Randomized controlled trial of molnupiravir SARS-CoV-2 viral and antibody response in at-risk adult outpatients
Nature Communications,
Год журнала:
2024,
Номер
15(1)
Опубликована: Фев. 23, 2024
Abstract
Viral
clearance,
antibody
response
and
the
mutagenic
effect
of
molnupiravir
has
not
been
elucidated
in
at-risk
populations.
Non-hospitalised
participants
within
5
days
SARS-CoV-2
symptoms
randomised
to
receive
(n
=
253)
or
Usual
Care
324)
were
recruited
study
viral
dynamics
on
whole
genome
sequence
from
1437
genomes.
Molnupiravir
accelerates
load
decline,
but
virus
is
detectable
by
Day
most
cases.
At
14
(9
post-treatment),
associated
with
significantly
higher
persistence
lower
anti-SARS-CoV-2
spike
titres
compared
Care.
Serial
sequencing
reveals
increased
mutagenesis
treatment.
Persistence
RNA
at
group
transition
mutations
following
treatment
cessation.
viability
similar
both
groups
post-molnupiravir
treated
samples
cultured
up
9
post
cessation
The
current
5-day
course
too
short.
Longer
courses
should
be
tested
reduce
risk
potentially
transmissible
molnupiravir-mutated
variants
being
generated.
Trial
registration:
ISRCTN30448031
Язык: Английский
COVID-19 therapeutics
Clinical Microbiology Reviews,
Год журнала:
2024,
Номер
37(2)
Опубликована: Май 21, 2024
SUMMARYSince
the
emergence
of
COVID-19
in
2020,
an
unprecedented
range
therapeutic
options
has
been
studied
and
deployed.
Healthcare
providers
have
multiple
treatment
approaches
to
choose
from,
but
efficacy
those
often
remains
controversial
or
compromised
by
viral
evolution.
Uncertainties
still
persist
regarding
best
therapies
for
high-risk
patients,
drug
pipeline
is
suffering
fatigue
shortage
funding.
In
this
article,
we
review
antiviral
activity,
mechanism
action,
pharmacokinetics,
safety
therapies.
Additionally,
summarize
evidence
from
randomized
controlled
trials
on
various
antivirals
discuss
unmet
needs
which
should
be
addressed.
Язык: Английский
Nanobodies to multiple spike variants and inhalation of nanobody-containing aerosols neutralize SARS-CoV-2 in cell culture and hamsters
Antiviral Research,
Год журнала:
2023,
Номер
221, С. 105778 - 105778
Опубликована: Дек. 7, 2023
The
ongoing
threat
of
COVID-19
has
highlighted
the
need
for
effective
prophylaxis
and
convenient
therapies,
especially
outpatient
settings.
We
have
previously
developed
highly
potent
single-domain
(VHH)
antibodies,
also
known
as
nanobodies,
that
target
Receptor
Binding
Domain
(RBD)
SARS-CoV-2
Spike
protein
neutralize
Wuhan
strain
virus.
In
this
study,
we
present
a
new
generation
anti-RBD
nanobodies
with
superior
properties.
primary
representative
group,
Re32D03,
neutralizes
Alpha
to
Delta
well
Omicron
BA.2.75;
other
members
neutralize,
in
addition,
BA.1,
BA.2,
BA.4/5,
XBB.1.
Crystal
structures
RBD-nanobody
complexes
reveal
how
ACE2-binding
is
blocked
explain
nanobodies'
tolerance
immune
escape
mutations.
Through
cryo-EM
structure
Ma16B06-BA.1
complex,
demonstrated
single
nanobody
molecule
can
trimeric
spike.
describe
method
large-scale
production
these
Pichia
pastoris,
formulating
them
into
aerosols.
Exposing
hamsters
aerosols,
before
or
even
24
h
after
infection
SARS-CoV-2,
significantly
reduced
virus
load,
weight
loss
pathogenicity.
These
results
show
potential
aerosolized
therapy
coronavirus
infections.
