Future Pharmacology,
Journal Year:
2024,
Volume and Issue:
4(4), P. 825 - 852
Published: Nov. 28, 2024
The
main
proteinase
(Mpro),
or
3CLpro,
is
a
critical
enzyme
in
the
severe
acute
respiratory
syndrome
coronavirus
2
(SARS-CoV-2)
lifecycle
and
responsible
for
breaking
down
releasing
vital
functional
viral
proteins
crucial
virus
development
transmission.
As
catalytically
active
dimer,
its
dimerization
interface
has
become
an
attractive
target
antiviral
drug
development.
Recent
research
extensively
investigated
enzymatic
activity
of
Mpro,
focusing
on
role
regulating
replication
complex
significance
maturation
infectivity.
Computational
investigations
have
identified
four
druggable
pockets,
suggesting
potential
allosteric
sites
beyond
substrate-binding
region.
Empirical
validation
through
site-directed
alanine
mutagenesis
targeted
residues
both
regions
corroborated
these
predictions.
Structural
studies
can
inform
therapeutic
approaches,
with
metadynamics
simulations
shedding
light
H163
Mpro
function
providing
insights
into
dynamic
equilibrium
to
wild-type
enzyme.
Despite
efficacy
vaccines
drugs
mitigating
SARS-CoV-2
spread,
ongoing
evolution,
selective
pressures,
continued
transmission
pose
challenges,
potentially
leading
resistant
mutations.
Phylogenetic
analyses
indicated
existence
several
variations
predating
introduction
human
population,
emphasizing
likelihood
spread.
Hydrogen/deuterium-exchange
mass
spectrometry
reveals
structural
influence
mutation.
At
same
time,
clinical
trials
3CLPro
inhibitors
underscore
reduced
offer
avenues
future
exploration.
Understanding
implications
mutations
holds
promise
shaping
forthcoming
strategies
against
COVID-19.
This
review
delves
factors
influencing
mutation
rates
identifies
areas
warranting
further
investigation,
comprehensive
overview
mutations,
categorization,
terminology.
Moreover,
we
examine
their
associations
outcomes,
illness
severity,
unresolved
issues,
prospects,
including
impact
vaccine
targeting.
Journal of Medicinal Chemistry,
Journal Year:
2025,
Volume and Issue:
unknown
Published: Jan. 16, 2025
The
main
protease
Mpro
is
a
clinically
validated
target
to
treat
infections
by
the
coronavirus
SARS-CoV-2.
Among
first
reported
inhibitors
was
peptidomimetic
α-ketoamide
13b,
whose
cocrystal
structure
with
paved
way
for
multiple
lead-finding
studies.
We
established
structure-activity
relationships
13b
series
modifying
residues
at
P1',
P3,
and
P4
sites.
Guided
structures,
we
reduced
P1'
substituent
size
better
fill
pocket
added
fluorine
pyridone
ring,
enabling
new
hydrogen
bond
Gln189
in
P3.
22
novel
analogues,
6d
12d
inhibited
IC50s
of
110
nM
40
nM,
improving
potency
up
9.5-fold.
Compound
had
pronounced
antiviral
activity
an
EC50
1.6
μM
stable
plasma
microsomes.
study
illustrates
potential
structure-based
design
systematically
improve
α-ketoamides.
Science Advances,
Journal Year:
2025,
Volume and Issue:
11(17)
Published: April 23, 2025
The
main
protease
(M
Pro
)
of
severe
acute
respiratory
syndrome
coronavirus
2
(SARS-CoV-2)
is
a
validated
drug
target.
Starting
with
lead-like
dihydrouracil
chemotype
identified
in
large-library
docking
campaign,
we
improved
M
inhibition
>1000-fold
by
engaging
additional
subsites
and
using
latent
electrophile
to
engage
Cys
145
.
Advanced
leads
from
this
series
show
pan-coronavirus
antiviral
activity,
low
clearance
mice,
for
AVI-4773
,
rapid
reduction
viral
titers
>1,000,000
after
just
three
doses.
Both
compounds
are
well
distributed
mouse
tissues,
including
brain,
where
concentrations
>1000×
the
90%
effective
concentration
observed
8
hours
oral
dosing
AVI-4516
shows
minimal
major
cytochrome
P450s
human
proteases.
also
exhibits
synergy
RNA-dependent
RNA
polymerase
inhibitor,
molnupiravir,
cellular
infection
models.
Related
analogs
strongly
inhibit
nirmatrelvir-resistant
mutant
virus.
properties
differentiated
existing
clinical
preclinical
inhibitors
will
advance
therapeutic
development
against
emerging
SARS-CoV-2
variants
other
coronaviruses.
Bioscience Reports,
Journal Year:
2024,
Volume and Issue:
unknown
Published: July 22, 2024
Coronaviruses
constitute
a
significant
threat
to
the
human
population.
