Minireview Highlight article

Novel 2019 coronavirus: Genome structure, clinical trials, and

outstanding questions

Manasi P Jogalekar1, Anurag Veerabathini2 and Prakash Gangadaran3,4

1
Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; 2Maxim Integrated Products Inc., Chandler, AZ
85225, USA; 3Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Kyungpook National University
Hospital, Daegu 41944, Republic of Korea; 4BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science,
School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
Corresponding author: Prakash Gangadaran. Email: prakash.gangadaran@hotmail.com: prakashg@knu.ac.kr

Impact statement Abstract

Early availability of the sequence, the Novel 2019 coronavirus has created havoc across the globe since its emergence in
genetic material of SARS-CoV-2 (the virus
December 2019 in Wuhan, China, and fast spreading potential. While we were able to
that causes COVID-19), has prompted
efforts towards identifying a safe and identify the causative agent within a few days of the disease outbreak, several questions
effective vaccine in the current public still remain unanswered. In this review, we discuss the extent of virus spread, current sta-
health emergency. To that end, under-
standing the pathophysiology of disease is tistics, SARS-CoV-2 genome organization, comparison between the novel coronavirus and
crucial for scientists around the world. causative agents involved in previous outbreaks, ongoing clinical trials and myths associ-
Since conventional vaccine development
and manufacturing may take several years, ated with the virus. Lastly, we provide insights into the future perspectives which could
it is important to think about alternative prove useful for the scientific community as they work on finding the cure against the
strategies that we could use to mitigate
imminent catastrophe. We hope that this
disease.
article will open up new avenues and pro-
vide insights that could potentially save
hundreds of lives affected by COVID-19.

Keywords: SARS-CoV-2, COVID-19, coronavirus, Wuhan, 2019-nCoV, MERS-CoV, SARS-CoV, China

Experimental Biology and Medicine 2020; 245: 964–969. DOI: 10.1177/1535370220920540

The beginning identified as novel severe acute respiratory syndrome

coronavirus 2 (SARS-CoV-2) or also referred to as
A deadly coronavirus infection originated in China in late
2019-nCoV.2
December 2019, when a group of people visiting China
COVID-19 is characterized by symptoms such as fever,
Seafood Market in Wuhan developed an unusual respira- sore throat, lesions in lungs, and difficulty in breathing.3
tory syndrome. By the time Chinese authorities announced People have also experienced dry cough, lymphopenia,
the outbreak, the disease had already spread among several fatigue, anorexia, arrhythmia, and shock.4 The severity of
people.1 Unfortunately, the Chinese doctor who suspected symptoms depends on the overall health of a person, extent
the possibility of Middle East respiratory syndrome of spread and virulence of the strain. A study involving
(MERS)-like disease outbreak has died due to exposure to infected people in Wuhan showed a tad higher incidence
the very same virus. The infection spread globally within a in males (54.3%) than females.4 While children are equally
short time due to extensive international travel to celebrate prone to getting infected as adults, the severity of symp-
Chinese Lunar New Year. Scientists worldwide have now toms appears to be less in children compared to adults.5,6
established that the mysterious illness is coronavirus dis- However, researchers are still gathering more evidence to
ease 2019 (COVID-19) and the virus associated with it is back this observation.

