Introduction

Coronaviruses belong to the Coronaviridae family in the Nidovirales order. Corona

represents crown-like spikes on the outer surface of the virus; thus, it was named as a
coronavirus. Coronaviruses are minute in size (65–125 nm in diameter) and contain a single-
stranded RNA as a nucleic material, size ranging from 26 to 32kbs in length. The subgroups of
coronaviruses family are alpha (α), beta (β), gamma (γ) and delta (δ) coronavirus. The severe
acute respiratory syndrome coronavirus (SARS-cov), H5N1 influenza A, H1N1 2009 and Middle
East respiratory syndrome coronavirus (MERS-cov) cause acute lung injury (ALI) and acute
respiratory distress syndrome (ARDS) which leads to pulmonary failure and result in fatality.
These viruses were thought to infect only animals until the world witnessed a severe acute
respiratory syndrome (SARS) outbreak caused by SARS-cov, 2002 in Guangdong. A decade
later, another pathogenic coronavirus, known as Middle East respiratory syndrome coronavirus
(MERS-cov) caused an endemic in Middle Eastern (1).

History
The novel human coronavirus disease COVID-19 has become the fifth documented
pandemic since the 1918 flu pandemic. COVID-19 was first reported in Wuhan, China, and
subsequently spread worldwide. The coronavirus was officially named severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2) by the International Committee on Taxonomy of
Viruses based on phylogenetic analysis. SARS-CoV-2 is believed to be a spillover of an animal
coronavirus and later adapted the ability of human-to-human transmission. Because the virus is
highly contagious, it rapidly spreads and continuously evolves in the human population. In this
review article, we discuss the basic properties, potential origin, and evolution of the novel human
coronavirus. These factors may be critical for studies of pathogenicity, antiviral designs, and
vaccine development against the virus. Currently, people all over the world have been affected
by coronavirus disease 2019 (COVID-19), which is the fifth pandemic after the 1918 flu
pandemic. As of now, we can trace the first report and subsequent outbreak from a cluster of
novel human pneumonia cases in Wuhan City, China, since late December 2019. The earliest
date of symptom onset was 1 December 2019. The symptomatology of these patients, including
fever, malaise, dry cough, and dyspnea, was diagnosed as viral pneumonia. Initially, the disease
was called Wuhan pneumonia by the press because of the area and pneumonia symptoms.
Whole-genome sequencing results showed that the causative agent is a novel coronavirus.
Therefore, this virus is the seventh member of the coronavirus family to infect humans. The
World Health Organization (WHO) temporarily termed the new virus 2019 novel coronavirus
(2019-nCoV) on 12 January 2020 and then officially named this infectious disease coronavirus
disease 2019 (COVID-19) on 12 February 2020. Later, the International Committee on
Taxonomy of Viruses (ICTV) officially designated the virus as SARS-CoV-2 based on
phylogeny, taxonomy and established practice. Subsequently, human-to-human transmission of
COVID-19 occurring within Hong Kong has been shown in clinical data. Since COVID-19
initially emerged in China, the virus has evolved for four months and rapidly spread to other
countries worldwide as a global threat. On 11 March 2020, the WHO finally made the
assessment that COVID-19 can be characterized as a pandemic, following 1918 Spanish flu
(H1N1), 1957 Asian flu (H2N2), 1968 Hong Kong flu (H3N2), and 2009 Pandemic flu (H1N1),
which caused an estimated 50 million, 1.5 million, 1 million, and 300,000 human deaths,
respectively (2).

Signs and symptoms

The WHO-China Joint Report from February 16 to 24, 2020 includes rates of symptom
occurrence at presentation from 55,924 confirmed cases of COVID-19. We identified symptoms
that were easily discernible or objective (i.e., fever, cough, diarrhea, and nausea/vomiting) in
comparison to other reported symptoms, such as inflammations of blood vessel epithelia,
neurological effects, and rash-like symptoms (3).

