Combination
antiviral
therapy
may
be
helpful
in
the
treatment
of
SARS-CoV-2
infection,
however
no
clinical
trial
data
are
available
and
combined
use
direct
acting
antivirals
(DAA)
monoclonal
antibodies
(mAb)
has
been
reported
only
anecdotally.
To
assess
cooperative
effects
dual
drug
combinations
vitro,
we
used
a
VERO
E6
cell
based
vitro
system
with
ancestral
B.1
or
highly
divergent
BQ.1.1
virus
to
test
pairwise
licensed
DAA,
including
nirmatrelvir
(NRM),
remdesivir
(RDV)
active
metabolite
molnupiravir
(EIDD-1931)
as
well
combination
RDV
four
mAbs
(sotrovimab,
bebtelovimab,
cilgavimab,
tixagevimab;
tested
susceptible
virus).
According
SynergyFinder
3.0
summary
weighted
scores,
all
had
an
additive
effect.
Within
DAA/DAA
combinations,
paired
scores
variants
were
comparable.
In
post-hoc
analysis
weighting
synergy
by
concentrations,
several
cases
synergistic
detected
at
specific
both
for
RDV/mAb
combinations.
This
was
supported
confirmation
experiments
showing
more
than
linear
shift
effective
concentration
(IC50)
increasing
concentrations
companion
drug,
although
effect
prominent
but
minimal
null
These
results
support
which
should
further
investigated
animal
models
before
introduction
into
clinic.
Med,
Год журнала:
2024,
Номер
5(1), С. 42 - 61.e23
Опубликована: Янв. 1, 2024
BackgroundOral
antiviral
drugs
with
improved
potency
and
safety
are
needed
to
address
current
challenges
in
clinical
practice
for
treatment
of
COVID-19,
including
the
risks
rebound,
drug-drug
interactions,
emerging
resistance.MethodsOlgotrelvir
(STI-1558)
is
designed
as
a
next-generation
targeting
SARS-CoV-2
main
protease
(Mpro),
an
essential
enzyme
replication,
human
cathepsin
L
(CTSL),
key
entry
into
host
cells.FindingsOlgotrelvir
highly
bioavailable
oral
prodrug
that
converted
plasma
its
active
form,
AC1115.
The
dual
mechanism
action
olgotrelvir
AC1115
was
confirmed
by
activity
inhibition
assays
co-crystal
structures
Mpro
CTSL.
displayed
inhibiting
replication
all
tested
variants
cell
culture
systems.
Olgotrelvir
also
inhibited
viral
cells
using
Spike-mediated
pseudotypes
In
K18-hACE2
transgenic
mouse
model
SARS-CoV-2-mediated
disease,
significantly
reduced
virus
load
lungs,
prevented
body
weight
loss,
cytokine
release
lung
pathologies.
demonstrated
potent
against
nirmatrelvir-resistant
E166
mutants.
showed
enhanced
bioavailability
animal
models
humans
significant
exposure
without
ritonavir.
phase
I
studies
(ClinicalTrials.gov:
NCT05364840
NCT05523739),
favorable
profile
activity.ConclusionsOlgotrelvir
inhibitor
CTSL
high
standalone
candidate
COVID-19.FundingFunded
Sorrento
Therapeutics.
Journal of Clinical Investigation,
Год журнала:
2023,
Номер
133(11)
Опубликована: Май 31, 2023
There
is
a
large
global
unmet
need
for
the
development
of
countermeasures
to
combat
hundreds
viruses
known
cause
human
disease
and
establishment
therapeutic
portfolio
future
pandemic
preparedness.
Most
approved
antiviral
therapeutics
target
proteins
encoded
by
single
virus,
providing
narrow
spectrum
coverage.
This,
combined
with
slow
pace
high
cost
drug
development,
limits
scalability
this
direct-acting
(DAA)
approach.
Here,
we
summarize
progress
challenges
in
broad-spectrum
antivirals
that
either
viral
elements
(proteins,
genome
structures,
lipid
envelopes)
or
cellular
proviral
factors
co-opted
multiple
via
newly
discovered
compounds
repurposing
drugs.
These
strategies
offer
new
means
developing
against
both
existing
emerging
threats
complement
DAAs.
International Journal of Infectious Diseases,
Год журнала:
2023,
Номер
133, С. 53 - 56
Опубликована: Май 5, 2023
Immunocompromised
patients
still
experience
unpredictable
courses
of
COVID-19,
despite
that
effective
vaccines
and
drugs
against
SARS-CoV-2
are
now
available.
Antiviral
combination
regimens
may
have
a
role
in
infection
immunocompromised
hosts,
but
current
knowledge
is
limited.
