Cell chemical biology,
Год журнала:
2024,
Номер
31(4), С. 632 - 657
Опубликована: Апрель 1, 2024
Over
four
years
have
passed
since
the
beginning
of
COVID-19
pandemic.
The
scientific
response
has
been
rapid
and
effective,
with
many
therapeutic
monoclonal
antibodies
small
molecules
developed
for
clinical
use.
However,
given
ability
viruses
to
become
resistant
antivirals,
it
is
perhaps
no
surprise
that
field
identified
resistance
nearly
all
these
compounds.
Here,
we
provide
a
comprehensive
review
profile
each
therapeutics.
We
hope
this
resource
provides
an
atlas
mutations
be
aware
agent,
particularly
as
springboard
considerations
next
generation
antivirals.
Finally,
discuss
outlook
thoughts
moving
forward
in
how
continue
manage
this,
next,
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2023,
Номер
unknown
Опубликована: Янв. 3, 2023
Abstract
The
antiviral
component
of
Paxlovid,
nirmatrelvir
(NIR),
forms
a
covalent
bond
with
Cys145
SARS-CoV-2
nsp5.
To
explore
NIR
resistance
we
designed
mutations
to
impair
binding
over
substrate.
Using
12
Omicron
(BA.1)
and
WA.1
replicons,
cell-based
complementation
enzymatic
assays,
showed
that
in
both
strains,
E166V
imparted
high
(∼55-fold),
major
decrease
WA1
replicon
fitness
(∼20-fold),
but
not
BA.1
(∼2-fold).
was
restored
by
L50F.
These
differences
may
contribute
potentially
lower
barrier
than
WA1.
is
rare
untreated
patients,
albeit
more
prevalent
paxlovid-treated
EPIC-HR
clinical
trial
patients.
Importantly,
NIR-resistant
replicons
or
E166V/L50F
remained
susceptible
a)
the
flexible
GC376,
b)
PF-00835231,
which
additional
interactions.
Molecular
dynamics
simulations
show
steric
clashes
between
rigid
bulky
t-butyl
β-branched
V166
distancing
warhead
from
its
target.
In
contrast,
through
“wiggling
jiggling”
accommodates
still
covalently
binds
Cys145.
PF-00835231
uses
strategically
positioned
methoxy-indole
form
β-sheet
overcome
E166V.
Drug
design
based
on
strategic
flexibility
main
chain-targeting
help
develop
second-generation
nsp5-targeting
antivirals
efficient
against
viruses.
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
Drug
resistance
poses
a
significant
challenge
in
the
development
of
effective
therapies
against
SARS-CoV-2.
Here,
we
identified
two
double
mutations,
M49K/M165V
and
M49K/S301P,
3C-like
protease
(3CLpro)
that
confer
to
novel
non-covalent
inhibitor,
WU-04,
which
is
currently
phase
III
clinical
trials
(NCT06197217).
Crystallographic
analysis
indicates
M49K
mutation
destabilizes
WU-04-binding
pocket,
impacting
binding
WU-04
more
significantly
than
3CLpro
substrates.
The
M165V
directly
interferes
with
binding.
S301P
mutation,
far
from
indirectly
affects
by
restricting
rotation
3CLpro's
C-terminal
tail
impeding
dimerization.
We
further
explored
mutations
clinically
used
inhibitors:
ensitrelvir
nirmatrelvir,
revealed
trade-off
between
catalytic
activity,
thermostability,
drug
3CLpro.
found
at
same
residue
(M49)
can
have
distinct
effects
on
inhibitors,
highlighting
importance
developing
multiple
antiviral
agents
different
skeletons
for
fighting
These
findings
enhance
our
understanding
SARS-CoV-2
mechanisms
inform
therapeutics.
Science Translational Medicine,
Год журнала:
2024,
Номер
16(738)
Опубликована: Март 13, 2024
Inhibitors
of
the
severe
acute
respiratory
syndrome
coronavirus
2
(SARS-CoV-2)
main
protease
(M
pro
)
such
as
nirmatrelvir
(NTV)
and
ensitrelvir
(ETV)
have
proven
effective
in
reducing
severity
COVID-19,
but
presence
resistance-conferring
mutations
sequenced
viral
genomes
raises
concerns
about
future
drug
resistance.
Second-generation
oral
drugs
that
retain
function
against
these
mutants
are
thus
urgently
needed.
We
hypothesized
covalent
hepatitis
C
virus
inhibitor
boceprevir
(BPV)
could
serve
basis
for
orally
bioavailable
inhibit
SARS-CoV-2
M
more
efficiently
than
existing
drugs.
Performing
structure-guided
modifications
BPV,
we
developed
a
picomolar-affinity
inhibitor,
ML2006a4,
with
antiviral
activity,
pharmacokinetics,
therapeutic
efficacy
similar
or
superior
to
those
NTV.
A
crucial
feature
ML2006a4
is
derivatization
ketoamide
reactive
group
improves
cell
permeability
bioavailability.
Last,
was
found
be
less
sensitive
several
cause
resistance
NTV
ETV
occur
natural
population.
Thus,
anticipatory
design
can
preemptively
address
potential
mechanisms
expand
treatment
options
variants.
Cell chemical biology,
Год журнала:
2024,
Номер
31(4), С. 632 - 657
Опубликована: Апрель 1, 2024
Over
four
years
have
passed
since
the
beginning
of
COVID-19
pandemic.
The
scientific
response
has
been
rapid
and
effective,
with
many
therapeutic
monoclonal
antibodies
small
molecules
developed
for
clinical
use.
However,
given
ability
viruses
to
become
resistant
antivirals,
it
is
perhaps
no
surprise
that
field
identified
resistance
nearly
all
these
compounds.
Here,
we
provide
a
comprehensive
review
profile
each
therapeutics.
We
hope
this
resource
provides
an
atlas
mutations
be
aware
agent,
particularly
as
springboard
considerations
next
generation
antivirals.
Finally,
discuss
outlook
thoughts
moving
forward
in
how
continue
manage
this,
next,
