Journal of Medicinal Chemistry,
Journal Year:
2024,
Volume and Issue:
67(8), P. 6495 - 6507
Published: April 12, 2024
We
have
witnessed
three
coronavirus
(CoV)
outbreaks
in
the
past
two
decades,
including
COVID-19
pandemic
caused
by
SARS-CoV-2.
Main
protease
(MPro),
a
highly
conserved
among
various
CoVs,
is
essential
for
viral
replication
and
pathogenesis,
making
it
prime
target
antiviral
drug
development.
Here,
we
leverage
proteolysis
targeting
chimera
(PROTAC)
technology
to
develop
new
class
of
small-molecule
antivirals
that
induce
degradation
SARS-CoV-2
MPro.
Among
them,
MPD2
was
demonstrated
effectively
reduce
MPro
protein
levels
293T
cells,
relying
on
time-dependent,
CRBN-mediated,
proteasome-driven
mechanism.
Furthermore,
exhibited
remarkable
efficacy
diminishing
SARS-CoV-2-infected
A549-ACE2
cells.
also
displayed
potent
activity
against
strains
enhanced
potency
nirmatrelvir-resistant
viruses.
Overall,
this
proof-of-concept
study
highlights
potential
targeted
as
an
innovative
approach
developing
could
fight
drug-resistant
variants.
ChemMedChem,
Journal Year:
2022,
Volume and Issue:
17(22)
Published: Sept. 27, 2022
COVID-19,
caused
by
SARS-CoV-2
infection,
continues
to
be
a
major
public
health
crisis
around
the
globe.
Development
of
vaccines
and
first
cluster
antiviral
drugs
has
brought
promise
hope
for
prevention
treatment
severe
coronavirus
disease.
However,
continued
development
newer,
safer,
more
effective
are
critically
important
combat
COVID-19
counter
looming
pathogenic
variants.
Studies
life
cycle
revealed
several
biochemical
targets
drug
development.
In
present
review,
we
focus
on
recent
design
medicinal
chemistry
efforts
in
small
molecule
discovery,
including
nirmatrelvir
that
viral
protein
synthesis
remdesivir
molnupiravir
target
RdRp.
These
FDA
approved
COVID-19.
Biomolecules,
Journal Year:
2023,
Volume and Issue:
13(9), P. 1339 - 1339
Published: Sept. 2, 2023
The
main
protease
(Mpro)
plays
a
pivotal
role
in
the
replication
of
severe
acute
respiratory
syndrome
coronavirus
2
(SARS-CoV-2)
and
is
considered
highly
conserved
viral
target.
Disruption
catalytic
activity
Mpro
produces
detrimental
effect
on
course
infection,
making
this
target
one
most
attractive
for
treatment
COVID-19.
current
success
SARS-CoV-2
inhibitor
Nirmatrelvir,
first
oral
drug
forms
COVID-19,
has
further
focused
attention
researchers
important
target,
search
new
inhibitors
thriving
exciting
field
development
antiviral
drugs
active
against
related
coronaviruses.
Journal of Medicinal Chemistry,
Journal Year:
2024,
Volume and Issue:
67(5), P. 3935 - 3958
Published: Feb. 16, 2024
As
SARS-CoV-2
continues
to
circulate,
antiviral
treatments
are
needed
complement
vaccines.
The
virus's
main
protease,
3CLPro,
is
an
attractive
drug
target
in
part
because
it
recognizes
a
unique
cleavage
site,
which
features
glutamine
residue
at
the
P1
position
and
not
utilized
by
human
proteases.
Herein,
we
report
invention
of
MK-7845,
novel
reversible
covalent
3CLPro
inhibitor.
While
most
inhibitors
reported
date
contain
amide
as
Gln
mimic
P1,
MK-7845
bears
difluorobutyl
substituent
this
position.
SAR
analysis
X-ray
crystallographic
studies
indicate
that
group
interacts
with
His163,
same
forms
hydrogen
bond
substituents
typically
found
P1.
In
addition
promising
vivo
efficacy
acceptable
projected
dose
unboosted
pharmacokinetics,
exhibits
favorable
properties
for
both
solubility
absorption
may
be
attributable
unusual
substituent.
Letters in Organic Chemistry,
Journal Year:
2024,
Volume and Issue:
21(7), P. 568 - 574
Published: Feb. 2, 2024
Abstract:
In
the
carbamate
Schiff
base
compound,
molecule
is
stabilized
by
intramolecular
hydrogen
bonding
interactions
along
with
π···π
stacking
and
C–H···π
contacts
that
lead
to
generating
diverse
supramolecular
architecture.
The
fingerprint
plots
associated
Hirshfeld
surface
analysis
indicate
most
important
contributions
for
crystal
packing
are
from
H⋯H/H⋯H
(81.8%),
H⋯O/O⋯H
(7.5%),
H⋯N/N⋯H
(1.9%)
interactions.
Furthermore,
a
computational
study
performed
find
interaction
energy
between
molecular
pairs,
description
of
active
site
compound
has
been
included.
inferred
role
various
types
energies
in
stabilizing
pair.
Additionally,
was
tested
as
possible
inhibitor
group
SARS-CoV-2
proteins
employing
docking
approach.
Papain-like
protease
(PLpro)
shown
have
highest
binding
affinities.
PLpro’s
score
falls
within
acceptable
levels
hit
compound.
The
Main
Protease
(Mpro)
plays
a
pivotal
role
in
the
replication
of
severe
acute
respiratory
syndrome
coronavirus
2
(SARS-CoV-2)
and
is
considered
highly
conserved
viral
target.
Disruption
catalytic
activity
Mpro
produces
detrimental
effect
on
course
infection,
making
this
target
one
most
attractive
for
treatment
COVID-19.
current
success
SARS-CoV-2
inhibitor
Nirmatrelvir,
first
oral
drug
forms
COVID-19,
has
further
focused
attention
researchers
important
target,
search
new
inhibitors
thriving
exciting
field
development
antiviral
drugs
active
against
related
coronaviruses.