Morphology and Genomic Structure of Corona Virus

Coronaviruses (CoVs) are enveloped single-stranded positive sense RNA viruses that
belong to the family Coronaviridae. On the basis of genomic organization and phylogenetic
relationship, coronaviruses have been classified into the subfamily Coronavirinae that consists
four genera Alphacoronavirus (αCoV), Betacoronavirus (βCoV), Gammacoronavirus (γCoV),
and Deltacoronavirus (δCoV). Evolutionary trend analysis of coronaviruses has revealed that
αCoV and βCoV originated from bats and rodents, while γCoV and δCoV were found to have
originated from avian species. The ability of CoVs to cross the species barrier has resulted in
some of the pathogenic CoVs. HKU1, NL63, OC43, and 229E CoVs are associated with mild
symptoms in humans, whereas severe acute respiratory syndrome CoV (SARS-CoV) and Middle
East respiratory syndrome CoV (MERS-CoV) are known to cause severe disease. In 2002–2003,
SARS-CoV emerged in China with 8000 clinical cases and 800 deaths. Since 2012, MERS-CoV
has caused persistent epidemics in the Arabian Peninsula. Both the viruses have been found to
originate from bats and then transmitted into intermediate mammalian host civets in the case of
SARS-CoV and camels in the case of MERS-CoV and eventually infected humans.
The size of coronavirus genome is in the range of 26 to 32 kb and comprise 6–11 open reading
frames (ORFs) encoding 9680 amino acid polyproteins. The first ORF comprises approximately
67% of the genome that encodes 16 non-structural proteins (nsps), whereas the remaining ORFs
encode for accessory and structural proteins. The genome of SARS-CoV-2 lacks the
hemagglutinin-esterase gene. However, it comprises two flanking untranslated regions (UTRs) at
5′ end of 265 and 3′ end of 358 nucleotides. Sequence variation among SARS-CoV-2 and SARS-
CoV revealed no significant difference in ORFs and nsps. The nsps includes two viral cysteine
proteases including papain-like protease (nsp3), chymotrypsin-like, 3C-like, or main protease
(nsp5), RNA-dependent RNA polymerase (nsp12), helicase (nsp13), and others likely to be
involved in the transcription and replication of SARS-CoV-2. In addition to nsps, four major
structural proteins are spike surface glycoprotein (S), membrane, nucleocapsid protein (N),
envelope (E) and accessory proteins encoded by ORFs. N-terminal glycosylated ectodomain is
present at the N-terminal end of M protein that comprises of three transmembrane domains (TM)
and a long C-terminal CT domain (4).

Figure 2: corona virus protein microscopes structure

Mechanism of action of Covid-19

The mechanism of viral entry and replication and RNA packing in the human cell is
mapped. The coronavirus spike (S) protein attaches to angiotensin converting enzyme 2 (ACE2)
receptors that is found on the surface of many human cells, including those in the lungs allowing
virus entry. The coronavirus S protein is subjected to proteolytic cleavages by host proteases (i.e.
trypsin and furin), in two sites located at the boundary between the S1 and S2 subunits (S1/S2
site). In a later stage happens the cleavage of the S2 domain (S2′ site) in order to release the
fusion peptide. This event will trigger the activation of the membrane fusion mechanism.
Searching for antibodies can find support on molecular targeting which can utilize the structural
information (aa sequence) of the binding region which is found in angiotensin-converting
enzyme 2 receptor. In this way this protocol could device a treatment to block the viral entry.
Typically, human cell ingests the virus in a process called endocytosis. Once entered the
cytoplasm, it has been suggested most likely that COVID-19 employs a unique three-step
method for membrane fusion, involving receptor-binding and induced conformational changes in
Spike (S) glycoprotein followed by cathepsin L proteolysis through intracellular proteases and
further activation of membrane fusion mechanism within endosomes. Then, the endosome opens
to release virus to the cytoplasm, and uncoating of viral nucleocapsid (N) is started
viaproteasomes which typically can hydrolyse endogenous proteins, but they are also capable of
degrading exogenous proteins such as the SARS nucleocapsid protein. A different two-step
mechanism has been suggested and in this case the virion binds to a receptor on the target host
cell surface through its S1 subunit and the Spike is cleaved by host proteases and then it is
expected the fusion at low pH between viral and host target membranes via S2 subunit. Finally,
the viral genetic material a single stranded RNA is fully released into the cytoplasm. There takes
place the replication and transcription processes which are mediated by the so-called
replication/transcription complex (RTC). Such complex is encoded in the viral genome and it is
made of non-structural proteins (nsp). The RTC is believed to induced double-membrane
structures in the cytoplasm of the infected cell. Following the positive RNA genome is translated
to generate replicase proteins from open reading frame 1a/b (ORF 1a/b). These proteins use the
genome as a template to generated full-length negative sense RNAs, which subsequently serve as
templates in generating addition full-length genomes. Structural viral proteins, M, S and E are
synthesizedthe cytoplasm and then inserted into the endoplasmic reticulum (ER) and transfer to
endoplasmic reticulum-Golgi intermediate compartment (ERGIC). Also, in the cytoplasm
nucleocapsids are formed from the encapsidation of replicated genomes by N protein, and as a
result they coalesce within the ERGIC membrane in order to self-assembly into new virions.
Finally, novel virions are exported from infected cells by transport to the cell membrane in
smooth-walled vesicles and then secreted via a process called exocytosis, so that can infect other
cells. In the meantime, the stress of viral production on the endoplasmic reticulum eventually
leads to cell death (5).

