Science Advances,
Journal Year:
2024,
Volume and Issue:
10(30)
Published: July 24, 2024
To
facilitate
the
detection
and
management
of
potential
clinical
antiviral
resistance,
in
vitro
selection
drug-resistant
severe
acute
respiratory
syndrome
coronavirus
2
(SARS-CoV-2)
against
virus
M
ACS Central Science,
Journal Year:
2023,
Volume and Issue:
9(8), P. 1658 - 1669
Published: July 24, 2023
The
SARS-CoV-2
main
protease
(Mpro)
is
the
drug
target
of
Pfizer's
oral
nirmatrelvir.
emergence
variants
with
mutations
in
Mpro
raised
alarm
potential
resistance.
To
identify
clinically
relevant
drug-resistant
mutants,
we
systematically
characterized
102
naturally
occurring
mutants
located
at
12
residues
nirmatrelvir-binding
site,
among
which
22
5
residues,
including
S144M/F/A/G/Y,
M165T,
E166
V/G/A,
H172Q/F,
and
Q192T/S/L/A/I/P/H/V/W/C/F,
showed
comparable
enzymatic
activity
to
wild-type
(kcat/Km
<
10-fold
change)
while
being
resistant
nirmatrelvir
(Ki
>
increase).
X-ray
crystal
structures
were
determined
for
six
representative
and/or
without
GC-376/nirmatrelvir.
Using
recombinant
viruses
generated
from
reverse
genetics,
confirmed
resistance
antiviral
assay
that
reduced
had
attenuated
viral
replication.
Overall,
our
study
identified
several
hotspots
warrant
close
monitoring
possible
clinical
evidence
resistance,
some
have
already
emerged
independent
passage
assays
conducted
by
others.
Science Translational Medicine,
Journal Year:
2022,
Volume and Issue:
15(678)
Published: Oct. 4, 2022
Protease
inhibitors
are
among
the
most
powerful
antiviral
drugs.
Nirmatrelvir
is
first
protease
inhibitor
specifically
developed
against
SARS-CoV-2
3CLpro
that
has
been
licensed
for
clinical
use.
To
identify
mutations
confer
resistance
to
this
inhibitor,
we
engineered
a
chimeric
vesicular
stomatitis
virus
(VSV)
expressed
polyprotein
composed
of
VSV
glycoprotein
(G),
3CLpro,
and
polymerase
(L).
Viral
replication
was
thus
dependent
on
autocatalytic
processing
precursor
protein
by
release
functional
viral
proteins
G
L,
effectively
inhibited
nirmatrelvir.
Using
system,
applied
nirmatrelvir
select
mutations.
Resistance
confirmed
retesting
selected
in
additional
VSV-based
systems,
an
independently
cellular
biochemical
assay,
recombinant
system.
We
demonstrate
some
mutants
cross-resistant
ensitrelvir
GC376,
whereas
others
less
resistant
these
compounds.
Furthermore,
found
already
existed
sequences
have
deposited
NCBI
GISAID
databases,
indicating
were
present
circulating
strains.
Biomedicine & Pharmacotherapy,
Journal Year:
2023,
Volume and Issue:
162, P. 114367 - 114367
Published: Feb. 6, 2023
Despite
the
need
for
novel,
effective
therapeutics
COVID-19
pandemic,
no
curative
regimen
is
yet
available,
therefore
patients
are
forced
to
rely
on
supportive
and
nonspecific
therapies.
Some
SARS-CoV-2
proteins,
like
3
C-like
protease
(3CLpro)
or
major
(Mpro),
have
been
identified
as
promising
targets
antiviral
drugs.
The
Mpro
has
a
role
in
protein
processing
well
pathogenesis
of
virus,
could
be
useful
therapeutic
target.
drug
nirmatrelvir
can
keep
from
replicating
through
inhibiting
Mpro.
Nirmatrelvir
was
combined
with
another
HIV
inhibitor,
ritonavir,
create
Paxlovid
(Nirmatrelvir/Ritonavir).
metabolizing
enzyme
cytochrome
P450
A
inhibited
by
ritonavir
lengthen
half-life
nirmatrelvir,
so
rintonavir
acts
pharmacological
enhancer.
exhibits
potent
activity
against
current
coronavirus
variants,
despite
significant
alterations
viral
genome.
Nevertheless,
there
still
several
unanswered
questions.
This
review
summarizes
literature
efficacy
treating
infection,
also
their
safety
possible
side
effects.
