Research Square (Research Square),
Год журнала:
2023,
Номер
unknown
Опубликована: Март 15, 2023
Resistance
to
nirmatrelvir
(Paxlovid)
has
been
shown
by
multiple
groups
and
may
already
exist
in
clinical
SARS-CoV-2
isolates.
Here
a
panel
of
main
protease
(Mpro)
variants
robust
cell-based
assay
are
used
compare
the
resistance
profiles
nirmatrelvir,
ensitrelvir,
FB2001.
The
results
reveal
distinct
mechanisms
("fingerprints")
indicate
that
these
next-generation
drugs
have
potential
be
effective
against
nirmatrelvir-resistant
vice
versa.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2023,
Номер
unknown
Опубликована: Фев. 9, 2023
Although
the
SARS-CoV-2
Omicron
variant
(BA.1)
spread
rapidly
across
world
and
effectively
evaded
immune
responses,
its
viral
fitness
in
cell
animal
models
was
reduced.
The
precise
nature
of
this
attenuation
remains
unknown
as
generating
replication-competent
genomes
is
challenging
because
length
genome
(30kb).
Here,
we
designed
a
plasmid-based
assembly
resc
ue
strategy
(pGLUE)
that
constructs
complete
infectious
viruses
or
noninfectious
subgenomic
replicons
single
ligation
reaction
with
>80%
efficiency.
Fully
sequenced
stocks
can
be
generated
1
3
weeks,
respectively.
By
testing
series
naturally
occurring
well
Delta-Omicron
chimeric
replicons,
show
nonstructural
protein
6
harbors
critical
attenuating
mutations,
which
dampen
RNA
replication
reduce
lipid
droplet
consumption.
Thus,
pGLUE
overcomes
remaining
barriers
to
broadly
study
reveals
deficits
function
underlying
attenuation.
Viruses,
Год журнала:
2023,
Номер
15(5), С. 1066 - 1066
Опубликована: Апрель 27, 2023
Early
detection
and
characterization
of
new
variants
their
impacts
enable
improved
genomic
surveillance.
This
study
aims
to
evaluate
the
subvariant
distribution
Omicron
strains
isolated
from
Turkish
cases
determine
rate
antiviral
resistance
RdRp
3CLpro
inhibitors.
The
Stanford
University
Coronavirus
Antiviral
&
Resistance
Database
online
tool
was
used
for
variant
analyses
uploaded
GISAID
as
(n
=
20.959)
between
January
2021
February,2023.
Out
288
different
subvariants,
B.1,
BA.1,
BA.2,
BA.4,
BE.1,
BF.1,
BM.1,
BN.1,
BQ.1,
CK.1,
CL.1,
XBB.1
were
main
determined
BA.1
(34.7%),
BA.2
(30.8%),
BA.5
(23.6%)
reported
most
frequently.
3CLPro-related
mutations
in
n
150,
0.72%
sequences,
while
rates
against
inhibitors
at
0.1%
0.6%,
respectively.
Mutations
that
previously
associated
with
a
reduced
susceptibility
remdesivir,
nirmatrelvir/r,
ensitrelvir
frequently
detected
(51.3%).
highest
A449A/D/G/V
(10.5%),
T21I
(10%),
L50L/F/I/V
(6%).
Our
findings
suggest
continuous
monitoring
variants,
due
diversity
lineages,
is
necessary
global
risk
assessment.
Although
drug-resistant
do
not
pose
threat,
tracking
drug
will
be
heterogenicity.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2021,
Номер
unknown
Опубликована: Ноя. 24, 2021
Abstract
Several
regulatory
agencies
have
either
licensed
or
given
emergency
use
approval
for
treatment
of
patients
at
risk
developing
severe
COVID-19
with
the
anti-viral
drug,
Molnupiravir.
Recent
trials
involving
Molnupiravir
suggested
drug
was
not
as
efficacious
earlier
studies
suggested.
This
study
aimed
to:
(i)
determine
effectiveness
active
metabolite
(NHC)
against
different
SARS-CoV-2
Variants
Concern
(VoCs),
(ii)
establish
therapeutic
window
NHC
in
a
human
lung
cell
model,
and
(iii)
evaluate
genetic
barrier
to
resistance.
Dose
response
assays
were
performed
parallel
IC50
(the
concentration
required
inhibit
virus
titre
by
50%)
variants.
Human
ACE-2
A549
cells
treated
time
points
before,
during
after
infection
SARS-CoV-2.
Multiple
passaging
presence
absence
used
whether
resistance
occurred.
To
obtain
genomic
information,
sequenced
regular
intervals.
After
20
passages
dose
sequencing
showed
did
appear
developed
The
had
equivalent
activity
four
VOCs
ranging
from
0.04
0.16μM
IC50.
efficacy
diminished
when
applied
24
hours
post-infection.
Our
results
suggest
that
administration
patients,
perhaps
pre-
post-exposure
rather
than
symptom
onset,
would
be
more
effective
option.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2023,
Номер
unknown
Опубликована: Апрель 18, 2023
Despite
unprecedented
efforts,
our
therapeutic
arsenal
against
SARS-CoV-2
remains
limited.
The
conserved
macrodomain
1
(Mac1)
in
NSP3
is
an
enzyme
exhibiting
ADP-ribosylhydrolase
activity
and
a
possible
drug
target.
To
determine
the
potential
of
Mac1
inhibition,
we
generated
recombinant
viruses
replicons
encoding
catalytically
inactive
domain
by
mutating
critical
asparagine
active
site.
While
substitution
to
alanine
(N40A)
reduced
catalytic
~10-fold,
mutations
aspartic
acid
(N40D)
~100-fold
relative
wildtype.
Importantly,
N40A
mutation
rendered
unstable
Research Square (Research Square),
Год журнала:
2023,
Номер
unknown
Опубликована: Март 15, 2023
Resistance
to
nirmatrelvir
(Paxlovid)
has
been
shown
by
multiple
groups
and
may
already
exist
in
clinical
SARS-CoV-2
isolates.
Here
a
panel
of
main
protease
(Mpro)
variants
robust
cell-based
assay
are
used
compare
the
resistance
profiles
nirmatrelvir,
ensitrelvir,
FB2001.
The
results
reveal
distinct
mechanisms
("fingerprints")
indicate
that
these
next-generation
drugs
have
potential
be
effective
against
nirmatrelvir-resistant
vice
versa.