Figure4: Transmission and life cycle of SARS-CoV-2 causing Covid-19

Medication used for the prevention of Covid 19

 Bronchodilators
  NSAIDS (Non-steroidal Anti-inflammatory Drugs)
 Kinase inhibitors
 Interleukin 1and 6
 Colchicine
 Corticosteroid
 Nutritional supplements
 Vaccines
 Antimalarial
 Antiviral
 Antibiotics
 Fibrinolytic
 Ivermectin

Bronchodilators
In this scenario, inhaled bronchodilators (IB) have been suggested as a possible treatment.
According to the WHO’s Anatomical Therapeutic Chemical (ATC) Classification, IB include
inhaled adrenergic, anticholinergics and corticosteroid. Thousands of hospitalized patients with
evidence of Covid-19 pneumonia worldwide have been prescribed these medications as part of
treatment for the disease. However, taking into account the pathophysiological mechanism of the
disease previously exposed, with development of hyper inflammation hypercoagulability and
potential fibrosis, the use of these drugs may be ineffective given the absence of airway
pathology (6).
Mechanism of action
The mechanism of action of bronchodilators includes targeting the beta-2 receptor, which is
a G-protein coupled receptor, in the lung airways. When the beta-2 receptor is activated, the
smooth muscle of the airway relaxes. Subsequently, the patient experiences better airflow for a
period. Consistent use of beta-2 agonists for an extended amount of time reduces their efficacy
due to the down-regulation of the beta-2 receptor in the airways. As such, a higher dose of
medicine is necessary to achieve the same result. Bronchodilator metabolism occurs in the
gastrointestinal tract by cytochrome P-450 enzymes. About 80% to 100% is excreted in the
urine, and less than 20% is excreted in faeces. Short-acting bronchodilators have a half-life of 3
to 6 hours, while longer-acting bronchodilators have a half-life of 18 to 24 hours (7).
NSAIDS
Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) commonly used during any
infection accompanied by fever. It is an effective antipyretic and analgesic and is available over
the counter (OTC). Acetaminophen and ibuprofen are the two most extensively used antipyretics.
Ibuprofen disappeared from the pharmacy shelves when quarantine measures were announced to
combat the 2019 coronavirus (COVID-19) disease pandemic, which led to global shortages of
ibuprofen. However, a while later information circulated on the news saying that ibuprofen
should be avoided as it could worsen COVID-19 symptoms (8).

