Abstract
The
ubiquitin
E2
variant
domain
of
TSG101
(TSG101‐UEV)
plays
a
pivotal
role
in
protein
sorting
and
virus
budding
by
recognizing
PTAP
motifs
within
ubiquitinated
proteins.
Disruption
TSG101‐UEV/PTAP
interactions
has
emerged
as
promising
strategy
for
the
development
host‐oriented
broad‐spectrum
antivirals
with
low
susceptibility
to
resistance.
is
challenging
target
characterized
an
extended
flat
binding
interface,
affinity
ligands,
complex
energetics.
Here,
we
assess
druggability
interface
searching
drug‐like
inhibitors
evaluating
their
ability
block
recognition,
impair
budding,
inhibit
viral
proliferation.
A
discovery
workflow
was
established
combining
vitro
miniaturized
HTS
assays
set
cell‐based
activity
including
high‐content
bimolecular
complementation,
virus‐like
particle
release
measurement,
antiviral
testing
live
infection.
This
approach
allowed
us
identify
chemically
diverse
molecules
that
IC50s
μM
range
are
able
disrupt
interaction
between
full‐length
proteins
human
cells
replication.
State‐of‐the‐art
molecular
docking
studies
reveal
active
compounds
exploit
hotspots
at
site,
unlocking
full
potential
TSG101‐UEV
pockets.
These
represent
hits
novel
through
targeted
optimization
also
valuable
tools
investigating
involvement
ESCRT
proliferation
different
families
study
secondary
effects
induced
disruption
ESCRT/virus
interactions.
Clinical and Translational Science,
Год журнала:
2024,
Номер
17(7)
Опубликована: Июль 1, 2024
Abstract
The
urgent
need
for
safe,
efficacious,
and
accessible
drug
treatments
to
treat
coronavirus
disease
2019
(COVID‐19)
prompted
a
global
effort
evaluate
repurposing
opportunities.
Pyronaridine
amodiaquine
are
both
components
of
approved
antimalarials
with
in
vitro
activity
against
severe
acute
respiratory
syndrome
2
(SARS‐CoV‐2).
In
does
not
always
translate
clinical
efficacy
across
therapeutic
dose
range.
This
study
applied
available,
verified,
physiologically
based
pharmacokinetic
(PBPK)
models
pyronaridine,
amodiaquine,
its
active
metabolite
N‐desethylamodiaquine
(DEAQ)
predict
concentrations
lung
tissue
relative
plasma
or
blood
the
default
healthy
virtual
population.
Lung
exposures
were
compared
published
data
reported
range
EC
50
values
SARS‐CoV‐2.
multicompartment
permeability‐limited
PBPK
model,
predicted
total
C
max
mass
pyronaridine
was
34.2
μM
on
Day
3,
30.5‐fold
greater
than
(1.12
μM)
0.530
μM,
8.83‐fold
(0.060
μM).
perfusion‐limited
DEAQ
3
(30.2
21.4‐fold
(1.41
Based
available
data,
DEAQ,
but
appeared
sufficient
inhibit
SARS‐CoV‐2
replication.
Simulations
indicated
standard
dosing
regimens
pyronaridine‐artesunate
artesunate‐amodiaquine
have
potential
COVID‐19.
These
findings
informed
strategies
select
most
relevant
compounds
investigation
Clinical
model
verification
may
become
from
ongoing
studies.
ACS Omega,
Год журнала:
2022,
Номер
7(32), С. 27950 - 27958
Опубликована: Авг. 8, 2022
Finding
antivirals
for
SARS-CoV-2
is
still
a
major
challenge,
and
many
computational
experimental
approaches
have
been
employed
to
find
solution
this
problem.
While
the
global
vaccination
campaigns
are
primary
driver
of
controlling
current
pandemic,
orally
bioavailable
small-molecule
drugs
biologics
critical
overcome
issue.
Improved
therapeutics
prophylactics
required
treat
people
with
circulating
emerging
new
variants,
addressing
severe
infection,
underlying
or
immunocompromised
conditions.
The
envelope
spike
challenging
target
viral
entry
inhibitors.
Pindolol
presented
good
docking
score
in
previous
virtual
screening
using
calculations
after
Food
Drug
Administration
(FDA)-approved
drug
library
2400
molecules
as
potential
candidates
block
protein
interaction
angiotensin-converting
enzyme
2
(ACE-2).