We
describe
the
case
73-year-old
Italian
man
affected
by
follicular
lymphoma
with
persistent
who
was
successfully
treated
co-administration
oral
antivirals
(10-day
molnupiravir
nirmatrelvir/ritonavir).
The
therapy
well
tolerated
both
from
clinical
biochemical
standpoint,
no
signs
toxicity.
also
performed
scoping
review,
to
sum
up
available
on
combined
antiviral
including
remdesivir,
molnupiravir,
or
nirmatrelvir/ritonavir.
Pending
further
studies
larger
cohorts
patients,
our
report
consistent
pre-clinical
data,
supporting
possible
use
selected
difficult-to-treat
COVID-19
cases.
Future Pharmacology,
Год журнала:
2023,
Номер
3(1), С. 80 - 107
Опубликована: Янв. 9, 2023
While
the
COVID-19
pandemic
seems
to
be
on
its
decline,
unclear
impacts
of
long-COVID
cases,
breakthrough
infections
in
immunocompromised
individuals,
vaccine
hesitancy,
and
inhomogeneous
health-care
accessibility
constitute
a
not
underestimated
threat.
These
along
with
preparedness,
ask
for
an
alert
identification
new
drugs
optimization
existing
as
therapeutic
treatment
options
this
potential
future
diseases.
Mpro
inhibitors
were
identified
early
potent
drug
candidates
against
coronaviruses,
since
they
target
viable
processing
machinery
within
virus,
i.e.,
main
protease
that
cleaves
polyproteins
encoded
by
viral
RNA
into
functional
proteins.
Different
strategies,
including
reversible
irreversible
inhibition
well
allosteric
inhibitors,
mostly
from
repurposing
endeavors,
have
been
explored
design
SARS-CoV-2
antivirals.
Ambitious
screening
efforts
uttered
outstanding
chemical
structural
diversity,
which
has
led
half
dozen
lead
compounds
being
currently
clinical
trials
emergency
FDA
approval
ritonavir-boosted
nirmatrelvir
therapeutic.
This
comprehensive
analysis
achieved
inhibitor
diversity
sorted
irreversible,
reversible,
binders,
discussion
emerging
resistance
reports
possible
evasion
is
aimed
at
stimulating
continuing
efforts.
Viruses,
Год журнала:
2024,
Номер
16(3), С. 366 - 366
Опубликована: Фев. 27, 2024
Viral
proteases
are
an
important
target
for
drug
development,
since
they
can
modulate
vital
pathways
in
viral
replication,
maturation,
assembly
and
cell
entry.
With
the
(re)appearance
of
several
new
viruses
responsible
causing
diseases
humans,
like
West
Nile
virus
(WNV)
recent
severe
acute
respiratory
syndrome
coronavirus
2
(SARS-CoV-2),
understanding
mechanisms
behind
blocking
protease’s
function
is
pivotal
development
antiviral
drugs
therapeutical
strategies.
Apart
from
directly
inhibiting
protease,
usually
by
targeting
its
active
site,
have
been
explored
to
impair
activity,
such
as
inducing
protein
aggregation,
allosteric
sites
or
degradation
cellular
proteasomes,
which
be
extremely
valuable
when
considering
emerging
drug-resistant
strains.
In
this
review,
we
aim
discuss
advances
on
a
broad
range
inhibitors,
therapies
molecular
approaches
inactivation
degradation,
giving
insight
different
possible
strategies
against
class
target.
Advanced Therapeutics,
Год журнала:
2024,
Номер
unknown
Опубликована: Сен. 18, 2024
Abstract
Host‐directed
therapies
(HDTs)
have
emerged
as
a
promising
strategy
to
combat
viral
infections
by
modifying
host
factors
and
immune
responses
restrict
replication
improve
patient
outcomes.
This
review
summarizes
the
latest
advances
future
potential
of
HDTs
in
antiviral
therapy.
With
developments
genomics
proteomics,
new
targets
essential
for
been
identified.
Gene‐editing
tools,
such
CRISPR‐Cas9,
enable
precise
manipulation
genes
linked
processes,
paving
way
innovative
HDTs.
Emerging
approaches,
including
RNA
interference
interference,
further
demonstrate
specifically
modify
inhibit
replication.
Additionally,
probiotics
are
being
explored
their
capacity
enhance
modulate
gut
microbiota,
offering
natural
safe
method
boosting
defenses.
Despite
these
advancements,
significant
challenges
remain,
particularly
deciphering
complex
host–virus
interactions
ensuring
safety
efficacy
therapies.
