The COVID-19 Pandemic: Theories to Therapies

Present COVID-19 pandemic has confronted almost every sector of the world creating terrible havoc and impacting day to day life of each individual. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2), identified and reported in Wuhan city, China spread across the globe with an unseen and unpredictable trajectory and limited knowledge of pathogenicity and epidemiology. With the major challenge lying in treatment and vaccine development, researchers and health care workers have come upfront to contribute in terms of knowledge and support. This review presents an overview of the structure, multiplication, and uniqueness of the novel coronavirus focusing on the ongoing treatments and scope of vaccines based on the current studies available in the literature.

the virus is known to have multiple names like SARS-CoV-2 [4] and HCoV-19 [5] and the outbreak as COVID-19 (coronavirus disease 2019). Phylogenetic analysis of whole genome (~29.9 kb) revealed that the novel virus is strikingly similar to a SARS-like coronavirus with a percentage match of 89.1 [3] indicating a zoonotic transfer from animal precisely bats sold at the wet market in Wuhan (Figure 1(a) and Figure 1(b)). But the fact that there were no bats present in the Huanan seafood market is drawing the attention of several researchers hinting at the virus to be lab-made.
Also, to substantiate, there are some reports claiming patients as early as November 17 th (which needs validation) and December 1 st which had no direct connection to the wet market, and no epidemiologist link to the later cases [6].
Investigations are ongoing throughout the world to trace the actual time of origin and its spread. As of now, there has been a report of 4 million cases of infection and 280,965 deaths in this global pandemic affecting 211 countries within four months. Current review provides an insight into the origin of the novel coronavirus-SARS-CoV2 and its distinctive features highlighting the multiplication and phenomenal spread.

Theories of Origin
All the coronaviruses infecting humans have animal origins like bats, rodents, or camels. The last outbreak of SARS in 2002-03 and MERS in 2012 are the results of zoonotic transfers across the species barrier which were considered highly pathogenic. Some theories suggest natural selection in humans [7] and the other way as natural selection in animals before zoonotic transfer with respect to the origin of novel coronavirus [8]. SARS-CoV2 is thought to be originated from bat with an intermediate host-pangolin before infecting humans [8]. Although genomic features of SARS-CoV are identical to Rhinolophus affinis (bat), the differences lie in the viral binding sites that share close similarity with the Malayan pangolins (Manis javanica) indicating a natural selection before human trans-mission [9]. With a common ancestor and an intermediate host, the chances are high that the SARS-CoV2 might have jumped to humans and prevailing in there before infecting a cluster [9]. Since the 2002-03 SARS outbreak, research on coronaviruses has drastically increased. There are reports of laboratory escape of SARS-CoV that might be another angle to look at [10]. More research and scientific transparency in this field is the need of the hour.

Classification and Structure of Coronavirus
Coronavirus belongs to the order Nidovirales and family Coronaviridae that divides into two sub-family namely Coronavirinae and Torovirinae. The Coronavirinae is further divided into a group of four-alpha, beta, gamma, and delta.
SARS-CoV2, a beta coronavirus is the seventh known coronavirus that infects humans and causes severe pneumonia-like disease along with SARS-CoV and MERS-CoV ( Figure 2). The alpha coronaviruses like HCoV-229E and HCoV-NL63 are known to show only minimal symptoms in humans [11].
All the viruses classified under this order are enveloped and have a positive non-segmented RNA genome of ~30 kb. The presence of 5' cap structure and poly A tail allows the virus to act like mRNA for translation. The genome organization of coronavirus is described as Figure 3). Structural proteins are essential for infection and viral assembly whereas genes coding for non-structural proteins seems to have a minor role in the replication in tissue culture while some have very important roles in pathogenesis [12] [13]. The spike comprises of two subunits-S1 and S2 which is 1285 amino acids long [9]. The receptor binding domain (RBD) is located in the S1 subunit that binds to ACE2 (angiotensin-converting enzyme 2) of human cells and triggers a cascade of inflammation in the respiratory tract [13] [14] [15]. ACE2 is an ectoenzyme that converts angiotension II to angiotension 1 -7, a key regulator of blood pressure angiotensin-converting enzyme [16].

