Design, synthesis, and biological evaluation of first-in-class indomethacin-based PROTACs degrading SARS-CoV-2 main protease and with broad-spectrum antiviral activity
European Journal of Medicinal Chemistry,
Год журнала:
2024,
Номер
268, С. 116202 - 116202
Опубликована: Фев. 6, 2024
To
date,
Proteolysis
Targeting
Chimera
(PROTAC)
technology
has
been
successfully
applied
to
mediate
proteasomal-induced
degradation
of
several
pharmaceutical
targets
mainly
related
oncology,
immune
disorders,
and
neurodegenerative
diseases.
On
the
other
hand,
its
exploitation
in
field
antiviral
drug
discovery
is
still
infancy.
Recently,
we
described
two
indomethacin
(INM)-based
PROTACs
displaying
broad-spectrum
activity
against
coronaviruses.
Here,
report
design,
synthesis,
characterization
a
novel
series
INM-based
that
recruit
either
Von-Hippel
Lindau
(VHL)
or
cereblon
(CRBN)
E3
ligases.
The
panel
was
also
enlarged
by
varying
linker
moiety.
resulted
very
susceptible
this
modification,
particularly
for
hijacking
VHL
as
ligase,
with
one
piperazine-based
compound
(PROTAC
6)
showing
potent
anti-SARS-CoV-2
infected
human
lung
cells.
Interestingly,
assays
both
uninfected
virus-infected
cells
most
promising
emerged
so
far
(PROTACs
5
demonstrated
INM-PROTACs
do
not
degrade
PGES-2
protein,
initially
hypothesized,
but
induce
concentration-dependent
SARS-CoV-2
main
protease
(Mpro)
Mpro-transfected
SARS-CoV-2-infected
Importantly,
thanks
target
degradation,
exhibited
considerable
enhancement
respect
indomethacin,
EC50
values
low-micromolar/nanomolar
range.
Finally,
kinetic
solubility
well
metabolic
chemical
stability
were
measured
6.
Altogether,
identification
first
class
Mpro
degraders
demonstrating
represents
significant
advance
development
effective,
anti-coronavirus
strategies.
Язык: Английский
SARS-CoV-2 replication and drug discovery
Molecular and Cellular Probes,
Год журнала:
2024,
Номер
77, С. 101973 - 101973
Опубликована: Июль 24, 2024
The
coronavirus
disease
2019
(COVID-19)
caused
by
the
severe
acute
respiratory
syndrome
2
(SARS-CoV-2)
has
killed
millions
of
people
and
continues
to
wreak
havoc
across
globe.
This
sudden
deadly
pandemic
emphasizes
necessity
for
anti-viral
drug
development
that
can
be
rapidly
administered
reduce
morbidity,
mortality,
virus
propagation.
Thus,
lacking
efficient
anti-COVID-19
treatment,
especially
given
lengthy
process
as
well
critical
death
tool
been
associated
with
SARS-CoV-2
since
its
outbreak,
repurposing
(or
repositioning)
constitutes
so
far,
ideal
ready-to-go
best
approach
in
mitigating
viral
spread,
containing
infection,
reducing
COVID-19-associated
rate.
Indeed,
based
on
molecular
similarity
previous
coronaviruses
(CoVs),
repurposed
drugs
have
reported
hamper
replication.
Therefore,
understanding
inhibition
mechanisms
replication
chemicals
known
block
CoV
multiplication
is
crucial,
it
opens
way
particular
treatment
options
COVID-19
therapeutics.
In
this
review,
we
highlighted
basics
underlying
drug-repurposing
strategies
against
SARS-CoV-2.
Notably,
discussed
replication,
involving
including
proteases
(3C-like
protease,
3CL
Язык: Английский
Evaluation of the effect of Remdesivir on some biomarkers in Iraqi patients with coronavirus 2019 (COVID-19): A cross-sectional study
Journal of Medicine and Life,
Год журнала:
2023,
Номер
16(8), С. 1231 - 1234
Опубликована: Авг. 1, 2023
COVID-19
is
a
new
virus
spreading
worldwide
that
can
cause
mild
to
severe
illness,
multi-organ
failure,
and
even
death.
Injectable
antiviral
Remdesivir
effective
in
treating
patients
with
moderate-to-severe
COVID-19.
Biomarkers
linked
clinical
outcomes
have
been
found
for
COVID-19,
although
only
few
therapies
studied.
This
study
aimed
assess
how
affects
several
biomarkers
those
changes
impact
the
severity
of
illness.
According
Chinese
care
guidelines
80
were
separated
into
two
groups:
group
1
did
not
receive
(RDV)
medication
Group
2
received
it
after
5
days.
has
recently
tested
high-risk,
individuals
confirmed
SARS-CoV-2
infection
who
hospitalized,
successfully
delayed
onset
From
February
2022
October
2023,
blood
samples
taken
from
participants
evaluate
ferritin,
Lactate
Dehydrogenase
(LDH),
C-reactive
protein.
The
results
this
investigation
showed
various
biomarkers,
including
protein,
lactate
dehydrogenase,
may
improve
more
quickly
RDV
treatment.
These
are
better
during
infection.
discoveries
enhance
understanding
treatment's
function.
In
conclusion,
there
clear
association
between
levels
before
treatment
cases
ranging
moderate
severe.
suggests
might
lead
elevation
biomarkers.
Язык: Английский
Microfluidic Diffusion Sizing Applied to the Study of Natural Products and Extracts That Modulate the SARS-CoV-2 Spike RBD/ACE2 Interaction
Molecules,
Год журнала:
2023,
Номер
28(24), С. 8072 - 8072
Опубликована: Дек. 13, 2023
The
interaction
between
SARS-CoV-2
spike
RBD
and
ACE2
proteins
is
a
crucial
step
for
host
cell
infection
by
the
virus.
Without
it,
entire
virion
entrance
mechanism
compromised.
aim
of
this
study
was
to
evaluate
capacity
various
natural
product
classes,
including
flavonoids,
anthraquinones,
saponins,
ivermectin,
chloroquine,
erythromycin,
modulate
interaction.
To
accomplish
this,
we
applied
recently
developed
microfluidic
diffusional
sizing
(MDS)
technique
that
allows
us
probe
protein-protein
interactions
via
measurements
hydrodynamic
radius
(Rh)
dissociation
constant
(KD);
evolution
Rh
monitored
in
presence
increasing
concentrations
partner
protein
(ACE2);
KD
determined
through
binding
curve
experimental
design.
In
second
time,
with
partners
present
equimolar
amounts,
complex
measured
different
products.
Five
nine
products/extracts
tested
were
found
formation
complex.
A
methanol
extract
Chenopodium
quinoa
Willd
bitter
seed
husks
(50
µg/mL;
bisdesmoside
saponins)
flavonoid
naringenin
(1
µM)
particularly
effective.
This
rapid
selection
effective
modulators
will
allow
better
understand
agents
may
prevent
infection.
Язык: Английский