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International Journal of Antimicrobial Agents 56 (2020) 106054
Contents lists available at ScienceDirect
International Journal of Antimicrobial Agents

journal homepage: www.elsevier.com/locate/ijantimicag
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2): a

global pandemic and treatment strategies
Atul Sharma a,∗, Swapnil Tiwari b, Manas Kanti Deb b, Jean Louis Marty c,d
a
School of Chemistry, Monash University, Clayton, VIC-3800, Melbourne, Australia
b
School of Studies in Chemistry, Pt. Ravishankar Shukla University, Raipur-492010, Chhattisgarh, India
c
Biocapteurs-Analyses-Environnement, Universite de Perpignan Via Domitia, 52 Avenue Paul Alduy, Perpignan CEDEX 66860, France
d
Sensbiotech, 21rue de Nogarede, 66400 Ceret, France
a r t i c l e i n f o a b s t r a c t
Article history: The emergence and rapid spread of coronavirus disease 2019 (COVID-19), caused by severe acute res-
Received 28 April 2020 piratory syndrome coronavirus-2 (SARS-CoV-2), a potentially fatal disease, is swiftly leading to public
Accepted 6 June 2020
health crises worldwide. The origin of SARS-CoV-2 infection was first reported in people exposed to a
seafood market in Wuhan City, China in December 2019. It has been suggested that the infection is likely
Keywords: to be of zoonotic origin and transmitted to humans through a not-yet-known intermediary. As of 22
Coronavirus May 2020, the World Health Organization reported that there were approximately 4,995,996 confirmed
SARS-CoV-2 cases and 327,821 deaths. SARS-CoV-2 is transmitted via inhalation or direct contact with droplets from
Chloroquine infected people. It has an incubation period ranging from 2 to ≥14 days. The rate of spread of SARS-
Severe acute respiratory syndrome
CoV-2 is greater than that for severe acute respiratory syndrome coronavirus and Middle East respiratory
Antiviral agents
coronavirus. The symptoms are similar to influenza (i.e. breathlessness, sore throat and fatigue) and in-
Biosensor
fected cases are isolated and treated. Infection is mild in most cases, but in elderly (>50 years) patients
and those with cardiac and respiratory disorders, it may progress to pneumonia, acute respiratory dis-
tress syndrome and multi-organ failure. People with strong immunity or those who have developed herd
immunity are asymptomatic. The fatality rate ranges from 3% to 4%. Recommended methods for diag-
nosis of COVID-19 are molecular tests (e.g. polymerase chain reaction) on respiratory secretions, chest
scan and common laboratory diagnosis. Currently, treatment is essentially supportive, and the role of
antiviral agents is yet to be established as a vaccine is not yet available. This review will focus on epi-
demiology, symptoms, transmission, pathogenesis, ongoing available treatments and future perspectives
of SARS-CoV-2.
© 2020 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.
1. Introduction avirus (SARS-CoV) and highly pathogenic influenza (avian influenza

A H7N9, pandemic H1N1) in China [4,6]. These viral pandemics
Since the 19th Century, pathogenic viral outbreaks and their have resulted in substantial numbers of deaths. For example, SARS-
complex interactions with humans and animals (species jump) CoV originated in bats and crossed over to humans via palm civets
have resulted in cross-species transmission, posing a great threat (host) in Guangdong Province, China; there were 8422 reported
to human health and safety [1,2]. With rapid globalization and hu- cases including 916 deaths (mortality rate 11%) in 26 countries [7].
man activities, pathogenic transmission across continents has es- MERS-CoV also originated in bats, with dromedary camels as the
calated and resulted in several pandemics, especially viral pan- intermediate host; there were 2494 reported cases including 858
demics [3,4]. Over the last two decades, there has been an up- deaths (mortality rate 34%) in 27 countries [8]. Similarly, 28,637
surge in newly identified coronaviruses, such as Middle East res- cases of Ebola infection were notified including 11,315 deaths (mor-
piratory syndrome coronavirus (MERS-CoV) in Saudi Arabia [5], tality rate ≤40%) [9]. These pandemic situations have caused sig-
haemorrhagic fever viruses (Lassa, Ebola) in West Africa, and novel nificant mortality and economic losses, and it is critical to prevent
coronaviruses including severe acute respiratory syndrome coron- the spread of emerging viruses. This review sheds light on the cur-
rent SARS-CoV-2 pandemic, epidemiology, global status and possi-
∗
ble treatment strategies with future potential.
Corresponding author. Address: School of Chemistry, Monash University,
Clayton-Victoria, Melbourne, VIC-3800, Australia.
Coronaviruses (subfamily Coronavirinae, order Nidovirales) are
E-mail address: [email protected] (A. Sharma). common human pathogens. They are enveloped, positive-sense,
https://doi.org/10.1016/j.ijantimicag.2020.106054
0924-8579/© 2020 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.
2 A. Sharma, S. Tiwari and M.K. Deb et al. / International Journal of Antimicrobial Agents 56 (2020) 106054
Fig. 1. (A) World map of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic (source: World Health Organization, accessed on 22 May 2020, time:
GMT+5.30). (B) Occurrence of SARS-CoV-2 across different states of India on 22 May 2020. (C) One-month data of active, cured and deceased cases of SARS-CoV-2 across
India on 22 May 2020 (source: Ministry of Health and Family Welfare, Government of India, accessed on 22 May 2020, time: GMT+5.30; https://www.covid19india.org/).
single-stranded RNA viruses that belong to the family Coronavir- 2. Origin and spread of SARS-CoV-2 (COVID-19)
diae, and are known to cause acute respiratory, hepatic and neuro-
logical diseases with varying severity in humans as well as animals Coronaviruses are enveloped, positive-sense RNA viruses with a
[10–12]. Coronaviruses are divided into four genera: alphacoron- diameter of 60–140 nm. These viruses are characterized by club-
avirus (α CoV), betacoronavirus (β CoV), gammacoronavirus (γ CoV) like spike projections of protein on the surface, with a crown-like
and deltacoronavirus (δ CoV) [13]. Among them, two novel β CoVs (latin for crown is ‘coronam’, hence named ‘coronavirus’) appear-
(i.e. SARS-CoV and MERS-CoV) have been reported with high mor- ance under the electron microscope [20]. In CoVs, the unusually
tality rates, as discussed above. The evolutionary analysis has no- large viral RNA genome (~30 kb) has a unique replication strat-
tified that α CoVs and β CoVs are mainly found in bats and ro- egy due to the presence of a 5 cap structure and a 3 poly (A)
dents, whereas δ CoVs and γ CoVs are mainly found in birds [11]. tail; these allow it to act as an mRNA for translation of the repli-
Coronaviruses are able to cross species barriers repeatedly and are case polyproteins. SARS-CoV-2 has strong affinity to bind with hu-
important human pathogens. In December 2019, an outbreak of man cell receptors, which differentiates it from other coronaviruses
pneumonia-like illness caused by a novel coronavirus occurred in [21]. Coronaviruses are known to cause a variety of diseases in
Wuhan, Hubei Province and spread throughout China to the rest of mammals and birds, ranging from enteritis in cows and pigs, to
the world [14]. In February 2020, the World Health Organization upper respiratory disease in chickens, to potentially fatal respira-
(WHO) named the disease ‘coronavirus disease 2019’ (COVID-19) tory infections in humans [21]. Previously, four different families
[15] and the International Committee on Virus Taxonomy named of viruses – HKU1, 229E, NL63 and OC43 – were identified with
the virus ‘severe acute respiratory syndrome coronavirus-2’ (SARS- transmission in humans leading to mild respiratory disease [22].