Continued
research
clinical
evaluation
realize
full
provides
comprehensive
overview
current
HDT
strategies,
emphasizing
promise
shaping
interventions.
Antiviral Research,
Год журнала:
2025,
Номер
236, С. 106099 - 106099
Опубликована: Фев. 10, 2025
The
emergence
of
new
human
viruses
with
epidemic
or
pandemic
potential
has
reaffirmed
the
urgency
to
develop
effective
broad-spectrum
antivirals
(BSAs)
as
part
a
strategic
framework
for
prevention
and
preparedness.
To
this
end,
host
nucleotide
metabolic
pathway
been
subject
intense
investigation
in
search
host-targeting
agents
(HTAs)
BSA
activity.
In
particular,
dihydroorotate
dehydrogenase
(hDHODH),
rate-limiting
enzyme
de
novo
pyrimidine
biosynthetic
pathway,
identified
preferential
target
HTAs.
Viral
replication
fact
relies
on
cellular
replenishment,
making
hDHODH
an
ideal
HTA
target.
depletion
pool
that
ensues
pharmacological
inhibition
activity
elicits
through
three
distinct
mechanisms:
it
blocks
viral
DNA
RNA
synthesis;
activates
effector
mechanisms
innate
antiviral
response;
mitigates
virus-induced
inflammatory
response.
However,
despite
spectacular
results
obtained
vitro,
inhibitors
examined
mono-drug
therapies
animal
models
infections
clinical
trials
have
produced
disappointing
levels
overall
efficacy.
overcome
inherent
limitation,
strategies
based
multi-drug
combination
treatments
should
be
considered
enable
efficacy
hDHODH-targeted
therapies.
Here,
we
review
state-of-the-art
applications
inhibitors,
discuss
challenges
emerged
from
their
testing
consider
how
they
might
addressed
advance
development
treatment
diseases.
Nature Communications,
Год журнала:
2024,
Номер
15(1)
Опубликована: Июнь 28, 2024
Abstract
In
a
pivotal
trial
(EPIC-HR),
5-day
course
of
oral
ritonavir-boosted
nirmatrelvir,
given
early
during
symptomatic
SARS-CoV-2
infection
(within
three
days
symptoms
onset),
decreased
hospitalization
and
death
by
89.1%
nasal
viral
load
0.87
log
relative
to
placebo
in
high-risk
individuals.
Yet,
nirmatrelvir/ritonavir
failed
as
post-exposure
prophylaxis
trial,
frequent
rebound
has
been
observed
subsequent
cohorts.
We
develop
mathematical
model
capturing
viral-immune
dynamics
nirmatrelvir
pharmacokinetics
that
recapitulates
loads
from
this
another
clinical
(PLATCOV).
Our
results
suggest
nirmatrelvir’s
vivo
potency
is
significantly
lower
than
vitro
assays
predict.
According
our
model,
maximally
potent
agent
would
reduce
the
approximately
3.5
logs
at
5
days.
The
identifies
earlier
initiation
shorter
treatment
duration
are
key
predictors
post-treatment
rebound.
Extension
10
for
Omicron
variant
vaccinated
individuals,
rather
increasing
dose
or
dosing
frequency,
predicted
incidence
significantly.
Antiviral Research,
Год журнала:
2024,
Номер
225, С. 105840 - 105840
Опубликована: Март 2, 2024
Host
targeting
antiviral
drugs
(HTA)
are
directed
against
cellular
mechanisms
which
can
be
exploited
by
viruses.
These
essential
for
viral
replication,
because
missing
functions
cannot
compensated
the
virus.
However,
this
assumption
needs
experimental
proof.
Here
we
compared
HTA
Zapnometinib
(ZMN),
with
direct
acting
antivirals
(DAA)
(Remdesivir
(RDV),
Molnupiravir
(MPV),
Nirmatrelvir
(NTV),
Ritonavir
(RTV),
Paxlovid
PAX)),
in
terms
of
their
potency
to
induce
reduced
drug
susceptibilities
SARS-CoV-2.
During
serial
passage
δ-B1.617.2
adaptation
all
DAAs
occurred,
while
inhibitory
capacity
ZMN
was
not
altered.
Known
single
nucleotide
polymorphisms
(SNPs)
responsible
partial
resistances
were
found
RDV,
NTV
and
PAX.
Additionally,
high
mutagenic
potential
MPV
confirmed
decreased
efficacies
first
time.
Reduced
DAA
efficacy
did
alter
ZMN.
results
show
that
confers
a
barrier
towards
development
resistance
has
act
partially
DAA-insensitive
Journal of Medicinal Chemistry,
Год журнала:
2025,
Номер
unknown
Опубликована: Янв. 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.