Journal of Medicinal Chemistry,
Год журнала:
2022,
Номер
65(20), С. 13852 - 13865
Опубликована: Окт. 13, 2022
The
coronavirus
disease
2019
(COVID-19)
pandemic
has
necessitated
the
development
of
antiviral
agents
against
severe
acute
respiratory
syndrome
2
(SARS-CoV-2).
3C-like
protease
(3CLpro)
is
a
promising
target
for
COVID-19
treatment.
Here,
we
report
new
class
covalent
inhibitors
3CLpro
that
possess
chlorofluoroacetamide
(CFA)
as
cysteine-reactive
warhead.
Based
on
an
aza-peptide
scaffold,
synthesized
series
CFA
derivatives
in
enantiopure
form
and
evaluated
their
biochemical
efficiency.
data
revealed
8a
(YH-6)
with
R
configuration
at
unit
strongly
blocks
SARS-CoV-2
replication
infected
cells,
its
potency
comparable
to
nirmatrelvir.
X-ray
structural
analysis
showed
YH-6
formed
bond
Cys145
catalytic
center
3CLpro.
strong
activity
favorable
pharmacokinetic
properties
suggest
potential
lead
compound
treatment
COVID-19.
Nature Communications,
Год журнала:
2025,
Номер
16(1)
Опубликована: Фев. 13, 2025
The
ever-evolving
SARS-CoV-2
variants
necessitate
the
development
of
additional
oral
antivirals.
This
study
presents
systematic
design
quinoline-containing
papain-like
protease
(PLpro)
inhibitors
as
potential
antiviral
drug
candidates.
By
leveraging
recently
discovered
Val70Ub
binding
site
in
PLpro,
we
designed
a
series
quinoline
analogs
demonstrating
potent
PLpro
inhibition
and
activity.
Notably,
X-ray
crystal
structures
6
lead
compounds
reveal
that
2-aryl
substitution
can
occupy
either
expected
or
BL2
groove
flipped
orientation.
vivo
Jun13296
exhibits
favorable
pharmacokinetic
properties
against
nirmatrelvir-resistant
mutants.
In
mouse
model
infection,
treatment
with
significantly
improves
survival,
reduces
body
weight
loss
lung
viral
titers,
prevents
tissue
damage.
These
results
underscore
promising
candidates,
instilling
hope
for
future
treatment.
inhibitor,
Jun13296,
displays
efficacy
infection
inhibits
mutants,
rendering
it
candidate.
Journal of the American Chemical Society,
Год журнала:
2022,
Номер
144(46), С. 21035 - 21045
Опубликована: Ноя. 10, 2022
Given
the
current
impact
of
SARS-CoV2
and
COVID-19
on
human
health
global
economy,
development
direct
acting
antivirals
is
paramount
importance.
Main
protease
(MPro),
a
cysteine
that
cleaves
viral
polyprotein,
essential
for
replication.
Therefore,
MPro
novel
therapeutic
target.
We
identified
two
inhibitors,
D-FFRCMKyne
D-FFCitCMKyne,
covalently
modify
active
site
(C145)
determined
cocrystal
structures.
Medicinal
chemistry
efforts
led
to
SM141
SM142,
which
adopt
unique
binding
mode
within
site.
Notably,
these
inhibitors
do
not
inhibit
other
protease,
papain-like
(PLPro),
involved
in
life
cycle
SARS-CoV2.
SM142
block
replication
hACE2
expressing
A549
cells
with
IC50
values
8.2
14.7
nM.
Detailed
studies
indicate
compounds
also
cathepsin
L
(CatL),
S
protein
promote
entry
into
host
cells.
biochemical,
proteomic,
knockdown
antiviral
activity
results
from
dual
inhibition
CatL.
intranasal
intraperitoneal
administration
lead
reduced
replication,
loads
lung,
enhanced
survival
infected
K18-ACE2
transgenic
mice.
In
total,
data
represent
promising
scaffolds
develop
drugs
against
Journal of Medicinal Chemistry,
Год журнала:
2022,
Номер
65(11), С. 7682 - 7696
Опубликована: Май 12, 2022
The
SARS-CoV-2
main
protease
(Mpro)
is
a
medicinal
chemistry
target
for
COVID-19
treatment.
Given
the
clinical
efficacy
of
β-lactams
as
inhibitors
bacterial
nucleophilic
enzymes,
they
are
interest
viral
serine
and
cysteine
proteases.
We
describe
synthesis
penicillin
derivatives
which
potent
Mpro
investigate
their
mechanism
inhibition
using
mass
spectrometric
crystallographic
analyses.
results
suggest
that
have
considerable
potential
via
involving
reaction
with
to
form
stable
acyl-enzyme
complex
shown
by
analysis.
highlight
proteases
employing
catalysis
related
acylating
agents.
Journal of Medicinal Chemistry,
Год журнала:
2022,
Номер
65(20), С. 13852 - 13865
Опубликована: Окт. 13, 2022
The
coronavirus
disease
2019
(COVID-19)
pandemic
has
necessitated
the
development
of
antiviral
agents
against
severe
acute
respiratory
syndrome
2
(SARS-CoV-2).
3C-like
protease
(3CLpro)
is
a
promising
target
for
COVID-19
treatment.
Here,
we
report
new
class
covalent
inhibitors
3CLpro
that
possess
chlorofluoroacetamide
(CFA)
as
cysteine-reactive
warhead.
Based
on
an
aza-peptide
scaffold,
synthesized
series
CFA
derivatives
in
enantiopure
form
and
evaluated
their
biochemical
efficiency.
data
revealed
8a
(YH-6)
with
R
configuration
at
unit
strongly
blocks
SARS-CoV-2
replication
infected
cells,
its
potency
comparable
to
nirmatrelvir.
X-ray
structural
analysis
showed
YH-6
formed
bond
Cys145
catalytic
center
3CLpro.
strong
activity
favorable
pharmacokinetic
properties
suggest
potential
lead
compound
treatment
COVID-19.