ISSN 1535-3702 Experimental Biology and Medicine 2020; 245: 964–969

Copyright ! 2020 by the Society for Experimental Biology and Medicine
 Jogalekar et al. Novel 2019 coronavirus 965
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Current statistics and global situation the nose while sneezing and coughing, can go a long way. It
is always a better idea to self-quarantine for a few days if
As of 28 March 2020, 649,904 confirmed cases have been
you are sick rather than going to work and putting others at
found globally, out of which 81,999 cases are in China. The
risk. Similarly, it is also important to stay away from people
number of confirmed cases and deaths in Hubei Province
who are sick and advise them to get tested.
alone has gone up to 67,801 and 3177, respectively. The
cumulative number of deaths in Mainland China has
reached 3299. Apart from China, 567,905 cases and 26,950 SARS-CoV-2 genome structure
deaths have been confirmed in 199 countries so far; the 2019-nCoV (a group 2B CoV) genome has been successfully
United States (Cases: 115,547; deaths: 1891), Italy (Cases: sequenced using a sample isolated from a positive patient,
92,472; deaths: 10,023) and Spain (Cases: 72,248; deaths: a noteworthy accomplishment in itself.15,16 Molecular tests
5812) being the worst-hit countries outside China.7 developed using this data have been tremendously helpful
Although, 137,283 out of the total number of infected in determining the accurate number of COVID-19 cases.
people worldwide recovered, it has recently been indicated Homology analysis revealed that both SARS-CoV-2 and
that they may have reduced lung function on a long-term SARS-CoV have
73% similar receptor binding domains
basis and this aspect of COVID-19 warrants further inves- with 8 out of 14 amino acid residues conserved in SARS-
tigation.7,8 Most of the reported cases are likely due to being CoV-2.15
in contact with the affected individual, knowingly (to care Like other coronaviruses, SARS-CoV-2 genome is
for their loved one) or unknowingly (by being admitted to made up of a single-stranded RNA, about
30 kb in size
the hospital where COVID-19 patients were being treated, (Figure 1). The genome encodes for both structural and
to receive treatment for other ailments or by being around non-structural proteins. Structural proteins include spike
an asymptomatic person).9 Interestingly, reports indicate glycoprotein (S; consists of 2 domains—S1 and S2), enve-
that the people who had no apparent connection with lope protein (E), membrane protein (M), and nucleocapsid
China Seafood Market have also been infected, confirming protein (N), all situated near 30 end of the strand.17 Lu
human-to-human transmission.10 It is likely that there are et al.15 suggests that S protein binds to angiotensin-
more cases than the above-mentioned numbers, since the converting enzyme 2 (ACE2) receptor in humans with
people with mild sickness may self-quarantine, and there- high affinity via its receptor-binding domain (RBD) to facil-
by go unreported. The Center for Systems Science and itate host cell entry. SARS-CoV-2 S-protein is also capable of
Engineering (CSSE) at Johns Hopkins University has devel- binding ACE2 receptors from bat, civets, and swine.18
oped a user-friendly and an interactive web-based tool to Enzymes such as papain‑like cysteine protease and
enable research community and public health officials to 3C‑like serine protease (3CL-protease) are located near 50
track COVID-19 cases in real-time.7 Bespoke Inc. has devel- end of the open reading frame and play a role in the pro-
oped a Chatbot called “Bebot” using artificial intelligence teolytic breakdown of polyprotein 1a (pp1a) and pp1ab to
tools that keeps people updated with the latest information form non-structural proteins such as RNA‑dependent
on the coronavirus and suggests preventive measures to RNA polymerase, helicase, and endoribonuclease. These
take to avoid infection.11 proteins enable viral replication and transcription. Crystal
World Health Organization (WHO) has declared global structures of spike protein and various enzymes encoded
health emergency and has identified COVID-19 as a pan- by SARS-CoV-2 genome have been deposited in protein
demic.12,13 In an effort to contain COVID-19 outbreak, data bank (PDB).19–22
travel restrictions and lockdown of cities within China
have been imposed. Other countries are also enforcing sim- Comparison of SARS-CoV-2 with severe
ilar restrictions on domestic and international travel, with acute respiratory syndrome coronavirus
increased scrutiny being conducted for passengers arriving
(SARS-CoV) and Middle East respiratory
from China. As a result, COVID-19 cases in China are going
down, while those in other countries are rising. Health care syndrome coronavirus (MERS-CoV)
workers and medical doctors are working overtime and on Due to technological advances, SARS-CoV-2 genome was
weekends to treat existing and new cases that are being sequenced within a month of an outbreak, while it took
added to the COVID-19 patient pool each day. It is of several months to identify causative agents in previous out-
utmost importance that we do our share to help mitigate breaks as SARS- and MERS-CoV.
this global pandemic. SARS-CoV-2 being a respiratory Phylogenetically, SARS-CoV-2 has shown the closest
virus, its transmission could occur within six feet through association with a couple of bat coronaviruses, bat-SL-
droplets released via infected person’s coughing and sneez- CoVZC45, and bat-SL-CoVZXC21 (88%), then with SARS-
ing.10 A striking new study has indicated that SARS-CoV-2 CoV (79%), and lastly with MERS-CoV (50%).15 RaTG3,
can stay in the air up to 3 h after being aerosolized and another bat CoV sequence, has shown 92% sequence iden-
anywhere from 4 h to three days on surfaces.14 There are a tity with SARS-CoV-2.18 S protein and protein 13 of SARS-
few basic precautions that each one of us can and should CoV-2 have shown the lowest sequence identity (80% and
take. Simple things like washing hands thoroughly before 73% respectively) with other group 2B CoVs, compared to
and after meals as well as after using toilet, avoiding touch- other proteins (>90% sequence identity).15 It has been sug-
ing face (eyes, nose, and mouth) with hands, sanitizing gested that furin, a host cell enzyme found in small intes-
doorknobs or other surfaces before touching, and covering tines, lungs and liver, activates a site on the SARS-CoV-2 S
966 Experimental Biology and Medicine Volume 245 June 2020
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Figure 1. Genomic organization of SARS-CoV-2.15 SARS-CoV-2 genome consists of
30 Kb RNA strand. It is organized as follows: 50 end, Papain like protease,
3C‑like serine protease (3CL-protease; PDB ID: 6Y2E), RNA-dependent RNA polymerase, Helicase, Endoribonuclease (PDB ID: 6VWW), Spike protein (PDB ID: 6VSB)
containing receptor-binding domain (RBD; PDB ID: 6VW1) which binds to a human receptor—angiotensin converting enzyme 2 (ACE2), envelope protein (E), mem-
brane protein (M), and nucleocapsid protein (N), 30 end. Enzymes are essential for viral replication and spike protein is needed for host cell entry. *Created with
BioRender. (A color version of this figure is available in the online journal.)