CoV-2) [16]. A group of virologists in China suggested renaming On 8 December 2019, adults in Wuhan, Hubei Province, China re-
SARS-CoV-2 as ‘human coronavirus 2019’ (HCoV-19) to distinguish ported severe pneumonia of unknown cause in local hospitals, and
it from SARS-CoV and for consistency with WHO’s name for the the common exposure of these initial cases was a seafood mar-
disease [17]. On 11 March 2020, WHO characterized SARS-CoV- ket trading live animals in Huanan [22]. A surveillance system
2 as a pandemic situation [18]. On 22 May 2020, there were was activated immediately, and respiratory samples of diseased pa-
4,995,996 confirmed cases of SARS-CoV-2 including 327,821 deaths tients were collected for aetiological investigations. On 31 Decem-
in 216 countries [19], and the number is increasing worldwide ber 2019, WHO notified this incident as an outbreak, and the Hua-
(Fig. 1A). In China, the total number of confirmed cases reported nan seafood market was closed on 1 January 2020. Based on vi-
is 84,520 including 4645 deaths. The USA has reported the high- rological investigations, on 7 January 2020, the virus outbreak was
est number of cases (1,525,186) and deaths (91,527) (mortality identified as a coronavirus infection that had >70% similarity with
rate >12%). Fig. 1B shows the spread of COVID-19 in India, which SARS-CoV and >95% homology with bat coronavirus. Environmen-
is a neighbouring country to China, where the number of active tal samples from Huanan seafood market were also reported to be
cases (118,447) is increasing on a daily basis (Fig. 1C) but with a positive for SARS-CoV-2 [23]. It was observed that the number of
low death rate (~3.0%). This review will discuss the epidemiology, cases increased exponentially; however, some cases did not have
transmission, pathogenesis, clinical manifestations, ongoing avail- direct exposure to the seafood market, suggesting that human-to-
able treatments and future perspectives of SARS-CoV-2. By sum- human transmission had occurred [24]. The first case was reported
marizing all information in one place, it is hoped that this review on 8 December 2019, but on tracing the virus back to where it
will be useful to the wider audience. originated and learning more about its spread, it was found that
A. Sharma, S. Tiwari and M.K. Deb et al. / International Journal of Antimicrobial Agents 56 (2020) 106054 3
Fig. 2. Percentage of cases of coronavirus disease 2019 in 11 main countries affected. Dates are: India (30 January–25 April 2020); USA (30 January–26 April 2020); Spain
(31 January–25 April 2020); Italy (29 January–25 April 2020); Germany (28 January–25 April 2020); UK (31 January–25 April 2020); France (24 January–25 April 2020); Iran
(19 January–25 April 2020); China (11 January–26 April 2020); Russia (31 January–25 April 2020); and Australia (25 January–26 April 2020) [19].
the first case was hospitalized on 17 November 2019. Massive mi- fined the diagnosis of viral pneumonia based on radiological fea-
gration of the Chinese population during Chinese New Year spread tures as one of the diagnostic criteria for COVID-19 [32]. Accu-
the epidemic globally, and cases were reported in other countries rate diagnosis using chest computer tomography (CT) may play
and on other continents. Transmission to healthcare professionals an important role in the management of patients infected with
treating infected patients was first reported between 20 and 23 SARS-CoV-2, especially when no scientifically proven treatment ex-
January 2020. To prevent further transmission, Wuhan was placed ists. Clinical features revealed by chest CT scan are indicated as
under lockdown, with restrictions place on 11 million people in pneumonia in infected patients. Other abnormal features, such as
terms of entry to and exit from the province. ARDS, acute cardiac injury, RNAaemia and ground-glass opacities,
Despite the extensive preventive measures, the spread of SARS- that lead to death have also been reported [24]. The major notable
CoV-2 in countries outside China was reported in populations with symptom is the presence of multiple peripheral ground glass opac-
no history of travel, suggesting that local human-to-human trans- ities in the subpleural regions of both lungs, which induce both
mission had started [25]. Considering the severity of the pan- systemic and localized immune responses leading to increased in-
demic, countries evacuated their citizens from Wuhan and other flammation [33]. Importantly, there are similarities in symptoms
‘hot’ SARS-CoV-2 zones using special flights, and started testing for between COVID-19 and earlier reported β CoV infections, such as
the virus or placing these people in isolation for 14 days for the dry cough, fever, dyspnoea and bilateral ground glass opacities
safety of asymptomatic people. Importantly, the number of new [24]. However, COVID-19 also exhibits other clinical features tar-
cases reported in China has reduced recently, but numbers have in- geting the lower respiratory region, such as rhinorrhoea, sneezing
creased exponentially in other countries [19]. Fig. 2 represents the and sore throat [29,34].
percentage distribution of total confirmed cases and deaths in vari- Additionally, investigation of chest radiographs of patients re-
ous countries on 25 April 2020. These numbers may underestimate vealed infiltrate in the upper lobe of the lung which is associ-
the total numbers of infected or confirmed cases and deaths due ated with increasing dyspnoea with hypoxaemia [35]. The above
to limitations of surveillance and testing in developing countries. discussions suggest that chest CT should be the preferred modal-
Although the probable origin of SARS-CoV-2 is bats, the intermedi- ity for diagnosis of COVID-19; however,the use of CT to diagnose
ary animal through which it crossed over to humans is uncertain. COVID-19 is controversial. Detailed CT scan features for COVID-19
Pangolins and snakes are the current suspects [11,22]. have been reported [27,36]. Patients infected with SARS-CoV-2 usu-
ally develop gastrointestinal symptoms such as diarrhoea, whereas
3. Symptoms and diagnosis a low percentage of patients with MERS-CoV or SARS-CoV expe-
rienced similar gastrointestinal distress. Therefore, it is important
Usually, the symptoms of COVID-19 appear after an incubation to test faecal and urine samples to exclude a potential alterna-
period of 2–14 days, with an average period of 5.2 days [26]. Most tive route of transmission, especially among healthcare workers,
commonly, the onset of COVID-19 is marked by fever, dry cough, patients etc.