Signal Transduction and Targeted Therapy,
Journal Year:
2022,
Volume and Issue:
7(1)
Published: Dec. 5, 2022
Abstract
The
outbreak
of
COVID-19
has
become
a
global
crisis,
and
brought
severe
disruptions
to
societies
economies.
Until
now,
effective
therapeutics
against
are
in
high
demand.
Along
with
our
improved
understanding
the
structure,
function,
pathogenic
process
SARS-CoV-2,
many
small
molecules
potential
anti-COVID-19
effects
have
been
developed.
So
far,
several
antiviral
strategies
were
explored.
Besides
directly
inhibition
viral
proteins
such
as
RdRp
M
pro
,
interference
host
enzymes
including
ACE2
proteases,
blocking
relevant
immunoregulatory
pathways
represented
by
JAK/STAT,
BTK,
NF-κB,
NLRP3
pathways,
regarded
feasible
drug
development.
development
treat
achieved
strategies,
computer-aided
lead
compound
design
screening,
natural
product
discovery,
repurposing,
combination
therapy.
Several
representative
remdesivir
paxlovid
proved
or
authorized
emergency
use
countries.
And
candidates
entered
clinical-trial
stage.
Nevertheless,
due
epidemiological
features
variability
issues
it
is
necessary
continue
exploring
novel
COVID-19.
This
review
discusses
current
findings
for
treatment.
Moreover,
their
detailed
mechanism
action,
chemical
structures,
preclinical
clinical
efficacies
discussed.
EBioMedicine,
Journal Year:
2023,
Volume and Issue:
91, P. 104559 - 104559
Published: April 14, 2023
Nirmatrelvir-ritonavir
(Paxlovid)
and
ensitrelvir
are
3-chymotrypsin-like
cysteine
protease
(3CLpro)
inhibitors
which
have
been
approved
for
the
treatment
of
COVID-19
in
2021
2022,
respectively.
Previous
studies
identified
3CLpro
mutations
that
associated
with
reduced
susceptibility
to
these
antivirals.
The
aim
current
study
was
estimate
global
prevalence
inhibitor-resistant
SARS-CoV-2
strains.We
compiled
a
list
nirmatrelvir
or
resistance
based
on
either
viral
replication
activity
assays,
determined
their
among
13.4
million
sequences
deposited
GISAID
as
December
14,
about
1
year
after
approval
nirmatrelvir-ritonavir.
We
analyzed
different
time
periods,
lineages
geographical
locations.Overall,
0.5%
(67,095/13,446,588)
contained
at
least
one
mutation
shown
affect
inhibitory
activity.
did
not
observe
any
increasing
trend
widespread
clinical
use
G15S
(2070
per
million)
T21I
(1386
were
most
prevalent
mutations,
dominant
some
lineages.
E166V
S144E,
previously
by
>
100-folds,
found
<1
sequences.Our
data
suggest
inhibitor
is
currently
rare.
However,
continuous
genotypic
phenotypic
surveillance
would
be
crucial
early
detection
resistant
mutants.Richard
Carol
Yu,
May
Tam
Mak
Mei
Yin,
Shaw
Foundation
Hong
Kong,
Michael
Tong,
Marina
Lee,
Government
Consultancy
Service,
Emergency
Key
Program
Guangzhou
Laboratory
(See
acknowledgements
full
list).
bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2022,
Volume and Issue:
unknown
Published: June 28, 2022
ABSTRACT
The
SARS-CoV-2
main
protease
(M
pro
)
is
the
drug
target
of
Pfizer’s
oral
Paxlovid.
emergence
variants
with
mutations
in
M
raised
alarm
potential
resistance.
In
this
study,
we
identified
100
naturally
occurring
located
at
nirmatrelvir
binding
site,
among
which
20
mutants,
including
S144M/F/A/G/Y,
M165T,
E166G,
H172Q/F,
and
Q192T/S/L/A/I/P/H/V/W/C/F,
showed
comparable
enzymatic
activity
to
wild-type
(k
cat
/K
m
<10-fold
change)
resistance
(K
i
>10-fold
increase).
X-ray
crystal
structures
were
determined
for
seven
representative
mutants
and/or
without
GC-376/nirmatrelvir.
Viral
growth
assay
that
reduced
led
attenuated
viral
replication.
Overall,
our
study
several
resistant
hot
spots
warrant
close
monitoring
possible
clinical
evidence
Paxlovid
One
Sentence
Summary
viruses
have
been
from
isolates.