protein, justifying rapid worldwide spreading of COVID- able to spread via healthcare workers just like its counter-
19 infection and symptoms observed in COVID-19 parts, indicating the possibility of super spreading.31,32
patients.23 S protein encoded by SARS-CoV-2 was also con- Super spreading events can be triggered by host factors33
siderably longer than other viruses.15 Epidemiological data and sometimes even via animals.34 Although all three
suggest that the estimated transmission rate of SARS-CoV-2 viruses maintain low R0 (the number of people infected
is similar to that of SARS- and MERS-CoV.24 Yet, SARS-CoV by a single patient), sudden rapid increase in the number
(10% mortality) and MERS-CoV (37% mortality) have been of SAR-CoV-2 cases suggest super spreading events at play.
found to be more lethal than SARS-CoV-2 (
2% fatality).9,25 In an effort to understand viral transmission, serial inter-
Like MERS-CoV, SARS-CoV-2 has an incubation period of val and incubation period for SARS-CoV-2 were deter-
5.2 days on average and death of the infected patient occurs mined. Results suggest shorter serial interval periods
within a median duration of 14 days from the onset of (
5–6 days) as well as viral shedding one to two days
symptoms, with this duration being 11.5 days in elderly prior to the onset of symptoms, indicating possible pre-
people 70 years of age.26,27 symptomatic transmission of SARS-CoV-2.35 What’s more,
Coronaviruses are zoonotic in nature, which means that a science news article reported the presence of viral RNA in
they have the ability to transmit between animals and blood, stool, sputum, and urine of patients long after the
end of symptoms, indicating multiple routes of
humans. It is likely that SARS-CoV-2 may also have had
transmission.36
intermediate animal host before it was transmitted to
humans, similar to SARS-CoV and MERS-CoV.15 SARS-
CoV-2 has been found to infect people of all ages including Current efforts to develop intervention and
individuals older than 50 as well as anyone having under- clinical trials
lying conditions such as cardiovascular disease, respiratory Coronavirus research is moving forward at record speed.
ailments, and diabetes. Similar trends were observed in Currently, there is no cure for 2019-nCoV infection.
previous outbreaks caused by SARS- and MERS-CoV.28,29 However, government agencies, global scientific communi-
Rothe et al.30 reported that asymptomatic patients are ty, public health officials, and medical doctors have come
also capable of transmitting SARS-CoV-2; a similar phe- together in an unprecedented fashion to tackle the corona-
nomenon was observed in case of MERS-CoV but not in virus problem from all angles. A quick search of
SARS-CoV.31 Initial reports suggest that SARS-CoV-2 is Clinicaltrials.gov with keywords “COVID-19” and “Novel
 Jogalekar et al. Novel 2019 coronavirus 967
...............................................................................................................................................................
2019 Coronavirus” shows
66 ongoing trials in various Distinguishing facts from myths
phases studying various aspects of COVID-19 and screen-
With the overwhelming amount of new information being
ing potential drug candidates.37
shared each day, it is easy to miss the fine line between facts
Within weeks of the outbreak, pharmaceutical compa-
and untrue stories or baseless claims. For example, the
nies Co-Diagnostics and Novacyt developed molecular
claim that hot baths can prevent us from getting COVID-
tests that specifically recognize 2019 coronavirus.38,39
19 is not true. Similarly, cold temperatures, hand dryers,
A pharmaceutical giant, Gilead and a biotech startup,
ultraviolet lamps, and antibiotics cannot kill SARS-CoV-2.
Moderna therapeutics, have developed a small molecule
No matter what the external temperatures are, human body
antiviral called remdesivir and novel mRNA vaccine
respectively, against 2019-nCoV. Remdesivir has previously temperature always remains constant (37 C). Likewise, we
been used to treat Ebola- and MERS-CoV-infected patients. do not have any information to validate the claims that
Since MERS-CoV exhibits similarities to SARS-CoV-2, the garlic, chlorine baths, or pneumonia vaccine are effective