fatigue and muscle pain, with other symptoms such as headache,
lymphopenia and dyspnoea. Some people may have diarrhoea or
nausea 1–2 days before infection [27–29]. Patients may face diffi- 4. Transmission of SARS-CoV-2
culties in breathing 5 days after the onset of infection, and acute
respiratory distress syndrome (ARDS) on day 8. If the patient’s con- Following the first case of transfer of SARS-CoV-2 from animal
dition worsens, they may experience abdominal distress and pneu- to human, several cases of local transmission and, most seriously,
monia, with other functional failures depending on their immune community transmission, have been reported, leading to the pan-
and health status [30]. The length of time from onset of infection demic status [18]. Based on the cases of infected people exposed
until death ranges from 6 to 41 days, with an average of 14 days at Wuhan seafood market, where live animals are sold routinely,
[31]. This period is dependent on several factors such as age and it was suggested that the origin of SARS-CoV-2 could be zoonotic.
health, and is shorter for patients with comorbidities and aged >70 Various efforts and retrosearching have been undertaken to iden-
years [31]. tify a reservoir host or intermediate carrier from where the infec-
The Diagnosis and Treatment Programme (6th version) of the tion might be transmitted to humans. Two species of snakes have
National Health Commission of the People’s Republic of China de- been identified as possible reservoirs of SARS-CoV-2; however, to
date, there is no consistent evidence for a coronavirus reservoir lar to that of SARS-CoV. This suggests that entry into the host cells
other than mammals and birds [29,37]. is most likely via the ACE2 receptor [20], as depicted in Fig. 3. The
According to reports, human-to-human transmission of SARS- SARS-CoV-2 virus or virion contains four different proteins (enve-
CoV-2 is possible when an individual is in the incubation stage or lope, spike protein, membrane and nucleoside) and an RNA strand.
showing symptoms, whereas some individuals are contagious and The spike protein helps to establish contact with human cells, and
remain asymptomatic (i.e. superspreaders). Transmission occurs via has a region which recognizes ACE2 receptors in human cells, es-
inhalation of respiratory droplets (>10 μm) of exhaled virus from pecially respiratory cells. As the virion binds with ACE2 protein,
an infected person (within 1 m). The virus remains airborne for another TMPRSS2 protein (on the exterior cell wall) helps to open
a prolonged period. Transmission also occurs via contact with in- the spike protein and cleave the membrane, allowing entry of the
fected surfaces, such as skin-to-skin, and through touching an in- virion. Next, the virion releases its RNA strand, which is translated
fected inanimate object then mediating it through the mouth, nose into protein and forms more RNA strands. During cell development
or eyes [4,30]. SARS-CoV-2 is reported to survive for several hours (Fig. 3), one strand of the virion enters the Golgi bodies and evolv-
on contaminated metal surfaces and sterile sponges. Latex surgical ing new virion those come out of cell where membrane and en-
gloves, if not changed after handling an infected patient, increase velop proteins are present. One virion particle has the ability to
the opportunity for transmission via touch. The relative contribu- make several hundred new virions in this way, each of which is
tions of large respiratory droplets, smaller airborne aerosols (<5 capable of infecting new cells.
μm) and direct surface contacts to the transmissibility of SARS- The pathogenesis of SARS-CoV-2 leading to acute respiratory
CoV-2 need to be evaluated to enable effective control of trans- disorders and pneumonia-like symptoms seems to be particularly
mission and infection. complex and is responsible for initiating an excessive immune re-
The faecal transmission route should also be considered, as action in the host. The cytopathic effect and cytokine storm are re-
SARS-CoV-2 has been detected in stool samples of infected patients lated to the clinical condition of patients with COVID-19 [42]. Lev-
[31]. Previously, it was reported that SARS-CoV can survive in stool els of pro-inflammatory cytokines and chemokines, including in-
samples for up to 4 days [6]. In other studies, the presence of coro- terleukin 6 (IL-6), tumour necrosis factor and macrophage inflam-
naviruses has been reported in water, sewage, and pure or pas- matory proteins, are elevated and play an important role in the
teurized settled sewage, and these viruses can remain infectious immunopathology of patients with COVID-19 [43]. During the pe-
for 3 days to 3 weeks [38]. The presence of stool from an infected riod of infection, cytokines are expressed in lung epithelial cells,
patient in wastewater may generate a further route of transmis- leukocytes and dendritic cells via the activation of pattern recogni-
sion via the generation of virus-laden aerosols during wastewater tion receptors (including Toll-like receptors TLR3, TLR7 and TLR8),
treatment. For example, a contaminated faulty sewage system in retinoic acid-inducible gene I and the NOD-like receptor family
a high-rise housing estate in Hong Kong in 2003 was linked to members. Also, direct virus-induced tissue damage and the syner-
a SARS outbreak in the surrounding area [39]. Therefore, aerosols gistic cytokine effect cause extensive tissue damage and multiple
arising from contaminated sewage represent a potential cause of organ dysfunction. An abundance of ACE2 protein on lung alve-
transmission of SARS-CoV-2 and needs further investigation. olar epithelial cells and enterocytes of the small intestine helps
Airborne dust is another possible route of transmission in res- to explain the routes of infection and disease manifestations. IL-
piratory diseases. Earlier reports have shown that transmission of 6 activates leukocytes, promotes differentiation of B lymphocytes
infectious diseases is linked to the presence of micro-organisms in and alters cell replication. IL-6 also stimulates the production of
airborne particulate matter (PM)/airborne dust [40]. Air pollution acute phase proteins, and plays a role in the thermoregulation
is common in some countries (e.g. India, China, Saudi Arabia, Iran), and anti-inflammatory response [44]. Furthermore, deficiency of
and airborne PM matter or dust may influence the rate of trans- IL-6 and antiIL-6R monoclonal antibody leads to the persistence of
mission of viral infections. Inhalation of virus-laden fine PM could influenza-like infection. Additionally, lymphocytes lack ACE2 recep-
transport the virus into deep alveolar tissue and tracheobronchial tors and compromise T lymphocytes. Most patients with COVID-19
regions, and increase the chance of infection [4]. Surface adsorp- have similar symptoms, such as fever, malaise and influenza-like
tion of SARS-CoV-2 on PM and airborne dust can contribute to features; however, some patients rapidly develop ARDS and multi-
long-range transport of the virus. Thus, an investigation of the sur- ple organ failure. Clinical examination reveals a reduced peripheral
vival of SARS-CoV-2 in airborne PM/dust will help to explain their lymphocyte count and lymphocytopenia (due to reduction of CD4
role in transmission. T and CD8 T cells). Importantly, ACE2 regulates blood pressure, and
Recently, Chen et al. conducted a small study on pregnant an attack of SARS-CoV-2 on ACE2 receptors in endothelial cells re-
women who were confirmed to have COVID-19. Although there sults in coagulation, hypotension, cardiac injury, kidney dysfunc-
is no evidence for transmission of viral infection from mother to tion and secondary infections [42].