Nature Microbiology,
Journal Year:
2023,
Volume and Issue:
8(5), P. 771 - 786
Published: May 4, 2023
Vaccines
and
monoclonal
antibody
treatments
to
prevent
severe
coronavirus
disease
2019
(COVID-19)
illness
were
available
within
a
year
of
the
pandemic
being
declared
but
there
remained
an
urgent
need
for
therapeutics
treat
patients
who
not
vaccinated,
immunocompromised
or
whose
vaccine
immunity
had
waned.
Initial
results
investigational
therapies
mixed.
AT-527,
repurposed
nucleoside
inhibitor
hepatitis
C
virus,
enabled
viral
load
reduction
in
hospitalized
cohort
did
reduce
outpatients.
The
molnupiravir
prevented
death
failed
hospitalization.
Nirmatrelvir,
main
protease
(Mpro),
co-dosed
with
pharmacokinetic
booster
ritonavir,
reduced
hospitalization
death.
Nirmatrelvir–ritonavir
received
Emergency
Use
Authorization
United
States
at
end
2021.
Immunomodulatory
drugs
such
as
baricitinib,
tocilizumab
corticosteroid,
which
target
host-driven
COVID-19
symptoms,
are
also
use.
We
highlight
development
challenges
that
remain
anticoronavirals.
Therapeutics
their
during
reviewed,
including
future
prospects
Signal Transduction and Targeted Therapy,
Journal Year:
2023,
Volume and Issue:
8(1)
Published: March 16, 2023
Abstract
Emerging
SARS-CoV-2
variants,
particularly
the
Omicron
variant
and
its
sublineages,
continually
threaten
global
public
health.
Small
molecule
antivirals
are
an
effective
treatment
strategy
to
fight
against
virus.
However,
first-generation
either
show
limited
clinical
efficacy
and/or
have
some
defects
in
pharmacokinetic
(PK)
properties.
Moreover,
with
increased
use
of
these
drugs
across
globe,
they
face
great
pressure
drug
resistance.
We
herein
present
discovery
characterization
a
new
generation
antiviral
candidate
(SY110),
which
is
potent
selective
inhibitor
main
protease
(M
pro
).
This
compound
displayed
vitro
activity
not
only
predominant
sublineage
BA.5,
but
also
other
highly
pathogenic
human
coronaviruses
including
SARS-CoV-1
MERS-CoV.
In
Omicron-infected
K18-hACE2
mouse
model,
oral
SY110
significantly
lowered
viral
burdens
lung
alleviated
virus-induced
pathology.
Importantly,
possesses
favorable
PK
properties
high
exposure
bioavailability,
outstanding
safety
profile.
Furthermore,
exhibited
sensitivity
several
drug-resistance
M
mutations.
Collectively,
this
investigation
provides
promising
variants
SARS-CoV-2.
Med,
Journal Year:
2023,
Volume and Issue:
4(11), P. 813 - 824.e4
Published: Sept. 7, 2023
Antiviral
and
antibody
therapies
for
severe
acute
respiratory
syndrome
coronavirus
2
(SARS-CoV-2)
are
being
recommended
high-risk
patients,
but
the
potential
development
of
multidrug-resistant
mutations
in
immunocompromised
patients
is
unclear.To
investigate
treatment
course
cases
prolonged
viral
shedding
an
patient
with
SARS-CoV-2
infection,
we
conducted
longitudinal
measurements
laboratory
tests,
chest
computed
tomography
(CT)
image
evaluations,
titers,
antigen
levels
nasopharyngeal
swabs.
Furthermore,
performed
whole-genome
sequencing
digital
PCR
analysis
to
examine
mechanisms
drug
resistance.We
present
a
case
65-year-old
man
history
malignant
lymphoma
who
was
treated
multiple
antiviral
therapies,
including
sotrovimab,
remdesivir,
paxlovid
(nirmatrelvir/ritonavir),
molnupiravir.
Initially,
decreased
after
treatments.
However,
virus
rebounded,
showed
no
virologic
response.
The
genome
revealed
single
Omicron
subvariant
(BA.1.1),
which
evolved
within
host
during
disease
progression.
viruses
had
acquired
resistance
nirmatrelvir
(3
chymotrypsin-like
protease
[3CLpro]
E166
A/V),
sotrovimab
(spike
P337L
E340K),
remdesivir
(RNA-dependent
RNA
polymerase
[RdRp]
V166L).Our
results
indicate
that
survival
fitness
persist
infected
subpopulation
selection
pressure.This
study
supported
by
JSPS
KAKENHI
Early-Career
Scientists
18K16292
(Y.H.),
Grant-in-Aid
Scientific
Research
(B)
20H03668
23H02955
YASUDA
Medical
Foundation
Uehara
Memorial
Takeda
Science
Kato
Bioscience
(Y.H.).