Severe
acute
respiratory
syndrome
coronavirus-2,
SARS-CoV-2,
is
highly
pathogenic
coronavirus
that
has
caused
COVID-19
pandemic.
It
led
global
viral
outbreak
with
an
exceptional
spread
and
high
death
toll,
highlighting
need
for
effective
antiviral
strategies.
3-chymotrypsin-like
protease
(3CLpro),
main
in
plays
indispensable
role
SARS-CoV-2
life
cycle
by
cleaving
polyprotein
produce
eleven
individual
non-structural
proteins
necessary
replication.
3CLpro
one
of
two
proteases
function
new
particles.
conserved
cysteine
identical
structural
folds
all
known
coronaviruses.
Inhibitors
binding
affinity
will
prevent
cleavage
polyproteins,
thus
impeding
Multiple
strategies
have
been
implemented
screen
inhibitors
against
3CLpro,
including
peptide-like
small
molecule
covalently
non-covalently
bind
active
site,
respectively.
In
addition,
allosteric
sites
identified
molecules
could
make
non-competitive
3CLpro.
essence,
this
review
serves
as
comprehensive
guide
understanding
intricacies
functional
dynamics
emphasizing
key
findings
elucidate
its
SARS-CoV-2.
Notably,
critical
resource
recognizing
advancements
identifying
developing
COVID-19,
some
which
are
already
approved
clinical
use
patients.
PLoS Pathogens,
Journal Year:
2024,
Volume and Issue:
20(9), P. e1012522 - e1012522
Published: Sept. 11, 2024
Nirmatrelvir
was
the
first
protease
inhibitor
specifically
developed
against
SARS-CoV-2
main
(3CLpro/Mpro)
and
licensed
for
clinical
use.
As
continues
to
spread,
variants
resistant
nirmatrelvir
other
currently
available
treatments
are
likely
arise.
This
study
aimed
identify
characterize
mutations
that
confer
resistance
nirmatrelvir.
To
safely
generate
Mpro
mutations,
we
passaged
a
previously
developed,
chimeric
vesicular
stomatitis
virus
(VSV-Mpro)
with
increasing,
yet
suboptimal
concentrations
of
Using
Wuhan-1
Omicron
variants,
selected
large
set
mutants.
Some
frequently
present
in
GISAID,
suggesting
their
relevance
SARS-CoV-2.
The
phenotype
subset
characterized
clinically
inhibitors
(nirmatrelvir
ensitrelvir)
cell-based,
biochemical
replicon
assays.
Moreover,
showed
putative
molecular
mechanism
based
on
silico
modelling.
These
findings
have
implications
development
future
generation
inhibitors,
will
help
understand
mechanisms
show
specific
thereby
informing
treatment
decisions.
ACS Omega,
Journal Year:
2024,
Volume and Issue:
unknown
Published: July 16, 2024
The
use
of
viral
protein
inhibitors
has
shown
to
be
insufficiently
effective
in
the
case
highly
variable
SARS-CoV-2.
In
this
work,
we
examined
possibility
designing
agents
that
bind
a
conserved
region
coronavirus
(+)RNA.
We
demonstrated
while
design
antisense
RNAs
is
based
on
complementary
interaction
nitrogenous
bases,
it
possible
semirigid
docking
methods
unnatural
peptide
nucleic
acids.
transition
from
N-(2-aminoethyl)glycine
chain
more
conformationally
rigid
piperidine-containing
backbone
allowed
us
significantly
increase
affinity
structures
target
RNA.
Nature Communications,
Journal Year:
2024,
Volume and Issue:
15(1)
Published: Aug. 12, 2024
Abstract
SARS-CoV-2
has
the
capacity
to
evolve
mutations
that
escape
vaccine-
and
infection-acquired
immunity
antiviral
drugs.
A
variant-agnostic
therapeutic
agent
protects
against
severe
disease
without
putting
selective
pressure
on
virus
would
thus
be
a
valuable
biomedical
tool
maintain
its
efficacy
despite
ongoing
emergence
of
new
variants.
Here,
we
challenge
male
rhesus
macaques
with
Delta—the
most
pathogenic
variant
in
highly
susceptible
animal
model.
At
time
challenge,
also
treat
aerosolized
RBD-62,
protein
developed
through
multiple
rounds
vitro
evolution
RBD
acquire
1000-fold
enhanced
ACE2
binding
affinity.
RBD-62
treatment
equivalently
suppresses
replication
both
upper
lower
airways,
phenomenon
not
previously
observed
clinically
approved
vaccines.
Importantly,
does
block
development
virus-specific
T-
B-cell
responses
elicit
anti-drug
immunity.
These
data
provide
proof-of-concept
can
prevent
from
virulent
variant.
