription-regulating sequences, are indicated (Figure~\ref{f-543d9fc8ffe7}).

Another report indicates the origin of these coronaviruses from bats and eventual transmission to the other mammalian hosts . This has been supported with the finding of SARS-CoV or MER-CoV in the Himalayan palm civets and the dromedary camels, respectively. Although the dynamics of the novel SARS-CoV-2 is currently unidentified, speculations indicate a possible animal origin.

The egress from the infected host cells witnesses the cleavage of certain coronavirus S-proteins into the subunits S1 and S2 \unskip~\citep{818884:19569054}. While the S1 accounts for the viral binding onto the host receptor, the S2 has been reported to contain the accessories required for successful membrane fusion. When called upon, the S1 binds to the host receptors to possibly expose the secondary cleavage site (S2'), located adjacent to fusion peptide for the cleavage facilitated by the host proteases, within the S2 \unskip~\citep{818884:19569041,818884:19569047}. Hypotheses indicate the occurrence of S2' proteolysis facilitates fusion peptide insertion into the host membranes. Such an event is mediated by the rearrangement of the S2 first heptad repeat region (HR1) into the extended \ensuremath{\alpha }-helix, followed by the formation of a six-helix bundle with HR1 by the S2 second heptad repeat region (HR2) in order to complete the viral-host membrane fusion and hence permit the release of viral genome into the infected host cell \unskip~\citep{818884:19569033}. The understanding of the S-protein structure and conformation states has gained the utmost significance in the present scenario to make way for the investigation of `S' antigenic surfaces in order to design prophylactic vaccines for these potential neutralizing antibody targets as the current therapeutic strategies are only supportive and the prevention of transmission is regarded the much-opined strategy. Ever since, exceptionally unprecedented efforts have been put into by the global, national and local governance to dilute the possible transmission routes of the SARS-CoV-2. Non-pharmaceutical methods like entry and exit screening of passengers, social and physical distancing interventions, as well as nationwide lockdowns of establishments and businesses have remained the only viable options in hand. Additionally, promotion of personal hygiene, self- and home-quarantine protocols have reduced the infection rates effectively.

With the place of SARS-CoV-2 origin, Wuhan, reporting very less or no incidence of infection in the past few weeks, we may consider it a model to gain insight on the possible outcomes of strictly following the above plans-of-action to reduce the incidence of COVID-19. Considering the anthroponotic nature of SARS-CoV-2, rise in incidences can be driven by increased human interaction amounting to a large-scale constant outbreak with a noteworthy shift in contact patterns from the baseline conditions \unskip~\citep{818884:19569035}. \unskip~\cite{818884:19569037} compiled data pertaining to the variations in basic reproduction number, average infection durations, initial proportion of infections, susceptibility across age-groups, and the role of youth in transmission dynamics of COVID-19 to investigate potential of non-pharmaceutical parameters in mitigating the magnitude of COVID-19 incidences. The conclusions highlighted the essentiality of these in flattening epidemic peak and thereby reducing the mounting pressure on the global health-care systems. In addition, the research group indicated resurgence of the disease in an event of premature or abrupt discontinuance of such non-pharmaceutical protocols \unskip~\citep{818884:19569037}. The physical distancing measures employed at the Wuhan was aimed at making happen a drastic shift in the social mixing patterns to control the outbreak. The study of contact patterns also plays an essential role in keeping the disease at bay. Although conditional, such patterns obtained from contact tracing are not necessarily but often limited to the densely- populated urban regions or high-income countries \unskip~\citep{818884:19569056}. In the Indian context, this was be addressed by extensive outreach by the means of frontline workers, like the Accredited Social Health Activists (ASHA), and mobile phone applications such as the `Aarogya Setu' app to quantify and trace contacts based on the existing information at the house-hold levels as well as regional demography. Thereby consolidating the statistics necessary to audit the impact of changes in population mixing and while simultaneously educating the citizens with the information required to avoid such contact(s). The use of such matrices may help the governments obtain up-to-date estimations of the epidemiological constraints \unskip~\citep{818884:19569059}. A similar technique is at present followed by the Wuhan authorities using an age-structured model of susceptible-exposed-infected-removed (SEIR) to monitor the distancing measures \unskip~\citep{818884:19569031}. Meanwhile, the world governments are putting in constant counter measures to eradicate any possible destructive effect upon with the convenience of health organizations coordinating the flow of information and setting up directives and guidelines to mitigate the COVID-19 burden. In parallel, the pan-national scientific communities are working tirelessly towards identification of the transmission mechanisms, understanding the clinical spectrum, development of novel diagnostic procedures, prophylactic and therapeutic measures pertaining to the SARS-CoV infection and the following COVID-19 disease. Nonetheless, numerous lacunae pertaining to the host-pathogen interaction and epidemic evolution do exist in these troubled times.