Mechanism of action
Ibuprofen is a non-selective inhibitor of an enzyme called cyclooxygenase (COX), which
is required for the synthesis of prostaglandins via the arachidonic acid pathway. COX is needed
to convert arachidonic acid to prostaglandin H2 (PGH2) in the body. PGH2 is then converted to
prostaglandins. The inhibition of COX by ibuprofen, therefore, lowers the level of prostaglandins
made by the body. The prostaglandins that are formed from PGH2 are important mediators of
sensations, such as pain, and inflammatory processes, such as fever and inflammation (9).
Janus kinase inhibitors
JAKinibs or other immunosuppressive drugs may improve the treatment of
COVID-19. In this regard, the latest studies show that baricitinib is a potential treatment for
ARDS in COVID-19. Furthermore, it can decrease the virus infectivity for lung cells. The ACE2
receptor has several regulators among which AP2-associated protein kinase-1 (AAK1) and
cyclin G-associated kinase (GAK) mediate clathrin-dependent endocytosis (Fig. 2). Baricitinib
not only interrupts the passage and intracellular assembly of SARS-CoV-2 into the target cells
via disruption of AAK1 signalling but it also reduces the inflammation in patients with AARDS
(10).
Mechanism of action
From the interaction of cytokines and growth factors with receptors located on the cellular
membrane. These enzymes phosphorylate and activate signal transducers and activators of
transcription proteins (STATs), which modulate intracellular activity including gene expression.
The JAK-mediated signalling pathway is pivotal in influencing immune system activation, as
cytokine receptors are expressed on most immune cells. JAK inhibitors modulate the signalling
pathway by preventing the phosphorylation and activation of STAT.Janus kinases are
intracellular enzymes that transmit signals arising (11).
Interleukin 1 And 6
Interleukin-1, an inflammatory cytokine, is considered to have diverse physiological
functions and pathological significances and play an important role in health and disease. In this
decade, interleukin-1 family members have been expanding and evidence is accumulating that
highlights the importance of interleukin-1 in linking innate immunity with a broad spectrum of
diseases beyond inflammatory diseases. In this review, we look back on the definition of
“inflammation” in traditional general pathology and discuss new insights into interleukin-1 in
view of its history and the molecular bases of diseases, as well as current progress in
therapeutics.
Mechanism of action
There are two individual forms of IL-1, IL-1α and IL-1β, isolated from two distinct
cDNAs, but they are indistinguishable in terms of their biological functions. Although the
homology between IL-1α and IL-1β is not high (27%) in terms of amino acid sequences, IL-1α
and IL-1β are structurally similar and show the same functions by sharing a common receptor,
IL-1 type 1 receptor (IL-1R1), and both have the same central β-barrel along with adjoining
loops. The difference between IL-1α and IL-1β is an N-terminal extension of 14 residues beyond
the N-terminus of IL-1α and IL-1β. The molecular weight of each precursor is approximately 31 
kDa, and IL-1α and IL-1β are processed by specific proteases to mature forms. The N-terminal
domain of IL-1α contains a nuclear localization sequence (NLS) and shows transcription
activity .IL-1α is produced as a 271-amino acid (AA) precursor protein. For transcription of the
IL-1α gene, transcription factor specificity protein 1 (Sp1) activates the IL-1α promoter activity
in the 5′-upstream GC box (− 60 to − 45 bp) and NF-κB, which is also activated by IL-1α itself,
and stimulates the consensus promoter region (− 103 to − 70 bp) to induce its own gene
expression and production in an autocrine manner. Precursor of IL-1α translocate into the
nucleus to bind to chromatin and also exists in a membrane-anchored form. Upon stress
responses, IL-1α is processed by Ca 2+-dependent protease calpain or other proteases, such as
cytotoxic T- lymphocytes (CTL)/natural killer (NK)-granzyme-B, mast cell chymase, or
neutrophil elastase to the C-terminal 159 AA as mature IL-1α.The IL-1α processing separates
NLS from its precursor, which is not linked to secretion or cell death, however, IL-1α is a key
danger signal that induces inflammation on release from necrotic cells .The IL-1α precursor
triggers IL-1R1 on resident macrophages in necrotic tissues, producing IL-1β as well as
chemokines as post-necrotic inflammation (12).
Colchicine
Colchicine as an off-label drug in health care outpatients, and shortly after in inpatients
with COVID-19 and pneumonia on lung CT scan. Herein, we report the results of an
observational retrospective study in which we used inverse probability of treatment weighting
based on propensity score to undergo colchicine treatment, in order to assess the hypothesis that
colchicine reduces mortality and time to clinical improvement in patients with COVID-19
pneumonia (13).
Mechanism of action:
 In the 1950’s and 1960’s the microtubule (MT) was identified as the primary cellular
target. MTs serve as a major part of our cellular cytoskeleton, and are essential to cellular
functions such as mitosis, as well as intracellular organelle and vesicle trafficking. MT dynamics
originate in a balance of polymer growth and shrinkage, mostly at the MT end that is distal to the
nucleus. These dynamics allow changes in MT distribution and in overall cell shape.
Structurally, MT are hollow cylinders composed of protofilaments, which in turn are made from
αβ, F tubulin heterodimers polymerized end to end. Colchicine binds to tubulin heterodimers and
alters the tubulin conformation, allowing the tubulin dimer-colchicine complex to add to the
growing end of a MT but preventing any further growth, thus poisoning the dynamics of that
MT. The exact mechanism by which this colchicine induced MT destabilization leads to
alteration of cell function remains unclear (14).

Corticosteroid
Ciclesonide, an inhaled corticosteroid, suppressed the replication of MERS-CoV and other
coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of
coronavirus disease 2019 (COVID-19), in cultured cells. The 90% effective concentration (EC 90) of
ciclesonide for SARS-CoV-2 in differentiated human bronchial tracheal epithelial cells was 0.55 μM (15).