drug molecule is being tested in COVID-19 patients.40 The against SARS-CoV-2. In addition, there is no evidence to
results for clinical trials NCT04280705, NCT04292730, and substantiate the claim that SARS-CoV-2 spreads via mos-
NCT04292899 are highly anticipated.41 In addition, chloro- quitoes.45 Unfortunately, panic situations created by such
quine, a drug routinely used in the clinic to treat malaria, myths have forced the general public to stock up on sup-
has shown success in inhibiting 2019-CoV replication plies even though they are not at risk, thereby resulting in
in vitro.27 On the contrary, Moderna has employed a disruption of supply chains, crashing of stock markets,
novel strategy for their vaccine by delivering chemically price surging, and shortage of essential supplies like
synthesized mRNA encoding instructions for the S protein gloves, masks, and goggles, putting health care workers
using lipid nanoparticles (NCT04283461).40 Inovio at risk across the globe.45,46 To meet an increasing
Pharmaceuticals Inc. is developing and testing a DNA- demand, governments and industries have been asked to
based vaccine in preclinical models.41 Companies like up their manufacturing by 40%.46 To avoid this situation
Sanofi and Janssen are working on cell-based vaccines.40 from happening again, we request our readers to validate
Regeneron pharmaceuticals and Vir Biotechnology are the information using trusted sources before sharing it on
developing neutralizing monoclonal antibodies, the social media platforms.
approach that worked against Ebola, SARS-CoV, and
MERS-CoV infections, and testing in preclinical Outstanding questions and future
models.40,41 Several clinical trials are exploring the poten- perspectives
tial of interferon alpha and beta (IFN-a and IFN-b) as well
as anti-retroviral drugs such as Lopinavir/Ritonavir (nor- While the scientific community all over the world is racing
mally used to treat HIV) to fight COVID-19. to find a cure for 2019-nCoV infection, some key questions
Recent study demonstrates that SARS-CoV-2 uses ACE2 still remain unanswered. The sources of primary COVID-19
for host cell entry and is dependent upon TMPRSS2, the infection and its subsequent transmission as well as
serine protease, for S protein priming, indicating that using involvement of any intermediate animal hosts are still
TMPRSS2 inhibitors could be an effective intervention unclear. In addition, there is a lot of uncertainty regarding
strategy to block viral entry into the host.42 The same the pathophysiological mechanisms of SARS-CoV-2
human receptor was used by SARS-CoV to facilitate entry advent. The sooner we find answers to these pressing ques-
into the lower respiratory tract epithelial cells.43 As dis- tions, the better chance we would have at stopping the
cussed previously, blockade of ACE2 receptor and furin spread of COVID-19 infection. We have some promising
enzyme may prove beneficial in preventing viral entry leads in terms of finding the source of primary infection
into the host cells. and the transmission of the virus. For example, one study
Another approach that has shown promise in China is has reported the involvement of two different viral strains
the use of a technique called plasmapheresis, where plasma in COVID-19 outbreak.47 Recent reports also suggest
rich in antibodies against SARS-CoV-2 is taken from recov- human-to-human transmission of the virus as well as the
ered patients and injected into sick patients. It has been possibility of transmission via snakes48 or bats15 but further
observed that COVID-19 patients had better blood oxygen- experiments are needed to confirm this information. There
ation and reduced inflammation, 24 h post-injection of anti- is an urgent need to generate animal models of COVID-19
bodies. In the United States, this approach is being in order to determine in vivo response to SARS-CoV-2.
implemented by the Mount Sinai Health System in While both SARS-CoV and MERS-CoV were able to infect
New York.44 non-human primates, the potential of SARS-CoV-2 to infect
Most of the clinical trials mentioned above are going other species is still unknown.
to take
3–6 months to complete phase I and another While it is remarkable that several pharmaceutical com-