Here,
we
expanded
evaluation
identify
five
beta-blockers
against
several
techniques,
such
microscale
thermophoresis,
NanoDSF,
vitro
assays
different
cell
lines.
These
data
identified
carvedilol
Kd
364
±
22
nM
activity
(EC50
7.57
μM,
CC50
18.07
μM)
Calu-3
cells.
We
shown
how
can
apply
multiple
that
be
further
optimized
improve
anti-SARS-CoV-2
activity.
ACS Omega,
Год журнала:
2023,
Номер
8(43), С. 40817 - 40822
Опубликована: Окт. 19, 2023
There
have
been
relatively
few
small
molecules
developed
with
direct
activity
against
the
severe
acute
respiratory
syndrome
coronavirus
2
(SARS-CoV-2).
Two
existing
antimalarial
drugs,
pyronaridine
and
quinacrine,
display
whole
cell
SARS-CoV-2
in
A549
+
ACE2
cells
(pretreatment,
IC50
=
0.23
0.19
μM,
respectively)
moderate
cytotoxicity
(CC50
11.53
9.24
respectively).
Moreover,
displays
vitro
PLpro
(IC50
1.8
μM).
Given
their
antiviral
activity,
these
compounds
are
strong
candidates
for
repurposing
COVID-19
prompt
us
to
study
structure–activity
relationship
of
9-aminoacridine
scaffold
using
traditional
medicinal
chemistry
identify
promising
new
analogs.
Our
studies
identified
several
novel
analogs
possessing
potent
U2-OS
GFP
1-10
1-11
<
1.0
μM)
as
well
>
4.0
Compounds
such
7g,
9c,
7e
were
more
active,
demonstrating
selectivity
indices
SI
10,
9c
displayed
strongest
≤
0.42
CC50
≥
4.41
10)
among
them,
indicating
that
it
has
potential
a
lead
molecule
this
series
COVID-19.
Pharmaceutics,
Год журнала:
2023,
Номер
15(3), С. 838 - 838
Опубликована: Март 3, 2023
A
fixed-dose
combination
of
pyronaridine
and
artesunate,
one
the
artemisinin-based
therapies,
has
been
used
as
a
potent
antimalarial
treatment
regimen.
Recently,
several
studies
have
reported
antiviral
effects
both
drugs
against
severe
acute
respiratory
syndrome
coronavirus
two
(SARS-CoV-2).
However,
there
are
limited
data
on
pharmacokinetics
(PKs),
lung,
trachea
exposures
that
could
be
correlated
with
artesunate.
The
purpose
this
study
was
to
evaluate
pharmacokinetics,
distribution
pyronaridine,
dihydroartemisinin
(an
active
metabolite
artesunate)
using
minimal
physiologically-based
pharmacokinetic
(PBPK)
model.
major
target
tissues
for
evaluating
dose
metrics
blood,
trachea,
nontarget
were
lumped
together
into
rest
body.
predictive
performance
PBPK
model
evaluated
visual
inspection
between
observations
predictions,
(average)
fold
error,
sensitivity
analysis.
developed
models
applied
multiple-dosing
simulation
daily
oral
steady
state
reached
about
three
four
days
after
first
dosing
an
accumulation
ratio
calculated
1.8.
artesunate
not
since
compounds
achieved
by
multiple
dosing.
elimination
half-life
estimated
19.8
0.4
h,
respectively.
Pyronaridine
extensively
distributed
lung
lung-to-blood
trachea-to-blood
concentration
ratios
(=Cavg,tissue/Cavg,blood)
25.83
12.41
at
state,
Also,
AUC
(dihydroartemisinin)
3.34
(1.51)
0.34
(0.15).
results
provide
scientific
basis
interpreting
dose–exposure–response
relationship
COVID-19
drug
repurposing.
Pharmaceuticals,
Год журнала:
2024,
Номер
17(5), С. 606 - 606
Опубликована: Май 9, 2024
A
non-structural
SARS-CoV-2
protein,
PLpro,
is
involved
in
post-translational
modifications
cells,
allowing
the
evasion
of
antiviral
immune
response
mechanisms.
In
this
study,
potential
PLpro
inhibitory
drugs
were
designed
using
QSAR,
molecular
docking,
and
dynamics.
combined
QSAR
equation
with
physicochemical
Free-Wilson
descriptors
was
formulated.