child, the cloud of uncertainty persists [41]. Understanding this fac-
tor is very important as pregnant mothers are more susceptible
to infection with respiratory pathogens and severe pneumonia. All 6. Therapeutics and treatment options
pregnant mothers in the study by Chen et al. underwent a cae-
sarean delivery, so it remains unclear whether viral transmission To date, no specific antiviral treatment or vaccine is available
can occur during vaginal birth. for treatment of COVID-19. Molecular interaction between virus
cell receptors and host cells, mainly with surface spike glycopro-
5. Pathogenesis of SARS-CoV-2 and clinical manifestations tein(s), is particularly important for the development of antivi-
ral treatment. Treatment of severe influenza still presents multi-
Recognition and receptor binding on host cells is the first step ple challenges. Several trials are currently underway, aiming to dis-
of viral infection, followed by fusion with the cell membrane [29]. cover a potential antiviral treatment for COVID-19. At present, the
It is reasoned that the lung epithelial cells are the primary target of only option available is the use of broad-spectrum antiviral drugs
the virus. Thus, it has been reported that human-to-human trans- [nucleoside analogues and human immunodeficiency virus (HIV)-
mission of SARS-CoV occurs by the receptor-binding domain of protease inhibitors] in combination with antimalarial drugs and
the SARS-CoV spike protein binding to angiotensin-converting en- some potential antibiotics. All possible treatment options for the
zyme 2 (ACE2) receptors [20,22]. Importantly, the sequence of the management of COVID-19 have been reviewed and are detailed be-
receptor-binding domain of the SARS-CoV-2 spike protein is simi- low.
Fig. 3. Schematic representation of the genesis and transmission of severe acute respiratory syndrome coronavirus-2 in humans.
6.1. Hydroxychloroquine/chloroquine the activity of these drugs is not limited to malaria, as they have
also been used in the treatment of autoimmune disorders (HIV)
Recent publications [45–47] have focused attention on the po- and viral infections associated with inflammation, and have broad-
tential benefits of chloroquine (CQ) and hydroxychloroquine (HCQ) spectrum activity against a range of microbial (viral, bacterial and
for the treatment of COVID-19. CQ is an amine acidotropic form fungal) infections and inhibit their replication cycles [49–52]. Dur-
of quinine, and has been used worldwide for decades as a front- ing long-term therapy, the clinical safety of HCQ is better than that
line drug for the treatment and prophylaxis of malaria [48]. HCQ of CQ, allowing a higher daily dose; however HCQ has fewer issues
is a 4-aminoquiniline analogue of CQ with a hydroxyl group at the with drug–drug interactions. The broad-spectrum antiviral effects
end of the CQ side chain. The pharmacokinetics of HCQ are sim- and clinical response of CQ and HCQ in SARS-CoV warrant particu-
ilar to those of CQ, and it can be used for long periods with im- lar attention for repurposing this drug for use in the treatment of
proved tolerability. The sulphate form of HCQ is available for oral COVID-19 [45,50].
administration with a higher dose than CQ for rapid gastrointesti-
nal absorption and renal elimination. Clinical indications and toxic 6.1.1. Antiviral potential of HCQ/ CQ against SARS-CoV-2
doses of these drugs are slightly different [45]. Regrettably, the effi- Due to the broad spectrum of activity of HCQ/CQ against
cacy of CQ/HCQ has declined gradually due to the continual emer- viruses, including most coronaviruses, particularly SARS-CoV, and
gence of CQ-resistant strains of Plasmodium falciparum. However, as coronaviruses enter cells through the endolysosomal pathway
[53], it is reasonable, given the current public health emergency • HCQ inhibits entry of the virus into the host cells by binding to
and the absence of any known efficient therapy, to further in- the host cell surface receptors by disabling ACE2 terminal gly-
vestigate the possible effects of CQ against SARS-CoV-2. In 2005, cosylation, leading to changes in surface morphology [54]. The
Vincent et al. reported that CQ had a strong antiviral effect on association between SARS-CoV-2 and the host cells is disrupted
SARS-CoV infection of primate cells treated pre or post infection, as ACE2 is needed for the virus to attach to the host cells. CQ
suggesting both a prophylactic and therapeutic advantage [54]. In- also inhibits quinone reductase-2, which is a structural neigh-
vitro studies described that lethal infection of newborn mice with bour of UDP-N-acetylglucosamine 2-epimerases [64] which are
recombinant HCoV-O43 could be avoided by administering CQ via involved in the biosynthesis of sialic acids (acidic monosaccha-
the mother’s milk. CQ has also proved to be effective against rides) present at the extremities of sugar chains present on cell
MERS-CoV [48], although in-vitro results against MERS-CoV remain transmembrane proteins, and one of the important components
controversial. required for ligand recognition.
In addition to several antiviral agents, CQ and HCQ have been • HCQ/CQ can impair the early stages of viral replication by in-
proposed as treatments that could reduce viral transmission. In- creasing the endosomal pH required for the virus–host cell in-
vitro studies have shown that CQ and HCQ can inhibit SARS-CoV-2 fusion. The inhibition likely involves endocytosis and annul-
transmission via alkalinization of the intracellular phagolysosome ment of virus–endosome fusion.
[55], which prevents virion fusion and uncoating, thereby decreas- • CQ can also interfere with the post-translational modification of
ing viral spread. In a recent report, the Chinese National Centre for viral proteins, which involves two enzyme proteases and gly-
Biotechnology Development indicated that CQ is one of the poten- cosyltransferases. The process occurs within the endoplasmic
tial drug candidates for the treatment of COVID-19. It has been in- reticulum/trans-Golgi network vesicles and may require a low
vestigated in hospitals in Beijing, Hunan Province and Guangdong pH. It localizes the M proteins in the Golgi complex beyond the
Province. According to preliminary reports [56,57], approximately site of virion budding, which suggests that this drug may in-
100 patients with COVID-19 treated with CQ experienced a more hibit replication of the SARS-CoV-2 virion.
rapid decline in fever and improvement in lung function. The im- • HCQ acts as an ionophoric agent for Zn2+ ions and thus in-
proved computed tomography (CT) images and shortening of re- creases the influx of Zn2+ ions into the cytoplasm of the host
covery time compared with control groups, with no serious ad- cells regardless of whether the host target cells are infected or
verse effects, led to the inclusion of CQ in the treatment guidelines not [62]. Zn2+ ions adhere to the RNA-dependent RNA poly-
for COVID-19 by the Chinese Medical Advisory Board. As a result, merase enzyme of the virus and stop SARS-CoV-2 intracellular
CQ was probably the first drug to be used in China and elsewhere polymerization.
as the front-line treatment of severe COVID-19. • HCQ not only attenuates the inflammatory response but also
Under the Ministry of Health and Family Welfare, the Indian decreases the level of cytokines, which is generally higher in
Council of Medical Research recommended chemoprophylaxis and patients infected with SARS-CoV-2. In one study, conducted by
therapeutic use of HCQ in patients with COVID-19, with a dosage Yao et al., it was reported that HCQ is more potent than CQ in
of 400 mg twice on day 1, then 400 mg once per week thereafter the inhibition of SARS-CoV-2 [65]. In addition, CQ can inhibit
for asymptomatic healthcare workers treating infected patients and IL-1β mRNA expression in THP-1 cells and reduce the release
for asymptomatic household contacts of confirmed cases [58]. For of IL-1β and tumour necrosis factor.