Corticosteroids are important therapeutic agents used to treat allergic and inflammatory
disorders or to suppress undesirable or inappropriate immune system actions. The term
corticosteroid is used clinically to describe agents with glucocorticoid activity. Cortisol is the
endogenous glucocorticoid, named for its effects on glucose metabolism but which also exerts
the other immunological actions of corticosteroids. Cortisol is produced in the adrenal gland
through cholesterol metabolism. A variety of other hormones, including mineralocorticoid,
aldosterone, and male and female sex hormones, are produced through the common pathway of
cholesterol metabolism. This common pathway and structural similarities among the hormones
help to explain some of the side effects and adverse reactions associated with pharmacologic
doses of cortisol and its synthetic analogues.
Mechanism of action:
Corticosteroids represent important and life-saving therapy when anti-inflammatory or
immunosuppressive effects are needed. Corticosteroids affect numerous steps in the
inflammatory pathway, which enhance their utility. To exert an effect, the steroid molecule
diffuses across cell membranes and binds to glucocorticoid receptors, which causes a
conformational change in the receptor. The receptor-glucocorticoid complex is able to move into
the cell nucleus, where it dimerizes and binds to glucocorticoid response elements.
Glucocorticoid response elements are associated with genes that either suppress or stimulate
transcription, which results in ribonucleic acid and protein synthesis; these effects are called
trans repression or transactivation, respectively. Ultimately, these agents inhibit transcription
factors that control synthesis of pro-inflammatory mediators, including macrophages,
eosinophils, lymphocytes, mast cells, and dendritic cells. Another important effect is inhibition
of phospholipase A2, which is responsible for production of numerous inflammatory mediators
(16).
Nutritional supplements:
Nutraceuticals and dietary supplements are related but distinct non-pharmaceutical products.
Nutraceuticals are classified as supplements with health benefits beyond their basic nutritional
value. The key difference between a dietary supplement and a nutraceutical is that nutraceuticals
should not only supplement the diet, but also aid in the prophylaxis and/or treatment of a
disorder or disease. However, dietary supplements and nutraceuticals, unlike pharmaceuticals,
are not subject to the same regulatory protocols that protect consumers of medicines. Indeed,
nutraceuticals do not entirely fall under the responsibility of the Food and Drug Administration
(FDA), but they are monitored as dietary supplements according to the Dietary Supplement,
Health and Education Act 1994 (DSHEA) and the Food and Drug Administration Modernization
Act 1997 (FDAMA). Due to increases in sales of dietary supplements and nutraceuticals, in 1996
the FDA established the Office of Dietary Supplement Programs (ODSP) to increase
surveillance. Novel products or nutraceuticals must now submit a new dietary ingredient
notification to the ODSP for review. There are significant concerns that these legislations do not
adequately protect the consumer as they ascribe responsibility to the manufacturers to ensure the
safety of the product before manufacturing or marketing. Manufacturers are not required to
register or even seek approval from the FDA to produce or sell food supplements or
nutraceuticals. Health or nutrient content claims for labeling purposes are approved based on an
authoritative statement from the Academy of Sciences or relevant federal authorities once the
FDA has been notified and on the basis that the information is known to be true and not
deceptive (17).

Vaccine
Vaccines are needed to prevent coronavirus disease 2019 (Covid-19) and to protect persons who
are at high risk for complications. The mRNA-1273 vaccine is a lipid nanoparticle–encapsulated
mRNA-based vaccine that encodes the perfusion stabilized full-length spike protein of the severe
acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes Covid-19 (18).

Protein Sub Unit Vaccine:

Submit vaccine is the one which is based on the synthetic peptides or recombinant
antigenic proteins, which are necessary for invigorating long-lasting protective and/or
therapeutic immune response. The subunit vaccine, however, exhibits low immunogenicity and
requires auxiliary support of an adjuvant to potentiate the vaccine-induced immune responses.
An adjuvant may enhance the biological half-life of the antigenic material, or it may ameliorate
the immunomodulatory cytokine response. The addition of an adjuvant, therefore, helps in
overcoming the shortcomings of the protein subunit vaccines. The S protein of the SARS-CoV-2
is the most suitable antigen to induce the neutralizing antibodies against the pathogen. The S
Protein consists of two subunits. The S1 subunit has the NTD, RBD, and RBM domains while
the S2 subunit comprises of FP, HR 1, &2. The virus enters into the cell via endocytosis by
utilizing the S-Protein mediated binding to the hACE2 receptor. Therefore, the S-Protein and its
antigenic fragments are the prime targets for the institution of the subunit vaccine. The S
glycoprotein is a dynamic protein, possessing two conformational states i.e. pre-fusion and post-
fusion state. Therefore, the antigen must maintain its surface chemistry and profile of the original
pre-fusion spike protein to preserve the epitopes for igniting good quality antibody responses.
Moreover, means to target the masked RBM as an antigen will enhance the neutralizing antibody
response and improve the overall efficacy of the vaccine.
PittCoVacc
It is a Micro-Needle Array (MNA) based recombinant SARS-CoV-2 vaccine which
involves the administration of rSARS-CoV-2 S1 and rSARS-CoV-2-S1fRS09 (recombinant
immunogens). A substantial increase in the antigen specific antibodies with a statistical
significance was observed in the pre-clinical trials at the end of two weeks in the mice models.
Furthermore, the immunogenicity of the vaccine was maintained even after the sterilization using
gamma radiation. The statistically significant titers of antibodies at the early stages and also
before boosting, support the feasibility of the MNA-SARS-CoV-2 vaccine.
mRNA vaccine (Moderna vaccine):
 It is a vaccine composed of synthetic mRNA encapsulated in Lipid nanoparticle (LNP)
which codes for the full-length, pre-fusion stabilized spike protein (S) of SARS-CoV-2. It has the
potential to elicit a highly S-protein specific antiviral response. Furthermore, it is considered to
be relatively safe as it is neither made up of the inactivated pathogen nor the sub-units of the live
pathogen. The vaccine has got a fast-track approval from FDA, to conduct the Phase II trials.
The company has released the interim phase I antibody data of eight participants who received
various dose levels. The participants of the 25 μg dose group gave results comparable to the
convalescent sera. Whereas, in participants who received the 100 μg dose, the levels of nAb
essentially surpassed the levels found in convalescent sera. The vaccine was found to be
predominantly safe and well tolerated in the 25 μg and 100 μg dose cohorts, while three
participants experienced grade 3 systemic symptoms after the administration of the second dose
of 250 μg dose levels (19).