The
r2,
q2,
r2test
values
0.833,
0.770,
0.721,
respectively.
From
equation,
it
found
that
presence
an
aromatic
ring
a
basic
nitrogen
atom
crucial
for
obtaining
good
activity.
Then,
series
structures
binding
sites
C111,
Y268,
H73
created.
best
compounds
to
exhibit
pIC50
9.124
docking
scoring
-14
kcal/mol.
stability
cavities
confirmed
by
dynamics
studies.
high
number
stable
contacts
interactions
over
time
exhibited
aryl-thiophenes
Pred14
Pred15,
making
them
candidates.
ABSTRACT
The
coronavirus
disease
2019
(COVID-19)
pandemic,
caused
by
severe
acute
respiratory
syndrome
coronavirus-2
(SARS-CoV-2),
continues
to
be
one
of
the
largest
dangers
human
health
around
world.
need
for
effective
antiviral
and
anti-inflammatory
treatments
is
still
extremely
high
as
newly
emerging
variants
threaten
efficacy
currently
used
treatment
options.
Many
compounds
are
at
inhibiting
SARS-CoV-2
infection
in
vitro
but
fail
recapitulate
that
vivo
.
There
a
major
demand
drugs
efficacious
broadly
highly
pathogenic
coronaviruses
including
SARS-CoV-2,
its
close
relatives
SARS-CoV-1
Middle
East
(MERS-CoV).
One
drug
with
potential
join
small
subset
active
both
orally
bioavailable
pyronaridine
triphosphate,
which
has
now
been
published
show
A549
cells
K18-hACE2
mouse
model,
respectively,
functioning
protease
inhibitor
papain-like
(PLpro).
In
our
studies,
resulted
significant
improvements
lung
inflammatory
pathology,
reducing
pro-inflammatory
cytokine
chemokine
levels,
weight
loss
seen
model
associated
severity
three
models,
SARS-CoV-1,
MERS-CoV.
Additionally,
we
found
can
safely
effectively
combined
therapeutics
molnupiravir
nirmatrelvir
(main
component
Paxlovid)
there
was
evidence
synergistic
effect
further
reduced
viral
titers,
levels.
These
results
indicate
represents
an
excellent
therapeutic
candidate
COVID-19
individually,
or
combination
other
approved
antivirals
well
option
such
MERS-CoV,
future
yet
emerge.
IMPORTANCE
Pyronaridine
tetraphosphate
on
WHO
Essential
Medicine
List
importance
widely
available
safe
malaria.
We
find
across
models
using
multiple
viruses
responsible
previous
outbreaks.
additively
combines
current
(protease
inhibit
infections.
many
demonstrate
cellular
few
this
level
impact
represent
promising
pandemic
outbreaks
well.
ACS Omega,
Год журнала:
2023,
Номер
8(13), С. 12532 - 12537
Опубликована: Март 24, 2023
Pyronaridine,
tilorone
and
quinacrine
are
cationic
molecules
that
have
in
vitro
activity
against
Ebola,
SARS-CoV-2
other
viruses.
All
three
also
demonstrated
vivo
Ebola
mice,
while
pyronaridine
showed
efficacy
mice.
We
recently
tested
these
antivirals
human
organic
cation
transporters
(OCTs)
apical
multidrug
toxin
extruders
(MATEs).
Quinacrine
was
found
to
be
an
inhibitor
of
OCT2,
were
less
potent,
displayed
variability
depending
on
the
substrate
used.
To
assess
whether
any
potential
interactions
with
additional
transporters,
we
now
screened
them
at
10
μM
various
efflux
uptake
including
P-gp,
OATP1B3,
OAT1,
OAT3,
MRP1,
MRP2,
MRP3,
BCRP,
as
well
confirmational
testing
OCT1,
MATE1
MATE2K.
Interestingly,
this
study
appears
a
more
potent
OCT1
OCT2
than
or
quinacrine.
However,
both
appear
inhibitors
None
compounds
inhibited
P-gp
OATP1B3.
Similarly,
previously
do
not
inhibit
OATP1B1
confirmed
behaves
similarly.
In
total,
observations
suggest
only
interact
OCTs
MATEs
differing
extents,
suggesting
they
may
involved
fewer
clinically
relevant
drug-transporter
involving
pharmaceutical
substrates
major
tested.