the treatment of diagnosed cases, no clinical information is avail-
able, except for some pre-clinical examination results, such as re- 6.2. Ivermectin
duction of viral load by administering HCQ in combination with
azithromycin [47]. On the basis of these preliminary findings, CQ Ivermectin is a synthetic derivative of macrocyclic lactones
and HCQ have been prescribed to treat patients with COVID-19 to commonly known as avermectins that possesses broad-spectrum
reduce the length of hospital stay and improve the SARS-CoV-2- antiparasitic activity. Ivermectin has been approved by the US Food
related pneumonia. WHO has also recommended that healthcare and Drug Administration as an antiparasitic agent. In recent years,
providers should use CQ [59] and HCQ [60] in adults and ado- it has shown potent antiviral activity against a broad range of
lescents who weigh ≥50 kg. Recently published guidelines from viruses, such as influenza A and dengue virus (DENV) [65–67]. It is
the Surviving Sepsis Campaign on the management of critically in- known to inhibit the interaction between the HIV-1 integrase pro-
fected patients concluded that there is a lack of evidence to offer tein (IN) and the importin (IMP) α /β heterodimer responsible for
any recommendations on standalone use of these drugs in patients importing the integrase protein [66,68]. Ivermectin also inhibits IN
admitted to the intensive care unit (ICU) [61]. It seems that dis- nuclear import and HIV-1 and DENV replication [69]. It has been
crepancies about the use of antimalarial drugs in the clinical man- reported that this drug potentially inhibits the nuclear import of
agement of patients in the ICU with severe COVID-19 require ex- host cell and viral proteins, as observed in the case of SV40 large
haustive research. This evidence, or the lack thereof, hardly justi- tumour antigen protein of simian virus and non-structural pro-
fies state-endorsed, widespread use of HCQ for prophylaxis. Long- tein 5 of DENV [68–71]. However, ivermectin did not show any
term use of these drugs for the treatment of malaria demonstrates potential efficiency against Zika virus. A clinical trial in Thailand
their safety during acute administration to humans; however, one (2014–2017) against DENV infection found that a single dose of
cannot ignore the minor risk of macular retinopathy, prolongation ivermectin can result in a significant reduction in viral NS1 pro-
of the QT interval in arrhythmic patients, and renal and hepatic tein in serum, but no change in clinical benefits was notified [72].
impairment, which depends on the cumulative dose [59,60]. A sur-
vey of the adverse effects of CQ/HCQ treatment in patients with 6.2.1. Ivermectin potential against SARS-CoV-2
COVID-19 with multiple organ dysfunction (e.g. cardiac injury and A series of clinical trials are underway to identify potential ther-
kidney malfunction) needs further evaluation. Currently, at least 10 apies or a vaccine for COVID-19. A group of researchers [72] from
clinical trials are testing CQ as a treatment for COVID-19 [62]. Monash University, Australia reported that ivermectin has shown
broad-spectrum in-vitro antiviral activity against SARS-CoV-2. In
an in-vitro experiment, they added a single dose of ivermectin to
6.1.2. Mode of action of CQ/HCQ Vero-hSLAM cells infected with SARS-CoV-2 for 2 h. After analysing
CQ/HCQ has multiple mechanisms of action that may be useful the cell pellets and supernatant for 3 days using reverse transcrip-
in the treatment of COVID-19 [45,63]: tase polymerase chain reaction (RT-PCR) to analyse the replica of
Fig. 4. Proposed antiviral mechanism of action of ivermectin against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). In the absence of ivermectin, IMP
α /β 1 binds to the coronavirus cargo protein in the cytoplasm, and crosses the membrane barrier through the nuclear pore complex into the nucleus where the complex
dissociates and the viral cargo infects and reduces the host cell’s antiviral response. In the presence of ivermectin, ivermectin binds to and destabilizes the IMP α /β 1
heterodimer, preventing the binding of IMP α /β 1 to the viral protein; this prevents the cargo protein from crossing the membrane barrier to enter the nucleus, thereby
preventing infection and improving the antiviral response [69].
SARS-CoV-2 RNA, a 93% reduction in viral RNA in the supernatant 6.3.1. Potential mechanism of action
was quantified in the sample treated with ivermectin compared SARS-CoV-2 enters the host cells and replicates, producing
with the control (DMSO treated), and a 99.9% reduction in cell- strands which contain multiple copies of RNA which accumulate
associated viral RNA. Efficiency increased to ~50 0 0 fold by 48 h, at the periphery of the host cells to be cleaved and released [80].
and no toxicity was observed [67,69]. In the above study, a serial 3-Chymotrypsin-like protease (3CLpro ) is an enzyme with a crucial
dilution method showed similar efficiency with IC50 of ivermectin role in processing viral RNA [81]. Lopinavir/ritonavir are protease
of ~2 μM. inhibitors that inhibit the action of 3CLpro and thereby disrupt the
process of viral replication and release from host cells [81]. Recent
evidence suggests that these drugs have in-vitro antiviral activity
6.2.2. Mode of action of ivermectin against SARS-CoV-2 [76,77,82]. Most importantly, coronavirus pro-
Earlier studies on SARS-CoV protein revealed a potential role teases, including 3CLpro , do not have a C2-symmetric pocket, which
for IMP α /β 1 in signal-dependent nucleocytoplasmic shutting of is a target site for HIV protease inhibitors. This brings into question
the SARS-CoV nucleocapsid protein [73], which potentially im- the potential potency of HIV protease inhibitors for the treatment
pacts host cell division [74]. Additionally, SARS-CoV protein (ORF6) of coronaviruses [83], and shows that C2 pockets are not important
antagonizes the antiviral activity of the STAT1 transcription fac- for antiviral action.
tor sequestering IMP α /β 1 on the membrane of rough endoplas-
mic reticulum/Golgi bodies [75]. Ivermectin’s nuclear transport in- 6.3.2. Clinical efficiency of protease inhibitors/antiviral drugs against
hibitory activity may be effective against SARS-CoV-2. Caly et al. SARS-CoV-2
hypothesized the inhibition of SARS-CoV-2 by ivermectin by the In Wuhan, an open-label randomized clinical trial was con-
inhibition of IMP α /β 1-mediated nuclear import of viral proteins ducted on 199 adult patients hospitalized with SARS-CoV-2
(Fig. 4), as shown for other RNA viruses [72]. Further identification pneumonia-like symptoms [84], treated with lopinavir 40 0 mg/10 0
and confirmation of this mechanism in SARS-CoV-2 infection still mg twice per day for 14 days (n=99) or standard care (n=100).
