Current and future therapeutical approaches for COVID-19

Abstract

We review the evolution of our clinical understanding of COVID-19, possible therapeutic targets, and prospects for COVID-19 management.

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Please
cite
this
article
in
press
as:
Duan,
Y.
et
al.
Current
and
future
therapeutical
approaches
for
COVID-19,
Drug
Discov
Today
(2020),
https://doi.org/10.1016/j.drudis.2020.06.018
Drug
Discovery
Today Volume
00,
Number
00 June
2020
REVIEWS
Current
and
future
therapeutical
approaches
for
COVID-19
Yongtao
Duan
1,5
,
Yongfang
Yao
2,5
,
Senthil
Arun
Kumar
3
,
Hai-Liang
Zhu
1,4
and
Junbiao
Chang
2
1
Henan
Provincial
Key
Laboratory
of
Children's
Genetics
and
Metabolic
Diseases,
Children's
Hospital
Affiliated
to
Zhengzhou
University,
Zhengzhou
University,
Zhengzhou
450001,
China
2
School
of
Pharmaceutical
Science,
Zhengzhou
University,
Zhengzhou,
Henan
450001,
China
3
Department
of
Endocrinology
and
Metabolism,
Genetics,
Children's
Hospital
Affiliated
to
Zhengzhou
University,
Zhengzhou
University,
Zhengzhou
450001,
China
4
State
Key
Laboratory
of
Pharmaceutical
Biotechnology,
Nanjing
University,
Nanjing
210093,
China
Coronavirus
2019
(COVID-19),
the
WHO-classified
novel
coronavirus
of
severe
acute
respiratory
syndrome
coronavirus
2
(SARS-CoV-2),
has
rapidly
become
a
global
pandemic.
To
tackle
both
its
spread
and
virulence,
research
is
ongoing
worldwide
to
develop
an
effective
anti-COVID-19
drug
or
vaccine.
In
this
review,
we
explore
the
clinical
understanding
and
severity
of
COVID-19
emergence
across
the
world,
with
a
focus
on
China.
We
also
discuss
potential
therapeutic
targets,
either
host
virus
based,
that
could
be
used
to
tackle
the
COVID-19
outbreak.
Introduction
During
the
early
weeks
of
December
2019,
the
first
case
of
pneu-
monia
caused
by
the
novel
coronavirus
defined
as
COVID-19
by
the
WHO
was
reported
in
Wuhan,
the
capital
city
of
Hubei
province,
China
[1].
Local
daily-wage
employees
of
the
Huanan
Seafood
Market
in
Wuhan
were
believed
to
be
the
initial
COVID-
19
carriers,
infecting
a
large
proportion
of
the
population
of
Wuhan
[2,3].
Since
its
emergence
and
as
of,
June
24,
2020,
COVID-19
had
infected
85098
individuals
across
China.
At
the
time
of
completion
of
the
review-draft
(by
24th
June
2020),
the
Iran,
Italy,
Chile,
Peru,
Spain,
UK,
India,
Russia,
Brazil,
and
USA
had
recorded
the
highest
population
count
of
COVID-19
cases,
ranging
from
209,970
to
2,424,492,819
to
1,573,
(www.
worldometers.info/coronavirus/).
Thus
far,

9,373,424
cases
of
COVID-19
have
been
recorded
worldwide,
with
the
total
number
of
deaths
reaching
480,140,
and
the
number
of
recovered
patients
5,062,840,
(www.worldometers.info/coronavirus/).
Although
SARS-CoV-2-encoded
proteins
share
similar
homolo-
gous
structures
with
SARS-CoV,
the
spike
(S)
ectodomain
of
the
COVID-19
virus
shows
a
higher
binding
affinity
(15
nM)
for
the
angiotensin-converting
enzyme
2
(ACE2)
receptor
protein
of
the
upper
bronchial
system,
which
is
10–20-fold
higher
compared
with
SARS-CoV.
Thus,
this
facilitated
the
unprecedented
transmis-
sion
of
COVID-19
among
humans
[4].
The
SARS-CoV-2
strain
can
spread
through
all
modes
of
physical
contact,
including
sneezing
and
coughing
[5].