What's New in SARS-CoV2?
The densely glycosylated spike protein is a fusion protein (trimeric class I) that  changes its confrontation and undergoes a structural rearrangement to enter into the target cell. The entire process begins when the S1 subunit binds to the receptor which leads to its destabilization and shedding of the subunit. This lets the stabilization of S2 subunit post fusion. According to Wrapp et al., these two states are referred to as "down and up" confrontation, where down is the receptor remote state and the later referred to as receptor ready state which is comparatively less stable. Biophysical assays made by Wrapp et al., indicates that the spike protein binds to the host cell ten times stronger than other SARS viruses.
Maybe that's the reason the SARS-CoV2 spreads so fast from person to person through respiratory transmission. The spike protein hence is the potential candidate for vaccine design and development [17]. The RBD essentially is the key element for binding and is the most adaptable fragment of the coronavirus family. Five out of six critical amino acids seemed to be different than the existing SARS-CoV that results in the high affinity binding to the host cell receptor [9].
Anderson et al., suggests the presence of polybasic cleavage site at S1/S2 junction allowing proper cleavage by proteases thereby indicating superior host selection and infection [9].

Entry and Replication of Coronaviruses
As the spike protein binds to the ACE2 receptor of the target cell, it unlocks its way into the host cell cytoplasm (Figure 4). The entry into the host cell is facilitated when TMPRSS2 (type 2 transmembrane protease) chops off the ACE2 thereby activating the spike protein, a mechanism followed by the influenza virus [18].
After entry, the virus unwraps the envelope or the E protein, thereby letting the nuclear content or the genomic RNA release in the cytosol. The ORF1a and

Pathogenicity, Incubation Period and Transmission Rate of COVID-19
The pandemic has taken over two hundred thousand lives affecting almost every part of the globe.

Treatments
With the exponential increase of cases and causalities every day, researchers and health officials are trying their best to cope and come up with a possible "treatment". Right now, the best treatment offered is care and intensive support.

Nucleoside Analogs
Nucleoside analog target RNA-dependent RNA polymerase to inhibit replication Advances in Infectious Diseases in broad-spectrum of viruses. Remdesivir and galidesivir, two experimental adenosine analog that leads to pre-mature termination of viral chains thereby inhibiting RNA synthesis demonstrates antiviral activity [30]. Remdesivir which is under clinical development for the treatment of Ebola is showing promising results. Studies confirm that remdesivir is effective in the control of SARS-CoV2 infection in vitro. National Institute of Health (NIH) has already started clinical trials to treat COVID-19. Ribavirin and favipiravir, two approved drugs for hepatitis C virus (HCV) and respiratory syncytial virus (RSV) were evaluated against SARS-CoV2 but the efficacy is uncertain. TMPRSS2 activity could be considered a potential drug to treat COVID-19 [31].

Protease Inhibitors
Currently, this drug has been approved in Japan for human intake [32] [33].

Host-Based
Chloroquine and hydroxychloroquine that is in use since the last 70 years as front-line medication for malaria is the next drug candidate. They restrict the glycosylation of spike protein with the ACE2 receptor [34] [35]. It also increases the endosomal pH required for viral fusion to the cell thereby blocking the entry into the target cells [31]. Li

Interferons, Antibodies and Corticosteroids
Tocilizumab, an immune-suppressor used to treat rheumatoid arthritis and juvenile chronic arthritis is currently one of the popular drugs with some success [36]. It has been observed that critical COVID-19 patients experience a cytokine Beside available drugs, clinicians are using convalescent plasma to treat the novel coronavirus patients which means serum from recovered patients carrying vital antibodies is administered into newly infected patients. This neutralizes the virus thereby reducing the viral load and further complication. Though this modality was already in use during the Ebola outbreak (2014-15) but seems to be highly effective at the present condition. However, the amount of serum available currently is essentially very low as the number of new cases is far more than the number of recovered patients.

Vaccines
The   [42]. Potential candidates for SARS-CoV2 vaccines include-the spike protein, the RBD, and the inactivated virus. The inactivated virus can be considered as the firstgeneration vaccines as they contain various structural proteins to induce neutralizing antibodies but the risk and safety concerns of investigators are higher. Incomplete or partial activation may pose a serious risk of infection or might even cause another SARS-like disease by inducing harmful inflammatory responses [43]. Recombinant vector-based vaccines expressing the S protein/RBD might produce neutralizing antibodies with a possible inhibition of viral binding and fusion to the host cell. According to a recent finding by Walls et al., SARS-CoV polyclonal antibodies inhibited the spike-mediated entry of SARS-CoV2 into VeroE6 cells [44]. With all potential and capabilities, the vaccine industry is working overtime to deliver and scale up a successful candidate.