needs to be evaluated and various clinical trials are ongoing. The baseline characteristics were similar in both groups, and most
patients were severely unwell and required urgent clinical atten-
tion. Even after 28 days of treatment, the intention-to-treat anal-
6.3. Lopinavir/ritonavir (protease inhibitors) and antiviral drugs ysis revealed no positive symptomatic relief in the primary out-
come between the two groups. Moreover, there was some evi-
Lopinavir/ritonavir are antiretroviral drugs with protease in- dence that lopinavir can reduce mortality, shorten ICU stay and
hibitor action, widely used for the treatment of HIV, and re- reduce time to discharge from hospital by 1 day. However, no clin-
cently suggested as potential candidates for the treatment of ical improvement was observed after 28 days in patients treated
COVID-19 [76,77]. Previous studies confirmed the effectiveness of with lopinavir. No difference in viral clearance was found between
lopinavir/ritonavir against other coronaviruses [66,78]. An open- the two groups, and conditions worsened due to the appearance
label, non-randomized study showed reduced risk of severe hy- of adverse side effects. The ELACOI (Efficacy of Lopinavir Plus Ri-
poxia or death in 41 patients with SARS-CoV infection treated with tonavir and Arbidol Against Novel Coronavirus Infection) study was
lopinavir/ritonavir compared with 111 patients treated with rib- conducted on 44 patients with COVID-19 [85], divided into three
avirin alone [78]. However, there is no evidence from randomized groups: lopinavir, umifenovir and control. No difference was ob-
trials for the efficacy of lopinavir/ritonavir for treatment of SARS- served in the primary results. No improvement in pyrexia, cough
CoV or MERS-CoV infection [79]. or lung CT was observed after 7 and 14 days, and the clini-
Table 1
Recommended guidelines for various dosage regimens for the treatment of coronavirus disease 2019 [52,55,86].
Drug Administration Dosage Duration of treatment
Chloroquine phosphate Oral 500 mg twice per day <10 days

Hydrochloroquine Oral For asymptomatic healthcare personnel, 400 mg twice on day 1, then For 7 weeks
400 mg once per week
For quarantining individuals following contact with positive cases, For 3 weeks
400 mg twice on day 1, then 400 mg once per week
Lopinavir/ ritonavir Oral 200 mg twice per day (2 capsules of 50 mg each time) <10 days
Ribavirin Intravenous infusion 500 mg two or three times per day in combination with <10 days
lopinavir/ritonavir or interferon-α
Interferon-α Vapour inhalation 5 million U twice per day <10 days
Arbidol Oral 200 mg three times per day <10 days
cal condition of patients deteriorated further [81]. Other studies fect lung cells. Baricitinib is a high-affinity AP2-associated protein
[86,87] conducted on hospitalized patients with COVID-19 treated kinase-1 (AAK1)-inhibiting drug with Janus kinase 1/2 (JAK 1/2) in-
with lopinavir and other protease inhibitors showed no potential hibition, which also binds to cyclin G-associated kinase (a regulator
improvement in clinical status, and patients exhibited a high rate of endocytosis) [95]. A plasma concentration of baricitinib at ther-
of unfavourable outcomes with no difference in time for viral clear- apeutic dose (i.e. 2 mg or 4 mg single dose) is sufficient to inhibit
ance compared with patients who did not receive this treatment. AAK1. It has been clinically tested on a selected population with
An unpublished in-vitro study [88] reported that darunavir COVID-19 using an appropriate patient population to reduce viral
(HIV-1 protease inhibitor) was not active against SARS-CoV-2; entry and inflammation in patients with a MuLBSTA score, and also
however, on 4 February 2020, a group of researchers in China predict viral mortality [96]. Due to the high affinity of baricitinib
[89] reported that, in an in-vitro experiment, darunavir 300 μM for AAK1 and JAK, its ability to ameliorate allied chronic inflamma-
inhibited SARS-CoV-2 infection, and the inhibition efficiency was tion in interferonopathies and pharmacokinetic properties make it
calculated to be 280-fold compared with the untreated group. In- a potential candidate for combination with direct-acting antivirals
vitro studies using mouse models treated with remdesivir (a nu- (lopinavir or ritonavir and remdesivir) to combat SARS-CoV-2 [97].
cleoside analogue) found stronger evidence for antiviral MERS-CoV
activity compared with lopinavir [90]. Wang et al. reported that 6.4.2. Interferon-α
remdesivir blocked SARS-CoV-2 infection with EC50 (effective con- According to WHO, the antiviral drug interferon (IFN)-α is rec-
centration to inhibit 50% of cells) of 0.77 μM with a high selectivity ommended for the treatment of COVID-19 [98]. IFN-α is a broad-
index (>129.87) [91]. Holshue et al. reported that remdesivir ex- spectrum antiviral agent usually used to treat hepatitis [99], and
hibited promising results in the treatment of patients with COVID- it has been reported to inhibit SARS-CoV reproduction in vitro
19 in the USA [92]. In China, a randomized, placebo-controlled, [100]. The recommended treatment regimen in adults is vapour
double-blind, multicentre phase III clinical trial was started on 5 inhalation of IFN-α at a dose of 5 million U dispersed in 2 mL
February 2020 to evaluate the efficacy of remdesivir in the treat- of sterile water twice per day. If IFN-α is administered in combi-
ment of COVID-19 [89]. Infected patients received an initial intra- nation with other antiviral drugs or nucleoside analogues, it could
venous infusion of 200 mg of remdesivir with subsequent doses of be more effective for the treatment of COVID-19. Currently, IFN-
100 mg for 9 consecutive days, and the control group was treated β 1a and IFN-α 2b are under investigation as potential candidates
in a similar manner with a placebo regimen. The outcomes of the for the treatment of patients with COVID-19. IFNs can improve
trial are expected by the end of April 2020. the immune system by turning on dormant parts, and aligning
In-vitro antiviral efficacy of remdesivir/lopinavir against SARS- them with the defence mechanism against SARS-CoV-2. Moreover,
CoV-2 on Vero-E6 cells at 50% effective concentration was reported as IFNs improve the immune system, the influenza-like symptoms
[82]. Ribavirin/favipiravir, which are in clinical trials, showed no vi- of COVID-19 may worsen as naturally occurring IFNs are respon-
ral inhibition even at higher concentrations (i.e. 100 μM). A syner- sible for influenza-like symptoms. For instance, if a patient is on
gistic effect of remdesivir and emetine could help to achieve 64.9% a ventilator or undergoing asthmatic treatment, the administration
inhibition in viral yield. This proves that the combinational ther- of IFN-based medicine could be catastrophic. WHO is investigating
apy may help to reduce the effective concentration of drugs and different IFNs to treat COVID-19, but no treatments exist to date.
increase clinical benefits. Several groups of researchers are working An open randomized clinical study has been launched in China on
on this class of drugs; however, due to insufficient evidence, only the efficacy and safety of IFN-α 2β for treatment of COVID-19 in
lopinavir is used to treat patients with COVID-19. Various dosage 328 adult patients; the results are due in June 2020 [101].