Язык: Английский
Potential of traditional medicines in alleviating COVID-19 symptoms
Frontiers in Pharmacology,
Год журнала:
2024,
Номер
15
Опубликована: Сен. 26, 2024
This
review
discusses
the
prevention
and
treatment
of
coronavirus
disease
2019
(COVID-19)
caused
by
infection
with
severe
acute
respiratory
syndrome
2
(SARS-CoV-2).
Mutations
in
its
spike
glycoprotein
have
driven
emergence
variants
high
transmissibility
immune
escape
capabilities.
Some
antiviral
drugs
are
ineffective
against
BA.2
subvariant
at
authorized
dose.
Recently,
150
natural
metabolites
been
identified
as
potential
candidates
for
development
new
anti-COVID-19
higher
efficacy
lower
toxicity
than
those
existing
therapeutic
agents.
Botanical
drug-derived
bioactive
molecules
shown
promise
dampening
COVID-19
cytokine
storm
thus
preventing
pulmonary
fibrosis,
they
exert
a
strong
binding
affinity
viral
proteins
inhibit
their
activity.
The
Health
Ministry
Thailand
has
approved
Andrographis
paniculata
(Jap.
Senshinren)
extracts
to
treat
COVID-19.
In
China,
over
85%
patients
infected
SARS-CoV-2
receive
treatments
based
on
traditional
Chinese
medicine.
A
comprehensive
map
stages
pathogenetic
mechanisms
related
effective
products
prevent
presented.
Approximately
10%
affected
long
COVID,
impairs
mitochondrial
DNA.
As
number
agents
is
limited,
adjuvant
botanical
drug
including
vitamin
C
E
supplementation
may
reduce
symptoms
progression
COVID.
Язык: Английский
Inhibitors of dihydroorotate dehydrogenase synergize with the broad antiviral activity of 4′-fluorouridine
Antiviral Research,
Год журнала:
2024,
Номер
233, С. 106046 - 106046
Опубликована: Дек. 3, 2024
RNA
viruses
present
a
constant
threat
to
human
health,
often
with
limited
options
for
vaccination
or
therapy.
Notable
examples
include
influenza
and
coronaviruses,
which
have
pandemic
potential.
Filo-
henipaviruses
cause
more
outbreaks,
but
high
case
fatality
rates.
All
rely
on
the
activity
of
virus-encoded
RNA-dependent
polymerase
(RdRp).
An
antiviral
nucleoside
analogue,
4'-Fluorouridine
(4'-FlU),
targets
RdRp
diminishes
replication
several
viruses,
including
A
virus
SARS-CoV-2,
through
incorporation
into
nascent
viral
delayed
chain
termination.
However,
effective
concentration
4'-FlU
varied
among
different
raising
need
fortify
its
efficacy.
Here
we
show
that
inhibitors
dihydroorotate
dehydrogenase
(DHODH),
an
enzyme
essential
pyrimidine
biosynthesis,
can
synergistically
enhance
effect
against
henipaviruses,
Ebola
virus.
Even
4'-FlU-resistant
mutant
was
re-sensitized
towards
by
DHODH
inhibition.
The
addition
uridine
rescued
replication,
strongly
suggesting
depletion
as
mechanism
this
synergy.
also
highly
SARS-CoV-2
in
hamster
model
COVID.
We
propose
impairment
endogenous
synthesis
inhibition
enhances
RNAs.
This
strategy
may
be
broadly
applicable
efficacy
analogues
Язык: Английский
The Tautomeric State of N4-Hydroxycytidine within Base-Paired RNA
ACS Central Science,
Год журнала:
2024,
Номер
10(5), С. 1084 - 1093
Опубликована: Апрель 25, 2024
Antiviral
nucleoside
analogues
(e.g.,
Molnupiravir,
Remdesivir)
played
key
roles
in
the
treatment
of
COVID-19
by
targeting
SARS-CoV-2
RNA-dependent
RNA
polymerase
(RdRp).
The
N4-hydroxycytidine
(NHC),
exists
two
tautomeric
forms
that
pair
either
with
G
or
A
within
RdRp
active
site,
causing
an
accumulation
viral
mutations
during
replication.
Detailed
insights
into
states
base
pairs
and
structural
influence
NHC
are
still
missing.