Till date, there has been no antiviral drug nor vaccine with a confirmed specificity and efficacy towards the SARS-CoV-2. This can be directly linked to the lack of access to either the molecular architecture of the virus or the mechanistic understanding of the infection. In a recent study by \unskip~\cite{818884:19569033}, as many as 26 out of 29 viral proteins were screened using the affinity purification mass spectrometry (AP-MS) technique in an attempt to identify any possible physical association with human proteins. Nearly 332 high confidence protein-protein interactions (PPIs) were observed among the SARS-CoV-2 {\textendash} Human proteins, of which about 67 were identified as the druggable host factors. These identified human proteins were found to be the targets for 69 FDA-approved prescription drugs available over the counter, under clinical trials and/or preclinical candidates \unskip~\citep{818884:19569049}. Deeper insights into the effective molecular may be availed upon recognition of the viral-infection mediating host-dependency factors. Any such attempt would promote developing broad-spectrum antiviral therapeutics against not just the currently ravaging SARS-CoV-2 but also keep the mankind future-ready to face any such threat by ever evolving coronavirus.

In another study, researchers have tried understand the microRNA (miRNA) repertoire, during avian infectious bronchitis virus (IBV) infection, in chicken embryo \unskip~\citep{818884:19569038}. It may be noted that the IBV belongs to the genus \textit{g}-coronavirus, causing highly contagious respiratory and reproductive tracts infections in chicken. miRNAs with probable antiviral resistance functions have been identified to be actively involved in downregulating the target gene transcript in the embryonic spleen. Surprisingly, no evidence was found for similar activity in the embryonic lungs. As many as 12 out of 14 differentially expressed (DE) miRNAs were found clustered as pairs or trios at four well-defined chromosomal regions, indicating a shared common probable target as well as deregulation mechanism, in an attempt to retain a higher possibility of participation in resistance towards the IBV infection. The observations made have henceforth shed a new light into understanding of complex host-virus interactions with a particular focus on the possible cellular manipulations occurring to facilitate antiviral resistance \unskip~\citep{818884:19569043}. The results may not be limited to understand the mechanistic underlying of IBV infection and pathogenesis but also contribute towards hypothesizing the molecular manifestations occurring in the event of SARS-CoV-2 infection.

Records pertaining to similarities, differences and due divergence occurring in the glycosylation sites of SARS-CoV and SARS-CoV-2 strains as well as an overview on their antigenic differences are now available \unskip~\citep{818884:19569046}. While a considerable variation of {\texttildeapprox}12.8\% has been proposed in a peptide sequence alignment study, {\texttildeapprox}23.6\% difference has been noted in the minimal receptor binding domains of the S-proteins belong to either strains. The increase in viral binding capacities and infectivity of the SARS-CoV-2 has been extrapolated to this major variation occurring in the spike protein minimal receptor binding domain. Novel glycosylation sites have been reported in the SARS-CoV-2 S-proteins, which are  believed to aid in altered glycosylation mediated interaction with the host cell surface receptors. In contrast, studies also indicate the presence of similar glycosylation sites in the minimal receptor binding domains found across the strains of coronaviruses \unskip~\citep{818884:19569036}. However, antigenic site comparisons have revealed the exhibition of novel CTL epitopes in the SARS-CoV- 2 virus. Thereby promoting a distinct antigenic response as compared to its sister strain of SARS- CoV.

Taking leads from this study, development of peptide-based vaccines may be successfully directed against the novel CTL epitopes. Furthermore, the epitope similarities in glycoproteins of either strains also suggest the use of SARS-targeting peptide-based vaccines may help prevent COVID-19 in the given circumstances. At this conjecture, the use of CTL epitope RVDFCGKGY in the design of prophylactic vaccine for SARS has yield remarkably efficient results in various \textit{in vivo } studies \unskip~\citep{818884:19569039}. Additionally, the structural divergence occurring insignificant in either glycoproteins, despite changes in the related peptide sequence, promotes the use of SARS- CoV attachment inhibitors as an alternative therapy for the SARS-CoV-2 \unskip~\citep{818884:19569046}. The proteomic studies highlighting the unique antigenicity of SARS-CoV-2 indicated the potential for a higher transmission and infection rates.