regimens of CQ, HCQ and other antiviral agents are undergoing
investigation for treatment for chemoprophylaxis and therapeutic 6.4.3. Arbidol
use, and these are summarized in Table 1. Arbidol is a potent broad-spectrum antiviral agent that has ac-
tivity against enveloped and non-enveloped viruses [102]. Arbidol
6.4. Other potential drug candidates/therapies is a well-known antiviral agent in Russia, China and some West-
ern countries. It was developed by the Russian Research Chem-
6.4.1. Baricitinib ical Pharmaceutical Institute. Since 1990, arbidol has been used
BenevolentAI is a target identification platform and knowledge as an over-the-counter medicine for prophylaxis and treatment
graph which is a large repository of structured medical information of ARDS, including influenza [102]. Arbidol exhibits a molecular
with abundant connections extracted from the available scientific mechanism of action against influenza viruses (influenza viruses A
literature by a machine learning process [93]. Based on a Benevo- and B) that differs from other antiviral drugs. The antiviral mecha-
lentAI graph (Fig. 5), Richardson et al. searched for approved drug nism of action of arbidol involves inhibition of virus-mediated fu-
candidates with potential efficiency for inhibition of propagation sion with the target membrane, which blocks virus entry into the
of SARS-CoV-2 [94]. Herein, baricitinib was identified as a poten- target cells [103]. According to the literature, arbidol has been ap-
tial candidate that may reduce the capability of SARS-CoV-2 to in- proved in Russia and China for the treatment of SARS, influenza
Fig. 5. BenevolentAI knowledge graph integrating biomedical data from existing structured and unstructured sources. Constructed on the basis of a fleet of algorithms to
establish new relationships suggesting new treatment methods for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). AAK1, AP2-associated protein kinase-1;
JAK 1/2, Janus kinase 1/2; GAK, cyclin-G-associated kinase [90,91].
and other viruses [104]. Recently, Deng et al. investigated combina- valescent plasma 200 mL into a patient with severe COVID-19 was
tion therapy of arbidol with lopinavir/ritonavir using a small sam- well tolerated, and clinical symptoms improved with an increase
ple [105], and a small number of studies have confirmed the suc- in oxyhaemoglobin saturation within 3 days of treatment. Rapid
cessful recovery of patients treated with arbidol and lopinavir. Zhu neutralization of viraemia and no significant side effects were also
et al. undertook a study on 50 patients divided into two groups: observed. The US Food and Drug Administration has issued guide-
lopinavir/ritonavir 40 0 mg/10 0 mg two times per day for 7 days lines to healthcare providers and investigators to further investi-
(n=34 patients), and arbidol 0.2 g three times per day (n=16 pa- gate the efficacy of CPT from individuals who have recovered from
tients). Data were analysed retrospectively [106]. After 14 days of COVID-19 [112,113], and also issued guidelines for donors of con-
treatment, no viral load was detected in the arbidol-treated group; valescent plasma antibodies [112]. CPT may not be effective in ev-
however, the viral load was 44.1% in the lopinavir/ritonavir-treated ery case, due to multiple organ failure or immunodeficiency, so a
group. No significant side effects were observed in either group. clinical trial is required to determine its feasibility and efficacy. In
This combination therapy has been recommended by the National another report, an uncontrolled case series of five critically ill pa-
Health Commission and National Administration of Traditional Chi- tients with COVID-19 and ARDS were treated with CPT containing
nese Medicine for the treatment of COVID-19 [104], with limited neutralizing antibodies, and this led to an improvement in their
clinical data available. An in-vitro study suggested that arbidol can clinical status [114]. In India, the Sree Chitra Tirunal Institute for
significantly inhibit SARS-CoV-2 infection at a concentration of 10– Medical Sciences and Technology has received approval for the use
30 μM [85]. of CPT for the treatment of patients with COVID-19 [115].
6.4.4. Convalescent plasma or blood plasma therapy

Convalescent plasma therapy (CPT) is akin to passive immuniza- 6.4.5. Vaccination for SARS-CoV-2
tion, and has been proposed as a preventive measure for SARS- To date, there is no evidence of a vaccine for SARS-CoV-2. Af-
CoV-2 infection. The principle of therapy is very simple, and based ter WHO’s response to the SARS-CoV-2 outbreak, a research and
on the premise that the plasma of a patient who has recovered development blueprint has been initiated to accelerate the devel-
from COVID-19 contains antibodies which are highly specific and opment of vaccines and therapeutics for the SARS-CoV-2 outbreak
have the ability to fight SARS-CoV-2 [107]. When antibodies ob- [116]. Under WHO’s coordination, several groups of scientists and
tained from recovered patients are ingested by a patient undergo- experts with diverse backgrounds around the world are working
ing treatment, they will start fighting the infection in the second on the development of a vaccine against SARS-CoV-2. According
patient. This is a potential treatment measure for those who are to one report, Bacille Calmette-Guérin (BCG) vaccine may be a po-
critically affected by the virus, and may be preventative in individ- tential candidate; however, WHO does not recommend the use of
uals at high risk of contracting the virus (e.g. healthcare workers, BCG vaccine for SARS-CoV-2 as little evidence is available on its
immediate families of patients and other high-risk contacts). potency [117]. Two clinical trials are addressing this question, and
Previously, CPT was employed successfully in the treatment of WHO will evaluate the evidence and announce when it is avail-
SARS [108], H1N1 [109], MERS [107] and H5N1 [110], with promis- able. Several vaccines are undergoing trials by various organiza-
ing efficacy and safety. A meta-analysis of 32 studies of SARS-CoV tions and research groups, including ChAdOx1 nCoV-19 (University
infection and severe influenza showed that CPT led to a significant of Oxford, 510 estimated participants, completion due May 2021)
reduction in mortality compared with placebo [111]. A pilot study [118], mRNA-1273 vaccine (Modern and Vaccine Research Centre;
on 10 patients with SARS-CoV-2 infection was conducted in China targets the spike protein of coronaviruses) [119] and other forms
to explore the feasibility of CPT [107]. A single transfusion of con- of vaccine [120].
