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
Inhibitors of SARS-CoV-2 Main Protease (Mpro) as Anti-Coronavirus Agents
Biomolecules,
Год журнала:
2024,
Номер
14(7), С. 797 - 797
Опубликована: Июль 4, 2024
The
main
protease
(Mpro)
of
SARS-CoV-2
is
an
essential
enzyme
that
plays
a
critical
part
in
the
virus’s
life
cycle,
making
it
significant
target
for
developing
antiviral
drugs.
inhibition
Mpro
has
emerged
as
promising
approach
therapeutic
agents
to
treat
COVID-19.
This
review
explores
structure
protein
and
analyzes
progress
made
understanding
protein–ligand
interactions
inhibitors.
It
focuses
on
binding
kinetics,
origin,
chemical
these
provides
in-depth
analysis
recent
clinical
trials
involving
covalent
non-covalent
inhibitors
emerging
dual
targeting
Mpro.
By
integrating
findings
from
literature
ongoing
trials,
this
captures
current
state
research
into
inhibitors,
offering
comprehensive
challenges
directions
their
future
development
anti-coronavirus
agents.
information
new
insights
inspiration
medicinal
chemists,
paving
way
more
effective
novel
COVID-19
therapies.
Язык: Английский
Main and papain-like proteases as prospective targets for pharmacological treatment of coronavirus SARS-CoV-2
RSC Advances,
Год журнала:
2023,
Номер
13(50), С. 35500 - 35524
Опубликована: Янв. 1, 2023
The
pandemic
caused
by
the
coronavirus
SARS-CoV-2
led
to
a
global
crisis
in
world
healthcare
system.
Despite
some
progress
creation
of
antiviral
vaccines
and
mass
vaccination
population,
number
patients
continues
grow
because
spread
new
mutations.
There
is
an
urgent
need
for
direct-acting
drugs
capable
suppressing
or
stopping
main
mechanisms
reproduction
SARS-CoV-2.
Several
studies
have
shown
that
successful
replication
virus
cell
requires
proteolytic
cleavage
protein
structures
virus.
Two
proteases
are
crucial
replicating
other
coronaviruses:
protease
(Mpro)
papain-like
(PLpro).
In
this
review,
we
summarize
essential
viral
proteins
required
its
life
cycle
as
targets
chemotherapy
infection
provide
critical
summary
development
against
COVID-19
from
drug
repurposing
strategy
up
molecular
design
novel
covalent
non-covalent
agents
inhibiting
replication.
We
overview
choice
Mpro
PLpro
promising
pharmacological
impact
on
cycle.
Язык: Английский
Revealing SARS-CoV-2 Mpro Mutation Cold and Hot Spots: Dynamic Residue Network Analysis Meets Machine Learning
Computational and Structural Biotechnology Journal,
Год журнала:
2024,
Номер
23, С. 3800 - 3816
Опубликована: Окт. 23, 2024
Язык: Английский
An isothermal calorimetry assay for determining steady state kinetic and enzyme inhibition parameters for SARS-CoV-2 3CL-protease
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Янв. 31, 2024
ABSTRACT
This
manuscript
describes
the
application
of
Isothermal
Titration
Calorimetry
(ITC)
to
characterize
kinetics
3CL
pro
from
Severe
Acute
Respiratory
Syndrome
CoronaVirus-2
(SARS-CoV-2)
and
its
inhibition
by
Ensitrelvir,
a
known
non-covalent
inhibitor.
is
main
protease
that
plays
crucial
role
producing
whole
array
proteins
necessary
for
viral
infection
caused
spread
COVID-19,
responsible
millions
deaths
worldwide
as
well
global
economic
healthcare
crises
in
recent
years.
The
proposed
calorimetric
method
proved
have
several
advantages
over
two
types
enzymatic
assays
so
far
applied
this
system,
namely
Förster
Resonance
Energy
Transfer
(FRET)
Liquid
Chromatography-Mass
Spectrometry
(LC-MS).
developed
ITC-based
assay
provided
rapid
response
activity,
which
was
used
directly
derive
kinetic
constants
K
M
k
cat
reliably
reproducibly,
their
temperature
dependence,
activation
energy
reaction
obtained
first
time.
further
revealed
existence
modes
competitive
mode
previously
inferred
crystallography
an
unprecedented
uncompetitive
mode,
yielding
respective
with
high
precision.
described
paper
thus
be
generally
widely
discovery
development
drugs
targeting
.