A
higher
level
of
COVID-19
cases,
87%,
has
been
recorded
among
the
adult
and
older
population
groups
(30–79
years
of
age)
[6].
Contradictorily,
a
moderate
(3%)
and
a
small
(1%)
number
of
cases
have
been
recorded
in
the
older
population
group
(80
years
old)
and
the
younger
population
group
(10–19
years)
[6].
Concomitantly,
people
with
prior
respiratory
ail-
ments
and
metabolic
complications,
such
as
type
2
diabetes
mellitus,
hypertension,
cardiovascular
complications,
and
can-
cer,
are
highly
susceptible
to
COVID-19
infection
with
in-
creased
mortality
[6,7].
Consistent
with
earlier
clinical
evidence
that
SARS-CoV
and
Middle
East
respiratory
syndrome
coronavirus
(MERS-CoV)
affected
males
more
than
females
[8],
Reviews 
Corresponding
authors:.
Zhu,
H.-L.
(zhuhl@nju.edu.cn),
Chang,
J.
(changjunbiao@zzu.edu.cn)
5
These
authors
equally
contributed
to
this
paper.
1359-6446/ã
2020
Elsevier
Ltd.
All
rights
reserved.
https://doi.org/10.1016/j.drudis.2020.06.018
www.drugdiscoverytoday.com
1

the
prevalence
of
COVID-19
has
been
recorded
in
the
male
population
at
a
higher
rate
compared
with
that
of
the
female
population
[3].
It
might
be
that
estrogen
receptor
activation
and
its
associated
signaling
cascades
in
females
confer
increased
protection
against
infection
with
COVID-19,
similar
to
the
results
of
clinical-based
research
studies
with
SARS-CoV
and
MERS-CoV
[9].
Moreover,
some
patients
with
SARS-CoV-2
have
become
infected
with
virus
from
asymptomatic
carriers
who
do
not
show
any
obvious
clinical
symptoms,
such
as
flu,
tiredness,
fever,
and
dry
cough,
but
are
able
to
pass-on
COVID-19
to
healthy
individu-
als
either
by
direct
or
indirect
physical
contact
through
nasal
droplets
and
sneezing
[10].
In
addition
to
this
major
barrier
to
the
control
of
COVID-19
spread,
it
is
difficult
to
control
the
spread
of
disease
from
recovered
patients
to
healthy
individuals
[11,12].
In
this
review,
we
focus
on
clinical
trials
involving
drugs
against
COVID-19,
potential
clinical
therapeutic
targets,
and
the
future
directions
of
COVID-19
management.
Clinical
lessons
learned,
current
therapeutic
molecules,
and
prospects
for
COVID-19
management
As
depicted
in
Fig.
1,
all
nonstructural
proteins
(NSPs),
which
represent
virus-based
targets,
are
crucial
for
the
design
of
thera-
peutic
efforts
to
ameliorate
colonization
of
the
virus
in
the
host,
especially
in
the
upper
bronchial
system.
The
catalytic
sites
of
the
functional
NSPs
of
the
Coronaviridae
can
be
targeted
to
attenuate
SARS-CoV,
MERS-CoV,
and
SARS-CoV-2
virulence.
Moreover,
the
functional
NSPs
interact
with
the
host
ACE2
to
enable
coronaviral
entry
to
the
cells
[13].
Given
the
current
lack
of
vaccines
to
either
attenuate
or
prevent
COVID-19
transmission,
targeting
any
of
the
crucial
invasion
steps
of SARS-CoV-2,such as the virus entry,transcription and
translation,
genome
synthesis
and
assembly,
and
virus
release
would
be
effective
in
reversing
its
pathogenesis
and
transmission
in
humans.
To
target
the
initial
colonization
of
SARS-CoV-2,
research
has
focused
on
the
use
of
potential
antiviral
agents
used
against
other
viruses,
such
as
SARS-CoV,
MERS-CoV,
hepatitis
B,
hepatitis
C,
HIV,
and
common
influenza
viruses
[14].
Past
lessons
During
the
initial
stages
of
the
COVID-19
outbreak,
from
late
December
2019
to
early
February
2020,
during
40,000
cases
were
confirmed
and
850
people
died
across
China,
patients
in
clinical
trials
were
treated
with
drugs
that
were
found
to
be
generally
ineffective
at
against
the
virus.