\bgroup
\fixFloatSize{images/e325f914-1b5d-4e7d-bad9-e9648936d5e1-upicture7.png}
\begin{figure*}[!htbp]
\centering \makeatletter\IfFileExists{images/e325f914-1b5d-4e7d-bad9-e9648936d5e1-upicture7.png}{\includegraphics{images/e325f914-1b5d-4e7d-bad9-e9648936d5e1-upicture7.png}}{}
\makeatother 
\caption{\boldmath {Structural divergence of spike glycoprotein}}
\label{f-f7a9816576bd}
\end{figure*}
\egroup
The PDB structures of spike glycoprotein of 2019-nCoV (PDBA) and SARS-CoV (PDBB) were based on cryo-EM structure of the SARS coronavirus spike glycoprotein (PDB ID 6ACC). The analysis suggests that both the structures exhibits insignificant divergence with 1.39 A\ensuremath{^\circ} deviation (Figure~\ref{f-f7a9816576bd}),\unskip~\citep{818884:19569046}. 

Collectively, for the first time the outcome shows the appearance of human 2019-nCoV is closely related to predecessor SARS-CoV. As a result, it should be renamed as SARS-CoV-2 and owing its pandemic potential it should be confirmed as a public health emergency of international concern at the earliest. Primarily the data affords the support that 2019-nCoV uses various novel glycosylation sites as SARS-CoV and may have a potential to become pandemic owing its antigenic discrepancy. Further, demonstration of novel CTL epitopes may impart opportunities for the improvement of peptide based vaccine for an anticipation of 2019-nCoV. Furthermore, the exposure of similar antigenic sites in both 2019-nCoV and SARS coronavirus, suggests the scope of SARS-associated peptide based vaccine for the prevention of 2019-nCoV. The similarity in the spike glycoprotein structures suggests the use of coronavirus specific attachment inhibitors as the current choice of treatment for 2019-nCoV \unskip~\citep{818884:19569046}.

Genome sequencing protocols helped in casual association of the COVID-19 causing novel coronavirus with SARS-CoV. As reported by the CDC, this was substantiated by the sequencing of two independent Tor2 and Urbani isolates. The availability of the viral genome data has accelerated the development of rapid PCR-based diagnostic tests by exploiting the reported sequence novelty. Such an exercise enables distinguish between already existing coronaviruses and the novel coronavirus apart from enabling the consolidation of data with regard to its association with SARS-CoV. Thereby significantly contributing towards the public health strategy to contain the virus spread \unskip~\citep{818884:19569052} and eventually support the development of prophylactic as well as therapeutic vaccines, comprising the neutralizing antibodies, as a promising effort to treat the pandemic \unskip~\citep{818884:19569058}.

The most number of neutralizing antibodies have been analyzed against the MERS-CoV as compared to all other strains of coronaviruses. The receptor-binding domain (RBD) of the S-protein has been the target of choice throughout these analyses carried out in an attempt to block its binding to the dipeptidyl peptidase 4 (DPP4) host cell membrane-anchored receptor. However, little is the understanding of the MERS-CoV epitopes and mechanisms involved in monoclonal antibody (mAb) targeting of the non-RBD regions. Reports suggest the binding of mAb 7D10 to the S-protein N-terminal domain (NTD) during the inhibition of viral entry into the host cell. Supporting this, epitope and critical residues on the NTD have been observed, using the structure determination and mutagenesis analysis techniques, facilitating the mAb binding and neutralization of the virus particles. Additionally, further investigations revealed that 7D10 neutralization was not limited to the DPP4 binding inhibition, but was also observed in the inhibition of change in prefusion to post-fusion conformation in the spike. Thereby providing 7D10 a wide-spectrum neutralization capability and also enabling elucidate the synergistic effect of the mAb on the efficacy of several other RBD-targeting antibodies \unskip~\citep{818884:19569057}.