Antimalarial
Chloroquine:
Some researchers have promoted chloroquine and hydroxychloroquine for the treatment
and prevention of illness from a variety of microorganisms, including SARS-CoV 2
Hydrochloroqunine can inhibit replication of SARS-CoV-2 in Vitro. Some observational studies
have suggested benefits of hydroxychloroquine for the treatment of Covid-19 (20).
Mechanism of action
Chloroquine inhibits the action of heme polymerase in malarial trophozoites, preventing the
conversion of heme to hemazoin. Plasmodium species continue to accumulate toxic heme, killing
the parasite. Chloroquine passively diffuses through cell membranes and into endosomes,
lysosomes, and Golgi vesicles; where it becomes protonated, trapping the chloroquine in the
organelle and raising the surrounding pH. The raised pH in endosomes, prevent virus particles
from utilizing their activity for fusion and entry into the cell. Chloroquine does not affect the
level of ACE2 expression on cell surfaces, but inhibits terminal glycosylation of ACE2, the
receptor that SARS-CoV and SARS-CoV-2 target for cell entry. ACE2 that is not in the
glycosylated state may less efficiently interact with the SARS-CoV-2 spike protein, further
inhibiting viral entry (21).

Antiviral
Antiviral drugs are a class of medicines particularly used for the treatment of viral
infections. Drugs that combat viral infections are called antiviral drugs. Viruses are among the
major pathogenic agents that cause number of serious diseases in humans, animals and plants.
Viruses cause many diseases in humans, from self-resolving diseases to acute fatal diseases.
Developing strategies for the antiviral drugs are focused on two different approaches: Targeting
the viruses themselves or the host cell factors. Antiviral drugs that directly target the viruses
include the inhibitors of virus attachment, inhibitors of virus entry, uncoating inhibitors,
polymerase inhibitors, protease inhibitors, inhibitors of nucleoside and nucleotide reverse
transcriptase and the inhibitors of integrase. The inhibitors of protease (ritonavir, atazanavir and
darunavir), viral DNA polymerase (acyclovir, tenofovir, Val ganciclovir and Val acyclovir) and
of integrase (raltegravir) are listed among the Top 200 Drugs by sales during 2010s. Still no
effective antiviral drugs are available for many viral infections.

Mechanism of action
The virus attaches to a host cell injecting its genetic material into the host cell during attachment
and penetration stage. In the next step, the viral DNA or RNA is itself incorporated into the
genetic material of the host cell inducing it to replicate the viral genome. This step involves the
uncoating, replication and assembly during the virus life cycle. During release, the host cell
releases the newly created viruses, either through the breakage of the cell, waiting cell death or
by budding off through the cell membrane (22).