7. Miscellaneous grated biomedical data which could be a possible link for identify-
ing treatment. The detection and quantification of biomarkers, such
Numerous attempts to identify a potential treatment are un- as cytokinins and IFNs, is important and useful in early screening
derway worldwide. Other individual drugs or classes of drugs of infection. The viral strands have different shelf lives on differ-
have been found to be effective in in-vitro experiments against ent surfaces. The presence of SARS-CoV-2 in human faecal matter
similar viruses, such as fusion peptide (EK1) [122], RNA synthe- has been confirmed, and it is known that the virus can survie in
sis inhibitors (e.g. TDF, 3TC), antibiotics (azithromycin) [46], anti- facal matter for a long duration. In underdeveloped nations, where
inflammatory drugs (e.g. hormones), neuraminidase inhibitors (e.g. faecal decomposition take place in open areas, the rate of contact
oral oseltamivir) and immunomodulators [36]. Additionally, Chi- with the virus may increase. Hence, faecal screening of patients
nese medicine, such as ShuFengJieDu capsules and Lianhuaqing- with COVID-19 is a promising challenge to understand transmis-
wen capsules, have shown potential in the prevention and treat- sion. The outer part of SARS-CoV-2 is made up of lipids that can be
ment of new respiratory infectious diseases such as influenza A disrupted by surfactant or handwashing. As discussed above, CPT
(H1N1) [121]. These drugs in combination with antiviral agents or blood plasma therapy could be a potential approach [107] in
can decrease the time required for viral shedding, or improve pa- the treatment of COVID-19, as patients who have recovered from
tients’ health conditions. Nonetheless, the efficacy and safety of COVID-19 have developed antibodies to SARS-CoV-2. Administra-
these drugs in COVID-19 need further evaluation and confirmation tion of these antibodies into an infected patient will help to pro-
by clinical experiments. vide a quick response against the infection. However, parameters
WHO has launched ‘Solidarity’, an international clinical trial to of clinical diagnosis will be required in this procedure, such as pa-
find an effective treatment for COVID-19 [122]. Four treatment op- tient’s clinical status and diagnosis of other disorders.
tions are being evaluated to assess their efficacy and safety against Natural resources such as plants and resinous matter with an-
viral infection, and other potential drug candidates may enter the tiviral characteristics are promising candidates for screening as
regimen at a later date. Until and unless there are satisfactory out- lead molecules for drug design and development for the treatment
comes from the various trials across the world, WHO and other of COVID-19. These existing natural resources will save time and
regulatory bodies – such as the Indian Council of Medical Re- be cost-effective in the current scenario of an international health
search and the European Union – are cautious about physicians emergency and lack of treatment modalities.
and healthcare professionals recommending or administering un- In future, the development of a biosensor (a device that can
proven treatments to patients with COVID-19. The agencies are also transform the biochemical signal into a measurable signal) with
concerned by individuals who are self-medicating with any types the ability to detect SARS-CoV-2 or a biomarker associated with
of medication which are thought to be effective (e.g. CQ) and caus- COVID-19 [124], wearable devices with the ability to detect clin-
ing serious side effects. ical symptoms/physiological signs related to the onset of SARS-
Very recently, a group of researchers from the Indian Institute CoV-2 (e.g. fever, cough and fatigue [125], and development of
of Technology, Delhi, India and Advanced Industrial Science & Tech- vaccine could help to achieve early detection and management
nology, Tsukuba, Japan revealed that Ashwagandha (Withania som- of SARS-CoV-2. Based on the authors’ experience [126,127] and
nifera, family solanaceae) and honeybee propolis contain bioactive other literature [128,129], a biosensor could be a promising so-
agents such as withanolides (from Ashwagandha) and caffeic acid lution to address fast screening of patients infected with SARS-
phenethyl ester (CAPE, from a mixture of honeybee propolis and CoV-2, and an alternative to the routinely employed RT-PCR tech-
fungal resin) that interact with a highly conserved protein, Mpro , nique. In one strategy, an optical biosensor could detect the pres-
of SARS-CoV-2 [123] using molecular docking tools. They found ence of SARS-CoV-2 in exhaled air, sneeze droplets or a swab sam-
that Wi-N (withanone) and CAPE bind to the substrate-binding ple from an individual, where biochemical signal generation is con-
pocket of Mpro of SARS-CoV-2 with equivalent efficacy and binding verted into a measurable optical signal such as colour change, co-
energies as an N3 protease inhibitor. Superimposition confirmed agulation or visual signal generation. For example, fluorescently
that all the ligands exhibited similar binding mechanisms, and the labelled biorecognition elements (nucleic acid, antibody, peptide)
binding free energies calculated using MM/GBSA for the N3 in- can be immobilized on the surface of nanoparticles (with the abil-
hibitor, CAPE and Wi-N were also comparable. This study predicted ity to quench the fluorescence, such as titanium dioxide nanopar-
that these natural compounds have the potential to inhibit the en- ticles, carbon nanotubes, graphene etc). In the absence of an anti-
zymes essential for virus survival, and will help in initial screening gen (virus in the present case), the fluorescence of labelled biore-
of anti-SARS-CoV-2 drugs. ceptors will be quenched due to fluorescence energy transfer be-
tween fluorescently labelled bioreceptors and nanoparticles. In the
8. Conclusions and future perspectives to control the presence of an antigen, the high-affinity molecular interaction be-
SARS-CoV-2 pandemic tween the antigen and the bioreceptors will lead to conformational
changes in the structure of bioreceptors, and result in fluores-
Since December 2019, SARS-CoV-2 has posed an ongoing threat cence recovery due to desorption from the nanoparticle surface or
to the human race. This viral strain infects host cells through ACE2 a decrease in the Förster resonance energy transfer phenomenon
to cause COVID-19, and also causes damage to the respiratory tract [126]. This signal can be analysed qualitatively for the presence of
and myocardium, although the specific mechanisms are still un- virus molecules by a switch on/off system [128], or could calcu-
certain. Patients infected with SARS-CoV-2 have an adverse prog- late these signals quantitatively against the concentration of anti-
nosis, and patients already suffering from cardiovascular disease, gen [129]. In another strategy, an aptasensor and immunosensor
ARDS and low immunity deserve particular attention. Based on the could be designed; for example, by capturing virion particles us-
spread of the epidemic in several countries, WHO declared this in- ing immobilized aptamer/antibody on a gold quartz crystal surface
fection to be a pandemic. SARS-CoV-2 has an incubation period mounted on an electrochemical quartz crystal nanobalance. The
of 2–14 days, and the infection is usually confirmed by PCR and binding of virion molecules to receptors will result in a change in
chest scan. To date, no medical treatment or vaccine is available to resonant energy or mass over the crystal surface, and the surface
treat COVID-19. Treatment with antiviral agents is essentially sup- can subsequently be regenerated with a regenerating agent (e.g.
portive, and higher doses have adverse effects. Therefore, there is 4.0 % w/v glycine or 0.10 M glycine), where lowering the pH will
an immediate need for medical treatment or a vaccine for COVID- break the binding interaction or regenration by addition of 1.0%
19. The BenevolentAI knowledge graph [93] shows features of inte- SDS [130,131]. Secondly, the addition of a surfactant (e.g. CTAB)
to the antigen eluted fraction will result in cell lysis by disrupting [13] Chan JF, Kok KH, Zhu Z, Chu H, To KK, Yuan S, et al. Genomic characteri-
the cell membrane of virion molecules, and the subsequent addi- zation of the 2019 novel human-pathogenic coronavirus isolated from a pa-
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Contents lists available at ScienceDirect

International Journal of Antimicrobial Agents

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2): a

1. Introduction avirus (SARS-CoV) and highly pathogenic inﬂuenza (avian inﬂuenza

Drug Administration Dosage Duration of treatment

Chloroquine phosphate Oral 500 mg twice per day <10 days

6.4.4. Convalescent plasma or blood plasma therapy

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