6–8 months for phase II before they can get an approval. panies are developing vaccines and antivirals for COVID-
In the meantime, we will have to rely on supportive care to 19, the potential drug candidates will have to go through
treat COVID-19 patients by administering antipyretics for various regulatory channels before getting approval. Once
fever, expectorants for cough, oxygen therapy for severe the vaccine formulations are approved, companies will
dyspnea, antibiotics for sepsis, and Glucocorticoids need to manufacture the doses in large amounts to meet
(adults) or methylprednisolone (children) to mitigate increasing global demand. To ensure that the entire vaccine
body’s immune response.4,12 development process goes smoothly, large funds are
968 Experimental Biology and Medicine Volume 245 June 2020
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needed. The Bill and Melinda Gates Foundation recently coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nat
launched COVID-19 Therapeutics Accelerator in collabora- Microbiol 2020;5:536–44
3. Wuhan Municipal Health Committee, www.wuhan.gov.cn/front/
tion with Wellcome and Mastercard to help identify treat-
web/showDetail/2019123108989 (accessed 7 March 2020)
ments for COVID-19. The joint venture is backed by a 4. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z,
generous funding of $125 million.49 Bill Gates, in his recent- Xiong Y, Zhao Y, Li Y, Wang X, Peng Z. Clinical characteristics of 138
ly published the New England Journal of Medicine article, hospitalized patients with 2019 novel coronavirus-infected pneumonia
urges national governments as well as private organiza- in Wuhan, China. JAMA 2020;323:1061–9
tions to support low- and middle-income countries 5. Key coronavirus question: how are children affected? – Harvard
(LMICs), usually the hardest-hit population in such situa- Gazette, https://news.harvard.edu/gazette/story/2020/02/key-coro
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tion.50 Since the process of vaccine development takes a lot
6. Dong Y, Mo X, Hu Y, Qi X, Jiang F, Jiang Z, Tong S. Epidemiology of
of time, it may be a better idea to screen currently existing COVID-19 Among Children in China. Pediatrics 2020; e20200702
drugs for their ability to treat COVID-19. That way, we may 7. Dong E, Du H, Gardner L. An interactive web-based dashboard to track
be able to find a solution quickly and in a cost-effective COVID-19 in real time. Lancet Infect Dis. Epub ahead of print 19
manner. In addition, each country should implement emer- February 2020. DOI: 10.1016/S1473-3099(20)30120-1
gency action plan to manage a pandemic situation like 8. Lei J, Li J, Li X, Qi X. CT imaging of the 2019 novel coronavirus (2019-
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COVID-19 - 11 March 2020, www.who.int/dg/speeches/detail/who-
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