Antibiotics
Azithromycin: Azithromycin is a macrolide antibiotic which inhibits bacterial protein synthesis,
quorum-sensing and reduces the formation of biofilm. Accumulating effectively in cells,
particularly phagocytes, it is delivered in high concentrations to sites of infection, as reflected in
rapid plasma clearance and extensive tissue distribution. Azithromycin is indicated for
respiratory, urogenital, dermal and other bacterial infections, and exerts immunomodulatory
effects in chronic inflammatory disorders, including diffuse pan bronchiolitis, post-transplant
bronchiolitis and rosacea. Modulation of host responses facilitates its long-term therapeutic
benefit in cystic fibrosis, non-cystic fibrosis bronchiectasis, exacerbations of chronic obstructive
pulmonary disease (COPD) and non-eosinophilic asthma (23).
Mechanism of action
In order to replicate, bacteria require a specific process of protein synthesis, enabled by
ribosomal proteins. Azithromycin binds to the 23S rRNA of the bacterial 50S ribosomal subunit.
It stops bacterial protein synthesis by inhibiting the transpeptidation/translocation step of protein
synthesis and by inhibiting the assembly of the 50S ribosomal subunit. This results in the control
of various bacterial infections. The strong affinity of macrolides, including azithromycin, for
bacterial ribosomes, is consistent with their broad‐spectrum antibacterial ..Azithromycin is highly
stable at a low pH, giving it a longer serum half-life and increasing its concentrations in tissues
compared to erythromycin (24).

Fibrinolytics
The fibrin-specific agents alteplase (accelerated infusion), reteplase, and TNK offer higher
efficacy and an acceptable risk profile in comparison to streptokinase. The cheaper but less
effective no fibrin-specific streptokinase remains the most widely used fibrinolytic agent
worldwide. Streptokinase is a nonspecific agent; hence, it activates both fibrin-bound and free
plasminogen resulting in unopposed plasmin, inducing a systemic lytic state with degradation of
fibrinogen and other clotting factors. Streptokinase use as part of a pharmacoinvasive strategy
has been reported from observational studies LMW but not as part of a randomized controlled
trial; it may be more likely to active platelets compared with fibrin-specific agents (25).
Mechanism of action:

Heparin, particularly LMWH, is often used to correct the thrombotic condition in

COVID-19, but pulmonary embolism is nevertheless seen in about 20–30% of severe cases. The
dose and intensity of anticoagulant therapy is also controversial. Treatment with anticoagulant
therapy alone may offer limited efficacy. Fibrinolytic therapy may therefore be effective against
COVID-19. Treatment of existing fibrin, which interferes with pulmonary circulation, using a
fibrinolytic drug is expected to improve thrombotic conditions. In fact, systemic administration
of the fibrinolytic drug tissue-type plasminogen activator (tPA) to ARDS in COVID-19 has been
attempted and appears effective in some cases. However, careful attention should be paid to
systemic administration of tPA for severe COVID-19 with ARDS. As mentioned above,
coagulation and fibrinolytic pathophysiology in COVID-19 can fluctuate significantly within just
a few days. Performing systemic fibrinolytic therapy is performed at a time of a marked decrease
in fibrinogen is extremely dangerous and may cause fatal bleeding, including cerebral
haemorrhage (26).

Ivermectin
Ivermectin has exhibited antiviral activity against awide range of RNA and some DNA
viruses, for example, Zika, dengue, yellow fever, and others. demonstrated specific action
against SARSCoV-2 in vitro with a suggested host-directed mechanism of action being the
blocking of the nuclear import of viral proteins that suppress normal immuneresponses.
However, the necessary cell culture EC50 may not be achievable in vivo. Other conjectured
mechanisms include inhibition of SARS-CoV-2 3CLProactivity (a protease essential for viral
replication), a variety of anti-inflammatory effects,19 and competitive binding of ivermectin with
the viral S protein as shownin multiple in silico studies.20 The latter would inhibit viral binding
to ACE-2 receptors suppressing infection. Hem agglutination via viral binding to sialic
acidreceptors on erythrocytes is a recently proposed pathologic mechanism21 that would be
similarly disrupted. Both host-directed and virus-directed mechanisms have thus been proposed,
the clinical mechanism may be multimodal, possibly dependent on disease stage, and a
comprehensive review of mechanisms of action is warranted (27).
Mechanism of action:
 A study by Lehrer et al. observed that ivermectin docked in the region of leucine 91 of
the SARS-CoV-2 spike protein and histidine 378 of the host cell ACE-2 receptor blocking its
entry into the host cell .In yet another study by Eweas et al., potential repurposed drugs such as
ivermectin, chloroquine, hydroxychloroquine, remdesivir, and favipiravir were screened and
molecular docking with different SARS-CoV-2 target proteins including S and M proteins,
RNA-dependent RNA polymerase (RdRp), nucleoproteins, viral proteases, and nsp14, was
performed. Ivermectin showed the following 5 important docking properties (28).