In
this
study,
we
investigate
properties
NHC:G
NHC:A
a
self-complementary
duplex
UV
thermal
melting
NMR
spectroscopy
using
atom-specifically
15N-labeled
versions
were
incorporated
oligonucleotides
solid-phase
synthesis.
analysis
revealed
Watson–Crick
via
its
amino
form,
whereas
equally
populated
conformations
detected
for
pair:
weakly
hydrogen-bonded
imino
form
another
conformation
shifted
toward
minor
groove.
Moreover,
found
variable
on
neighboring
environment.
This
study
provides
conclusive
experimental
evidence
existence
pairs.
Язык: Английский
Efficacy of late-onset antiviral treatment in immunocompromised hosts with persistent SARS-CoV-2 infection
Journal of Virology,
Год журнала:
2024,
Номер
98(9)
Опубликована: Авг. 29, 2024
Immunocompromised
people
are
at
high
risk
of
prolonged
severe
acute
respiratory
syndrome
coronavirus
2
(SARS-CoV-2)
infection
and
progression
to
disease
2019
(COVID-19).
However,
the
efficacy
late-onset
direct-acting
antiviral
(DAA)
therapy
with
therapeutics
in
clinical
use
experimental
drugs
mitigate
persistent
viral
replication
is
unclear.
In
this
study,
we
employed
an
immunocompromised
mouse
model,
which
supports
SARS-CoV-2
explore
treatment
options.
Tandem
immuno-depletion
CD4
Язык: Английский
Identification of antibody-resistant SARS-CoV-2 mutants via N4-Hydroxycytidine mutagenesis
Antiviral Research,
Год журнала:
2024,
Номер
231, С. 106006 - 106006
Опубликована: Сен. 16, 2024
Язык: Английский
Efficacy of late-onset antiviral treatment in immune-compromised hosts with persistent SARS-CoV-2 infection
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Май 23, 2024
The
immunocompromised
are
at
high
risk
of
prolonged
SARS-CoV-2
infection
and
progression
to
severe
COVID-19.
However,
efficacy
late-onset
direct-acting
antiviral
(DAA)
therapy
with
therapeutics
in
clinical
use
experimental
drugs
mitigate
persistent
viral
replication
is
unclear.
In
this
study,
we
employed
an
mouse
model,
which
supports
explore
treatment
options.
Tandem
immuno-depletion
CD4
Язык: Английский
Inhibitors of dihydroorotate dehydrogenase synergize with the broad antiviral activity of 4′-fluorouridine
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Окт. 6, 2024
ABSTRACT
RNA
viruses
present
a
constant
threat
to
human
health,
often
with
limited
options
for
vaccination
or
therapy.
Notable
examples
include
influenza
and
coronaviruses,
which
have
pandemic
potential.
Filo-
henipaviruses
cause
more
outbreaks,
but
high
case
fatality
rates.
All
rely
on
the
activity
of
virus-encoded
RNA-dependent
polymerase
(RdRp).
An
antiviral
nucleoside
analogue,
4′-Fluorouridine
(4′-FlU),
targets
RdRp
diminishes
replication
several
viruses,
including
A
virus
SARS-CoV-2,
through
incorporation
into
nascent
viral
delayed
chain
termination.
However,
effective
concentration
4′-FlU
varied
among
different
raising
need
fortify
its
efficacy.
Here
we
show
that
inhibitors
dihydroorotate
dehydrogenase
(DHODH),
an
enzyme
essential
pyrimidine
biosynthesis,
can
synergistically
enhance
effect
against
henipaviruses,
Ebola
virus.
Even
4′-FlU-resistant
mutant
was
re-sensitized
towards
by
DHODH
inhibition.
The
addition
uridine
rescued
replication,
strongly
suggesting
depletion
as
mechanism
this
synergy.
also
highly
SARS-CoV-2
in
hamster
model
COVID.
We
propose
impairment
endogenous
synthesis
inhibition
enhances
RNAs.
This
strategy
may
be
broadly
applicable
efficacy
analogues
Graphical
Abstract
HIGHLIGHTS
Strong
synergy
Activity
combination
previously
resistant
Broadly
active
diverse
set
Successful
pathogenic
Nipah
Язык: Английский