One
such
drug
was
oseltamivir,
selected
because
COVID-19
symptoms
include
fever
and
other
symptoms
common
to
influenza
infections
[15].
Oseltamivir
is
a
potent
neuraminidase
inhibitor
that
effectively
attenuates
the
virulence
of
influenza
viruses
A
and
B,
but
did
show
any
noticeable
effects
against
COVID-19
because
the
virus
does
not
secrete
neur-
aminidase
[16].
Moreover,
the
treatment
of
patients
with
COVID-
19
with
antibacterial
drugs,
including
moxifloxacin,
ceftriaxone,
and
azithromycin,
either
as
a
single
drug
or
in
combination,
showed
little
health
benefit
[17].
In
addition,
the
long-term
use
of
a
higher
dose
of
antibiotics
during
the
COVID-19
outbreak
was
found
to
be
linked
with
the
adverse
clinical
symptoms
of
severe
respiratory
ailments,
including
hyperinflammation,
shock,
circu-
latory
impairment,
and
other
organ
damage.
Corticosteroids
mimicking
the
natural
corticosteroids
of
the
human
body
have
been
commonly
used
to
treat
patients
with
defective
adrenal
glands
who
fail
to
synthesize
sufficient
levels
of
corticosteroids
[18].
However,
corticosteroids
have
also
been
wide-
ly
prescribed
at
a
higher
dose
in
patients
with
immunological
disorders,
inflammation,
and/or
an
impaired
salt/water
balance
[18].
Nevertheless,
there
is
no
clear
clinical
evidence
of
the
core
therapeutic
benefits
of
corticosteroids
in
treating
respiratory
symptoms
of
respiratory
syncytial
virus
(RSV),
common
influenza
viruses,
SARS-CoV,
and
MERS-CoV
[19,20].
Research
was
con-
ducted
to
evaluate
the
efficacy
of
corticosteroids
in
low
to
mild
doses
for
treating
the
adverse
clinical
symptoms
induced
by
cor-
onaviruses
[21].
Concomitantly,
patients
with
COVID-19
were
treated
with
corticosteroids
as
a
supplementary
drug
for
a
minimal
duration
of
3–15
days,
with
no
substantial
improvement
in
symp-
toms
[6,15].
This
shortened
treatment
time
was
because
cortico-
steroid
are
well
known
for
their
long-term
adverse
effects
and
other
secondary
level
complications
[16,22].
Thus,
this
lack
of
success
with
the
aforementioned
drugs
also
contributed
to
the
increased
mortality
among
patients
with
COVID-19
across
China,
alongside
impairments
in
the
early
diag-
nosis
and
treatment
of
COVID-19;
delayed
action
from
healthcare
professionals
to
break
the
virus
transmission
chain;
a
poor
under-
standing
of
COVID-19
virulence
and
its
transmission
efficacy
among
the
common
population;
and
inadequate
clinical
diagnos-
tic
kits
and
other
essential
medical
facilities,
such
as
respiratory
ventilators,
protective
medical
gowns
and
gloves,
to
handle
patients
critically
ill
with
COVID-19
[23].
Present
therapeutics
with
clinical
significance
for
COVID-19
management
Chemical
agents
To
manage
the
emerging
COVID-19
outbreak
and
its
associated
mortality,
300
clinical
trials
have
been
performed
on
patients
with
COVID-19
in
China
[24].
Some
of
the
clinical
drugs
used
in
these
trials
have
shown
promising
results
in
reversing
COVID-19
clinical
symptoms
[25]
(Table
1).
To
tackle
the
SARS-CoV
epidemic,
lopinavir
and
ritonavir
drug
combinations
[US
Food
and
Drug
Administration
(FDA)
approved]
that
inhibit
viral
3-chymotrypsin-like
cysteine
protease
[33],
sup-
plemented
withribavirin,effectively
controlled
SARS-CoV
virulence
and
the
associated
mortality
rate
[34].
Such
outcomes
resulted
in
14
clinical
trials
using
lopinavir
and
ritonavir
drug
combinations
to
treat
patients
with
COVID-19.