Rising infectious diseases, such as severe acute respiratory syndrome (SARS) and Zika virus disease, present a main threat to public health \unskip~\citep{818884:19569040}. Although extreme research attempts, how, when and where new diseases emerge are still a source of huge uncertainty. A severe respiratory disease was recently reported in Wuhan, Hubei province, China. As of 25 January 2020, at least 1,975 cases had been reported since the first patient was hospitalized on 12 December 2019. 

In another study conducted on a single patient reporting with severe respiratory complications coupled with cough, nausea and fever, at the central hospital of Wuhan on 26 December 2019, the metagenomic transcript sequencing of the bronchoalveolar lavage fluid sample was carried out. The findings revealed the presence of a new RNA virus strain belonging to the Family \textit{Coronaviridae}. Phylogenetic mapping studies carried out further on the novel virus, then assigned as `WH-Human 1' coronavirus, revealed the 89.1\% nucleotide similarity to the group of SARS-like coronaviruses earlier reported in the bats found in China. Thereby highlighting the constantly occurring possibility of zoonotic viral spill-over to bear severe implications on the mankind \unskip~\citep{818884:19569051}.

Ubiquitin-like domain 2 (Ubl2) neighbouring the N-terminus of coronavirus papain-like protease (PLpro) may be regarded a critical component in protease regulation and thereby the viral infection. In a study conducted on MERS PLpro, it was observed that the absence of the Ubl2 domain showed no change in the viral ability to infect the host cells. The same has been tested \textit{in vitro } to prove that the Ubl2 domain was not associated with the MERS.

PLpro catalytic function. The X-ray structures of the MERS PLpro minus Ubl2 domain and the MERS PLpro containing the Ubl2 domain appeared nearly identical and catalysis of the former against different substrates showed no variation in the enzyme kinetics or stability. It was thereby concluded that MERS PLpro catalytic core was solely responsible for the observed infectivity of the virus \unskip~\citep{818884:19569048}.

Studies have helped establish the modelled homo-trimer structure of the SARS-CoV-2 S- protein, responsible for host cell adhesion, in both ligand-free (closed) and ligand-bound (open) conformations. The N- and O- linked glycosylation sites of these S- glycoproteins have also been reported different from the SARS-CoV `S'. Emphasis was also laid upon the capabilities of SARS-CoV-2 to hoodwink the host immune system. Furthermore, the study reportedly drew attention of the researcher by concluding that the SARS-CoV-2 S-protein interacts with a key human immune regulatory factor CD26 to provide for take over and subsequent establishment of the virulence. Hence revealing a possible mechanistic target unique to SARS-CoV-2 infection to be considered during the due drug development process \unskip~\citep{818884:19569053}.

Knowledge regarding the atomic structure of the SARS-CoV-2 spike-protein is now considered the key to understand the viral protein expression and antigenicity, which may pave way for vaccine development. Evaluation of the spike mutations occurring in the virus, due to genetic drifts, may be facilitated by the availability of structural data. Such information would also help define the surface exposure of such residues and antibody epitope mapping. Structural information would also shed light on the homogeneity of the viral construct and establishment of the prefusion conformation to identify potential epitopes for the neutralizing Ab development or to employ the B-lymphocyte guided probes for isolation of the neutralizing human mAbs.

Furthermore, screening of promising small molecules with fusion inhibition potentials can be achieved using the atomic details of the viral surface proteins. Any of which would result in encouraging the current attempts focussed towards vaccine production, development of antiviral therapeutics and eventually accelerating the improvement of medical counter measures \unskip~\citep{818884:19569034}.
    
\section{Conclusion}
In summary, we have highlighted the ongoing discoveries on the treatment of COVID-19 and possible future perceptions in the treatment methodologies. This outbreak spotlighted the need of novel vaccines, rapid methods to determine the illness, and to develop the diagnostic tools against this infectious disease. Although, researchers are strived to work in this line of research, it is still challenging to obtain the novel drug-like molecule(s). All these indicate that much more extensive works are needed for the discovery, prevention and control of COVID-19. Further, it would be a great asset to the scientific society to establish the mechanism of the action.
    
\section{Acknowledgment}
\textbf{\space }All the researchers working in the current pandemic for the development of new tools and techniques to cure this pandemic are highly appreciated.

\textbf{Conflict of Interest }

The authors declare no conflict of interest. 

\textbf{Funding Support}

None.
    

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