Remedisiver

Remdesivir inhibits SARS-CoV-2 replication, reduces viral load, and exerts protective effects in
SARS-CoV-2 infected animals. Remdesivir also reduces the pathological process, alleviates mild
symptoms, and improves pulmonary lesions in SARS-CoV-2-infecetd animals. Remdesivir has
been used as a compassionate drug for treating COVID-19 patients.
Mechanism of action:
 Remdesivir is the only FDA-approved drug for the treatment of COVID-19 patients.
The active form of remdesivir acts as a nucleoside analog and inhibits the RNA-dependent RNA
polymerase (RdRp) of coronaviruses including SARS-CoV-2. Remdesivir is incorporated by the
RdRp into the growing RNA product and allows for addition of three more nucleotides before
RNA synthesis stalls. Here we use synthetic RNA chemistry, biochemistry and cryoelectron
microscopy to establish the molecular mechanism of remdesivir-induced RdRp stalling. We
show that addition of the fourth nucleotide following remdesivir incorporation into the RNA
product is impaired by a barrier to further RNA translocation. This translocation barrier causes
retention of the RNA 3ʹ-nucleotide in the substrate-binding site of the RdRp and interferes with
entry of the next nucleoside triphosphate, thereby stalling RdRp. In the structure of the
remdesivir-stalled state, the 3ʹ-nucleotide of the RNA product is matched and located with the
template base in the active center, and this may impair proofreading by the viral 3ʹ-exonuclease.
These mechanistic insights should facilitate the quest for improved antivirals that target
coronavirus replication (29).

Lopinavir and ritonavir

Lopinavir is the main antiviral agent, whereas ritonavir acts as a pharmacokinetic
“booster” that increases lopinavir plasma concentrations by inhibiting cytochrome 3A4 enzymes.
The combination is an approved antiretroviral therapy for adults with HIV-1 infection. However,
in vitro data also suggest antiviral activity of lopinavir against SARS-CoV-1, with a half-
maximal effective concentration (EC50) of 4.1 µg/mL; Middle East respiratory syndrome-CoV,
with an EC50 of 10.8 µg/mL; and, only recently, SARS-CoV-2, with an EC50 of 16.4 µg/mL.
Importantly, the EC50 for HIV-1 is 0.07 µg/mL, more than 200-fold lower than for SARS-CoV-
2 (30).
Mechanism of action:
The drug combination lopinavir–ritonavir has been suggested as an antiviral treatment
for COVID-19. Lopinavir is a HIV-1 protease inhibitor, which is combined with ritonavir to
increase its plasma half-life. Lopinavir is also an inhibitor of the severe acute respiratory
syndrome coronavirus (SARS-CoV) main protease, which is critical for replication and appears
to be highly conserved in SARS-CoV-2.4,5 Lopinavir has in vitro inhibitory activity against
SARS-CoV, SARS-CoV-2, and Middle East respiratory syndrome (MERS) coronavirus.6–9 In a
marmoset model of MERS, lopinavir–ritonavir improved clinical, radiological, and pathological
outcomes and reduced viral loads. A study of lopinavir–ritonavir in a ferret model of COVID-19
found reduced clinical symptoms in treated animals but no effect on virus titres (31).

COVID 19 Covalescrnt plasma

Convalescent plasma recipients were retrospectively propensity-score matched to control
patients who were admitted during the same period, between 24 March 2020 and 8 April 2020.
Analyses were performed at 1:4 and 1:2 ratios (convalescent plasma recipients to controls), with
and without replacement. In sampling without replacement, each untreated control can be
matched to only one treated case, while sampling with replacement allows each untreated control
to be matched by similarity in propensity score to more than one treated case. Each method has
distinct, we used both methods for sensitivity analyses. After matching was established, control
patients were retrospectively chart reviewed by a medical data team who were blinded to
information about the matched convalescent plasma recipient. Predictors not readily available in
the system database, such as duration of symptoms before hospital admission and exposures to
specific pharmacotherapies (azithromycin, hydroxychloroquine, broad-spectrum antibiotics,
therapeutic-dose anticoagulation, corticosteroids, remdesivir, mesenchymal stem cells and
interleukin (IL)-1 and IL-6 inhibitors), were manually collected after match (32).

Anticoagulant
Anticoagulants are the cornerstone therapy for thrombosis prevention and treatment. While
anticoagulants are commonly employed, their use is often associated with adverse drug events
and increased readmission rates. In older patients presenting to an Emergency Department with a
warfarin adverse drug event, about half required hospitalization. Despite novel anticoagulants
being touted as replacements for warfarin and heparin products, rivaroxaban has been associated
with serious thrombotic events while dabigatran has been associated with serious bleeding. Since
anticoagulant use enhances the risk for Emergency Department visits by as much as 35-fold,
clinicians must be familiar with anticoagulants, their pharmacological properties,
pharmacodynamics, dosing, monitoring, and toxicity (33).
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