That
lopinavir
and
ritonavir
drug
combinations
effectively
attenuated
the
adverse
clinical
symptoms,
such
as
fever,
of
five
patients
with
COVID-19
demands
further
clinical
validation
[35].
By
contrast,
a
recent
clinical
trial
using
these
drug
combinations
failed
to
show
any
noticeable
therapeutic
effects
on
the
adult
patients
with
COVID-19
over
other
patients
who
received
standard
medication
[36].
Thus,
there
is
a
need
for
a
more
in-depth
clinical
trial
on
these
drug
combinations.
Ribavirin,
another
FDA-approved
effective
antiviral
drug
com-
monly
used
to
treat
hepatitis
C
virus
and
RSV,
has
been
widely
referred
to
in
combinations
with
effective
antibiotics
and/or
with
or
without
hormonal
treatment
[16].
As
a
potent
inhibitor
of
the
viral
RNA-dependent
RNA
polymerase
(RdRp),
ribavirin
effectively
controlled
COVID-19
virulence
when
co-administered
with
rito-
navir/lopinavir
drug
combinations
[27].
REVIEWS
Drug
Discovery
Today Volume
00,
Number
00 June
2020
DRUDIS-2718;
No
of
Pages
8
Please
cite
this
article
in
press
as:
Duan,
Y.
et
al.
Current
and
future
therapeutical
approaches
for
COVID-19,
Drug
Discov
Today
(2020),
https://doi.org/10.1016/j.drudis.2020.06.018
2
www.drugdiscoverytoday.com
Reviews 

Given
that
chloroquine
derivatives
exhibited
a
strong
inhibito-
ry
action
against
SARS-CoV
colonization
[16,37],
clinicians
showed
that
chloroquine
derivatives
together
with
remdesivir
effectively
controlled
the
proliferation
of
a
clinically
isolated
SARS-CoV-2
strain
[28].
A
clinical
trial
using
chloroquine
phos-
phate
to
treat
COVID-19
virulence
has
since
been
approved
by
the
National
Health
Commission
of
the
People’s
Republic
of
China
[38].
Arbidol,
a
potent
antiviral
drug
targeting
virus-associated
in-
flammatory
cytokines,
has
been
used
to
treat
patients
with
COVID-19
and
severe
pneumonia;
it
has
not
shown
any
adverse
effects
and,
thus,
is
under
study
in
both
China
and
Russia
[39].
In
Drug
Discovery
Today Volume
00,
Number
00 June
2020
REVIEWS
DRUDIS-2718;
No
of
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Please
cite
this
article
in
press
as:
Duan,
Y.
et
al.
Current
and
future
therapeutical
approaches
for
COVID-19,
Drug
Discov
Today
(2020),
https://doi.org/10.1016/j.drudis.2020.06.018
Host receptor
(DPP4/ACE2)
Endosomal
pathway
Non-endosomal pathway
Replication-transcription
complex
Genome replication
Budding and assembly
Vesicle
Exocytosis
mRNA sythesis and spllicing
Translation
Host-based target
Virus-based target
Translation of ORF1a/b
Translation of ORF1a/b
Rough ER
pp1a
pp1ab
DPP4/ACE2
inhibitor
Furin
inhibitor
Cathespin inhibitor
TMPRSS2
inhibitor
Endosomal acidification
inhibitor
PLpro/3CLpro
inhibitor RdRp/Hel
inhibitor
Membrane-binding
photosensitizer
Interferon inducers Recombinant
interferon α and
β
nsp 1-16
Drug Discovery Today
FIGURE
1
Virus-based
and
host-based
targets
against
the
coronavirus
replication
cycle.
Coronaviruses,
including
severe
acute
respiratory
syndrome
coronavirus
2
(SARS-
CoV-2)
gain
the
entry
into
the
host
cell
via
the
endosomal
pathway
and/or
the
cell
surface
non-endosomal
pathway.
Viral
translation,
replication,
assembling
and
exocytosis
then
occur
using
key
proteins,
which
could
be
potential
therapeutic
targets
against
SARS-CoV-2.