Язык: Английский
Are protein–ligand docking programs good enough to predict experimental poses of noncovalent ligands bound to the SARS-CoV-2 main protease?
Drug Discovery Today,
Год журнала:
2024,
Номер
29(10), С. 104137 - 104137
Опубликована: Авг. 15, 2024
Hundreds
of
virtual
screening
(VS)
studies
have
targeted
the
severe
acute
respiratory
syndrome-coronavirus
2
(SARS-CoV-2)
main
protease
(M-pro)
to
identify
small
molecules
that
inhibit
its
proteolytic
action.
Most
use
AutoDock
Vina
or
Glide
methodologies
[high-throughput
VS
(HTVS),
standard
precision
(SP),
extra
(XP)],
independently
in
a
workflow.
Moreover,
Protein
Data
Bank
(PDB)
includes
multiple
complexes
between
M-pro
and
various
noncovalent
ligands,
providing
an
excellent
benchmark
for
assessing
predictive
capabilities
docking
programs.
Here,
we
analyze
ability
three
by
using
target
structures/preparations
predict
experimental
poses
these
complexes.
Our
aims
are
optimize
setup
methodologies,
minimize
false
positives,
maximize
identification
chemotypes
SARS-CoV-2
inhibitor
campaign.
Язык: Английский
An isothermal calorimetry assay for determining steady state kinetic and Ensitrelvir inhibition parameters for SARS-CoV-2 3CL-protease
Scientific Reports,
Год журнала:
2024,
Номер
14(1)
Опубликована: Дек. 31, 2024
Язык: Английский
Identification of potential corticosteroid binding sites on the SARS CoV-2 main protease Mpro — in silico docking study
Biophysical Bulletin,
Год журнала:
2024,
Номер
51, С. 53 - 63
Опубликована: Авг. 12, 2024
Background:
Currently,
an
increase
in
the
number
of
new
cases
Covid-19
caused
by
severe
acute
respiratory
syndrome
virus
(SARS-CoV-2)
is
recorded
Ukraine
and
world.
SARS-CoV-2
provokes
exacerbation
chronic
diseases
activates
inflammatory
allergic
reactions.
A
course
increases
duration
hospitalization
mortality
rate
among
population.
Pathogenetic
therapy
carried
out
with
systemic
corticosteroids,
which
suppress
cytokine
storm
mitigating
SARS-CoV-2-induced
response
inhibit
main
protease
Mpro,
a
key
component
viral
replication.
Objectives:
The
aim
this
study
to
identify
potential
corticosteroid
binding
sites
on
SARS
CoV-2
Mpro
based
analysis
energetic
topological
characteristics
complexes
as
well
investigate
inhibitory
activity
selected
corticosteroids
against
Mpro.
Material
Methods:
crystal
structure
(ID:
6LU7
from
Protein
Data
Bank)
(www.rcsb.org)
was
chosen
docking
target.
Molecular
methods
(AutoDock
Tools
1.5.7,
AutoDock
Vina
1.1.2)
were
used
gain
insight
into
affinity
such
dexamethasone
(DEX),
prednisone
(PRED),
prednisolone
(PNL),
methylprednisolone
(Medrol),
triamcinolone
(TAC),
hydrocortisone
(HCT).
Visualization
results
done
PyMol
2.5.
protein-ligand
interaction
profiler
(PLIP)
LigPlot+
web
tool
non-covalent
interactions
between
ligands
(https://plip-tool.biotec.tu-dresden.de).
Results:
In
silico
demonstrated
that
all
bound
amino
acid
residues
II
III
domains
energy
range
-7.8…-6.6
kcal/mol.
high
found
for
dexamethasone-Mpro
(-7.8
kcal/mol);
prednisone,
prednisolone,
methylprednisolone,
triamcinolone,
energies
-7.4,
-7.0,
-7.5,
-7.6
-6.6
kcal/mol,
respectively.
It
shown
hydrogen
bonds
hydrophobic
involved
formation
ligand-protein
mainly
through
Arg131,
Lys137,
Thr199,
Asp289,
Leu272,
Leu286,
Leu287,
Tyr239,
Gly275,
formed
catalytic
distal
ligand
binding.
inhibition
constant
has
ranged
1.90
×
10-6
14.4
M.
Conclusion:
Our
showed
favorable
dexamethasone,
are
located
site
domain
affinities
confirming
stability
complexes.
low
constants
values
further
confirm
effectiveness
inhibitors
activity.
Based
identified
Язык: Английский