Abbreviations:
3CLpro,
3-chymotrypsin-like
cysteine
protease;
ACE2,
angiotensin-converting
enzyme
2;
AP,
accessory
protein;
DPP4,
dipeptidyl
peptidase
4;
E,
envelope;
ER,
endoplasmic
reticulum;
Hel,
helicase;
M,
membrane;
N,
nucleocapsid;
ORF,
open
reading
frame;
PLpro,
protease
papain-like
protease;
RdRp,
RNA-dependent
RNA
polymerase;
S,
spike;
TMPRSS2,
transmembrane
serine
proteases
2.
www.drugdiscoverytoday.com
3
Reviews 

REVIEWS
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Discovery
Today Volume
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Number
00 June
2020
DRUDIS-2718;
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of
Pages
8
Please
cite
this
article
in
press
as:
Duan,
Y.
et
al.
Current
and
future
therapeutical
approaches
for
COVID-19,
Drug
Discov
Today
(2020),
https://doi.org/10.1016/j.drudis.2020.06.018
TABLE
1
Summary
of
anti-SARS-CoV-2
compounds
against
COVID-19
currently
in
clinic
trials
Names
Structure
targets
Original
indication
Activity
against
SARS-CoV-2
reported
No.
of
clinic
trials
Refs
Lopinavir/ritonavir
Protease;
3CLpro;
CYP3A4
HIV
Yes
14
[26]
Ribavirin
RdRp
HCV
and
RSV
Yes
(EC
50
=
109.5
mM)
2
[27,28]
Chloroquine
Endosomal
acidification
Malaria
Yes
(EC
50
=
1.13
mM)
20
[28]
Hydroxychloroquine
Endosomal
acidification
Malaria
No
10
Arbidol
Clathrin-
dependent
trafficking
Influenza
Yes
(EC
50
=
10–
30
mM)
8
[29]
Dipyridamole
Phosphodiesterase
Ischemic
heart
disease
Yes
(EC
50
=
100
nM)
1
[30]
Darunavir/cobicistat
3CLpro
HIV
Yes
2
[31]
Remdesivir
RdRp
Ebola
virus
Yes
(EC
50
=
0.77
mM)
2
[28]
Favipiravir
RdRp
Influenza
Yes
(EC
50
=
62
mM)
4
[28]
4
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addition,
both
in
vitro
and
in
vivo
studies
have
explored
the
additional
therapeutic
advantages
of
arbidol
as
a
drug
that
exhibits
a
strong
immune
response
by
disrupting
the
viral
capsid
binding
the
host
cell
membrane
[16,40].
Arbidol
has
been
prioritized
with
the
other
potential
clinical
drugs
discussed
earlier
for
clinical
trials
to
tackle
the
COVID-19
outbreak,
supported
by
the
sixth
edition
of
Guidelines
for
the
Prevention,
Diagnosis,
and
Treatment
of
Novel
Coronavirus-induced
Pneumonia
[XX].
Dipyridamole,
an
antiplatelet
and
phosphodiesterase
inhibitor
drug
that
targets
intracellular
cAMP/cGMP
levels,
including
posi-
tive-stranded
RNA
viruses,
has
been
suggested
to
be
an
effective
antiviral
drug
[41,42].
Dipyridamole
effectively
inhibited
the
rep-
lication
of
SARS-CoV
at
a
half-maximal
effective
concentration
(EC
50
)
concentration
of
100
nM
in
vitro
[30].
This
clinical
profi-
ciency
of
dipyridamole
emphasized
its
possible
usage
as
an
adju-
vant
to
strengthen
the
immune
system
as
well
as
to
inhibit
viral
proliferation
and
hypercoagulation
[30].
Darunavir,
a
potent
retrovirus
inhibitor,
together
with
cobici-
stat,
which
controls
cytochrome
P4503A
(CYP3A)
activity
result-
ing
in
the
breakdown
of
antiviral
agents,
has
been
used
to
treat
patients
with
HIV
[43].
Although
Darunavir
is
intended
to
inhibit
viral
proteinases
[31],
research
is
required
to
prove
its
clinical
significance
in
reversing
COVID-19
virulence.
Animal
studies
showed
that
remdesivir
inhibited
the
virulence
of
SARS-CoV
and
MERS-CoV
[32].
In
vitro
research
also
confirmed
that
remdesivir
treatment
profoundly
inhibited
SARS-CoV-2
pro-
liferation
at
an
EC
50
concentration:
0.77–1.76
mM
[28].
Favipiravir,
which
markedly
inhibits
influenza-dependent
RNA
polymerase,
exhibits
profound
antiviral
activity
against
many
viruses,
including
arenavirus,
bunyavirus,
and
filovirus,
which
result
in
fatal
hemorrhagic
fever
[16,44].
In
addition
to
these
viruses,
favipiravir
treatment
effectively
inhibited
the
prolifera-
tion
of
SARS-CoV-2
in
Vero
E6
culture
cells,
with
an
EC
50
value
of
62
mM
[32].
Based
on
this
positive
outcome,
the
Ministry
of
Science
and
Technology,
China
recently
recommended
favipiravir
for
COVID-19
management
in
a
larger
group
of
patients
[45].
Other
potential
drugs
of
high
therapeutic
value
include
balox-
avir
and
marboxil,
which
target
the
viral
cap-dependent
endonu-
clease
(although
this
is
absent
in
SARS-CoV-2)
[32];
TMC310911
targets
viral
protease
activity
[46];
emtricitabine/tenofovir
alafe-
namide
and
azvudine
target
the
viral
reverse
transcriptase
and
have
been
tested
on
patients
with
COVID-19
[47,48].
Although
Drug
Discovery
Today Volume
00,
Number
00 June
2020
REVIEWS
DRUDIS-2718;
No
of
Pages
8
Please
cite
this
article
in
press
as:
Duan,
Y.
et
al.
Current
and
future
therapeutical
approaches
for
COVID-19,
Drug
Discov
Today
(2020),
https://doi.org/10.1016/j.drudis.2020.06.018
TABLE
1
(Continued
)
Names
Structure
targets
Original
indication
Activity
against
SARS-CoV-2
reported
No.
of
clinic
trials
Refs
Emtricitabine/
tenofovir
alafenamide
Reverse
transcriptase
HIV
No
1
Azvudine
Reverse
transcriptase
HIV
No
3
ASC09/ritonavir
(ASC09F)
3CLpro
HIV
No
6
Baloxavir
marboxil
Endonuclease
Influenza
No
2
Oseltamivir
Neuraminidase
Influenza
No
2
Abbreviations:
3CLpro:
3-chymotrypsin-like
cysteine
protease;
CYP3A4,
cytochrome
P450
3A4;
HCV,
hepatitis
C
virus;
RdRp,
RNA-dependent
RNA
polymerase;
RSV,
respiratory
syncytial
virus
www.drugdiscoverytoday.com
5
Reviews 

these
clinical
drugs
showed
promising
therapeutic
effects
against
COVID-19
virulence,
there
is
still
a
need
for
an
in-depth
clinical
trial
to
confirm
their
efficacy
in
a
larger
group
of
patients
with
COVID-19.
The
pharmacokinetics
(PK)
of
all
emerging
COVID-19
drugs,
such
as
absorption,
distribution,
metabolism
and
excretion,
including
the
druggable
effect
on
the
host
body
(pharmacodynamics;
PD),
can
be
studied
using
PK/PD
modeling
[49].
A
PK/PD
drug
model
would
reveal
the
correlation
between
drug
exposure
and
its
associated
PD
effect
in
silico
[49].
Of
the
empirical
and
mechanistic
models
of
PK/
PD
available,
empirical
models
that
comprise
direct-link,
spline-
function,
logistic-regression,
and
circadian
models
could
be
used
to
study
disease
progression
in
patients
with
COVID-19
with
or
with-
out
drug
exposure
in
silico
[49].
Mechanistic
model
studies,
which
primarily
rely
on
data
from
clinical
biomarkers
in
the
context
of
COVID-19
virulence
in
the
presence
or
absence
of
a
drug,
would
confer
a
brief
clinical
understanding
of
the
druggable
effect
against
COVID-19
in
humans
and
other
species
as
well
as
the
determined
drug
dosage
for
COVID-19
management
[49].
PK/PD
analyses
are
conducted
at
three
various
levels:
Level
1
reveals
the
direct
correla-
tion
between
the
drug
exposure
and
its
relevant
responseusing a
plot
graph
with
the
measured
unbound
plasma
drug
concentration
plotted
against
the
relevant
PD
response
(in
vivo);
this
generates
the
effective
drug
dosage
concentration
based
on
the
ratio
of
mean
unbound
plasma
drug
concentration/half-maximal
inhibitory
con-
centration
(IC
50
);
Level
2
generates
the
PD
response
turnover
rate,
K
out
,
in
response
to
the
noticeable
changes
in
the
drug
and
biological
system;
Level
3
(with
the
supportive
pre-established
models)
unra-
vels
the
pharmacological
response
to
the
drug
at
various
dosages
among
the
patients
involved
in
the
experimental
study.
The
corre-
lation
of
biomarkers
with
the
generated
PK/PD
models
would
also
provide
a
mechanistic
understanding
of
the
mechanism
of
action
of
the
drugs
to
enable
translational
research
and
intersubject
drug
evaluation
on
a
wider
scale
[49].
Biological
agents
Convalescent
plasma
therapy
using
clinically
procured
blood
plasma
samples
of
patients
with
a
particular
virus
has
been
adopted
to
treat
patients
with
SARS-CoV-2
[50].
It
has
been
pro-
posed
that
convalescent
blood
plasma
(CBP)
infusion
into
such
patients
would
effectively
attenuate
the
pathogenicity
of
the
virus,
with
its
eventual
removal
from
the
patient’s
blood.
Although
the
methodology
of
CBP
transfusion
has
certain
constraints
for
clini-
cal
trials,
clinical
treatment
using
the
CBP
of
patients
with
COVID-
19
has
been
considered
to
be
both
promising
and
effective
for
treating
patients
critically
ill
with
COVID-19.
To
test
CBP
transfu-
sion
on
a
large
scale,
certain
clinical
factors
must
be
taken
into
consideration,
such
as
the
transmission
of
intermittent
pathogens
between
the
donor
and
the
recipient
and
the
precise
recruitment
of
donors
with
sufficient
immunoglobulin
titers
to
produce
no-
ticeable
effects
against
the
pathogenicity
of
that
particular
patho-
gen
in
the
patients
[51].
Bone
marrow-derived
mesenchymal
stem
cells
(MSCs)
have
been
used
to
treat
patients
with
acute
respiratory
distress
syn-
drome
(ARDS),
with
no
adverse
effects
recorded
during
the
rele-
vant
trial
[52].
To
date,
there
are
13
clinical
trials
in
progress
to
manage
SARS-CoV-2
using
MSCs,
with
promising
initial
clinical
results
in
seven
patients
with
COVID-19,
who
showed
a
remark-
able
improvement
in
their
clinical
condition
within
14
days
of
treatment
without
any
noticeable
adverse
effects.
Interferon-alpha
(IFN-a),
a
potent
immune
cytokine
released
during
pathogen
infection,
improved
pulmonary
function
when
coupled
with
other
antiviral
agents,
such
as
lopinavir,
ritonavir,
and
remdesivir,
in
patients
with
MERS-CoV
[53].
The
therapeutic
combination
of
ribavirin
and
IFN-a
was
acknowledged
in
the
sixth
edition
of
Guidelines
for
the
Prevention,
Diagnosis,
and
Treatment
of
Novel
Coronavirus-induced
Pneumonia
[XX].
Patients
with
COVID-19
and
other
severe
health
conditions
have
shown
increased
circulatory
levels
of
proinflammatory
cytokines,
especially
interleukin
6
(IL-6),
which
might
be
responsible
for
ad-
verse
clinical
symptoms,
such
as
septic
shock,
organ
tissue
damage
associated
with
heart,
liver,
and
kidney,
and
respiratory
dysfunction
[54].
In
one
ongoing
clinical
trial
(ChiCTR2000029765),
clinicians
are
targeting
the
increased
levels
of
IL-6
using
the
IL-6-specific
monoclonal
antibody
tocilizumab
to
treat
patients
critically
ill
with
COVID-19.
Clinicalresults from
21Chinesepatients
with
COVID-19
showed
a
reduced
body
fever
after
treatment
improved
their
respi-
ratory
function
[55].
These
results
suggested
targeting
additional
circulatory
proinflammatory
cytokines,
such
as
IL-1
and
IL-17,
using
cytokine-specific
neutralizing
antibodies
[55].
Following
successful
results
from
these
clinical
trials,
it
would
be
possible
to
adopt
a
proficient
biological
strategy
to
treat
COVID-19
virulence
in
immu-
nocompromisedpatients.Amonoclonal
antibodylabeled
‘CR3022’,
raised
against
the
receptor-binding
domain
of
the
S
membrane
glycoprotein
of
SARS-CoV-2,
could
benefit
patients
by
disrupting
its
colonization
in
the
upper
respiratory
system
[56].
Also,
mono-
clonal
antibodies
generated
specifically
against
the
functional
pro-
teins
of
SARS-CoV-2
and/or
its
potential
agonist
ACE2,
which
controls
viral
entry,
would
significantly
benefit
patients
in
terms
of
a
quick
recovery
and
a
restricted
transmission
rate.
Future
clinical
strategies
for
COVID-19
management
To tackle the COVID-19 outbreak within a short timeframe, treatment
using
drug
repurposing
against
the
virus-
and
host-based
targets
could
resolve
similar
clinical
issues
in
the
future.
In
the
long
term,
the
development
of
novel-multifaceted-pan-CoV
antiviral
drugs
against
coronaviruses
might
result
in
an
efficacious
treatment
for
SARS-CoV-
2.
A
profound
activation
of
the
bitter
taste
receptors
[taste
2
receptor
member 4 (T2R4); taste 2 receptor member 38 (T2R38); taste 2 receptor
member
43
(T2R43)
and
taste
2
receptor
member
46
(T2R46)]
using
bitter
taste
compounds,
including
nicotine
(as
agonists),
could
atten-
uate
COVID-19
virulence
with
increased
intracellular
calcium-depen-
dent
nitric
oxide
(NO)
production
accompanied
by
reduced
secretion
of the proinflammatory cytokines in the upper respiratory system [57–
59].
This
increased
NO
production
further
strengthens
the
ciliary
beat
frequency
with
the
resulting
mucociliary
clearance
of
the
invading
pathogens
[57].
The
idea
of
triggering
the
innate
immune
response
by
the
activation
of
bitter
taste
receptors,
and
reducing
the
production
of
proinflammatory
cytokines
by
the
stimulation
of
ACE2
and
neuronal
acetylcholine
receptors
using
nicotine,
will
be
validated
in
patients
with
COVID-19
in
the
near
future.
Concluding
remarks
All
of
proposed
therapeutic
strategies
discussed
herein,
including
the
on-going
clinical
trials
of
COVID-19
management,
have
to
overcome
substantial
obstacles,
such
as
the
possibility
of
spontaneous
mutation
REVIEWS
Drug
Discovery
Today Volume
00,
Number
00 June
2020
DRUDIS-2718;
No
of
Pages
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Please
cite
this
article
in
press
as:
Duan,
Y.
et
al.
Current
and
future
therapeutical
approaches
for
COVID-19,
Drug
Discov
Today
(2020),
https://doi.org/10.1016/j.drudis.2020.06.018
6
www.drugdiscoverytoday.com
Reviews 

of
SARS-CoV-2,
restricted
animal
models
for
preclinical
studies,
a
lack
of
patients
for
clinical
study,
the
high
maintenance
costs
of
experimental
set-ups,
and
retention
of
the
sustainability
of
clini-
cal-based
therapeutic
study
outcomes.
In
addition,
all
the
basic
criteria
of
each
clinical
trial
must
be
well
studied
and
abide
by
the
proper
clinical
guidelines,
regardless
of
study
type.
Only
with
such
concerted
research
efforts
is
the
research
community
likely
to
be
successful
in
its
search
for
a
therapeutic
with
proven
effects
against
COVID-19.
Conflict
of
interest
None
declared.
Acknowledgments
This
work
was
supported
by
National
Natural
Science
Foundation
of
China
(Project
No.81903623
and
U1804283),
Henan
Province
Novel
Coronavirus
Control
and
Prevention
Emergency
Science
and
Technology
Tackling
Key
Project
(201100311500)
and
Henan
Medical
Science
and
Technology
Program
(2018020601).
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