Non-structural
protein
10
(nsp10)
and
non-structural
16
(nsp16)
are
part
of
the
RNA
synthesis
complex,
which
is
crucial
for
replication
severe
acute
respiratory
syndrome
coronavirus
2
(SARS-CoV-2).
Nsp16
exhibits
2'-O-methyltransferase
activity
during
viral
messenger
capping
active
in
a
heterodimeric
complex
with
enzymatically
inactive
nsp10.
It
has
been
shown
that
inactivation
nsp10-16
interferes
severely
replication,
making
it
highly
promising
drug
target.
As
information
on
ligands
binding
to
(nsp10-16)
still
scarce,
we
screened
site
potential
drug-like
fragment-like
compounds
using
X-ray
crystallography.
The
set
234
consists
derivatives
natural
substrate
S-adenosyl
methionine
(SAM)
adenine
derivatives,
some
have
described
previously
as
methyltransferase
inhibitors
nsp16
binders.
A
docking
study
guided
selection
many
these
compounds.
Here
report
structures
binders
SAM
two
them,
toyocamycin
sangivamycin,
present
additional
crystal
presence
second
substrate,
Cap0-analog/Cap0-RNA.
identified
hits
were
tested
solution
antiviral
cell
culture.
Our
data
provide
important
structural
various
molecules
bind
can
be
used
novel
starting
points
selective
inhibitor
designs.
Journal of Medicinal Chemistry,
Год журнала:
2024,
Номер
67(8), С. 6495 - 6507
Опубликована: Апрель 12, 2024
We
have
witnessed
three
coronavirus
(CoV)
outbreaks
in
the
past
two
decades,
including
COVID-19
pandemic
caused
by
SARS-CoV-2.
Main
protease
(MPro),
a
highly
conserved
among
various
CoVs,
is
essential
for
viral
replication
and
pathogenesis,
making
it
prime
target
antiviral
drug
development.
Here,
we
leverage
proteolysis
targeting
chimera
(PROTAC)
technology
to
develop
new
class
of
small-molecule
antivirals
that
induce
degradation
SARS-CoV-2
MPro.
Among
them,
MPD2
was
demonstrated
effectively
reduce
MPro
protein
levels
293T
cells,
relying
on
time-dependent,
CRBN-mediated,
proteasome-driven
mechanism.
Furthermore,
exhibited
remarkable
efficacy
diminishing
SARS-CoV-2-infected
A549-ACE2
cells.
also
displayed
potent
activity
against
strains
enhanced
potency
nirmatrelvir-resistant
viruses.
Overall,
this
proof-of-concept
study
highlights
potential
targeted
as
an
innovative
approach
developing
could
fight
drug-resistant
variants.
Pharmaceutics,
Год журнала:
2024,
Номер
16(2), С. 217 - 217
Опубликована: Фев. 2, 2024
The
COVID-19
pandemic,
caused
by
severe
acute
respiratory
syndrome
coronavirus
2
(SARS-CoV-2),
has
presented
an
enormous
challenge
to
health
care
systems
and
medicine.
As
a
result
of
global
research
efforts
aimed
at
preventing
effectively
treating
SARS-CoV-2
infection,
vaccines
with
fundamentally
new
mechanisms
action
some
small-molecule
antiviral
drugs
targeting
key
proteins
in
the
viral
cycle
have
been
developed.
most
effective
drug
approved
date
for
treatment
is
PaxlovidTM,
which
combination
two
protease
inhibitors,
nirmatrelvir
ritonavir.
Nirmatrelvir
reversible
covalent
peptidomimetic
inhibitor
main
(Mpro)
SARS-CoV-2,
enzyme
plays
crucial
role
reproduction.
In
this
combination,
ritonavir
serves
as
pharmacokinetic
enhancer,
it
irreversibly
inhibits
cytochrome
CYP3A4
responsible
rapid
metabolism
nirmatrelvir,
thereby
increasing
half-life
bioavailability
nirmatrelvir.
tutorial
review,
we
summarize
development
pharmaceutical
chemistry
aspects
Paxlovid,
covering
evolution
warhead
design,
synthesis
mechanism
well
its
inhibition
mechanism.
efficacy
Paxlovid
novel
virus
mutants
also
overviewed.
Journal of Infection and Public Health,
Год журнала:
2023,
Номер
16(12), С. 1961 - 1970
Опубликована: Сен. 30, 2023
Several
therapeutics
have
been
developed
and
approved
against
SARS-CoV-2
occasionally;
nirmatrelvir
is
one
of
them.
The
drug
target
Mpro,
therefore,
it
necessary
to
comprehend
the
structural
molecular
interaction
Mpro-nirmatrelvir
complex.Integrative
bioinformatics,
system
biology,
statistical
models
were
used
analyze
macromolecular
complex.Using
two
complexes,
study
illustrated
interactive
residues,
H-bonds,
interfaces.
It
informed
six
nine
H-bond
formations
for
first
second
complex,
respectively.
maximum
bond
length
was
observed
as
3.33
Å.
ligand
binding
pocket's
surface
area
volume
noted
303.485
Å2
295.456
Å3
complex
308.397
304.865
complex.
proteome
dynamics
evaluated
by
analyzing
complex's
NMA
mobility,
eigenvalues,
deformability,
B-factor.
Conversely,
a
model
created
assess
therapeutic
status
nirmatrelvir.Our
reveals
landscape
will
guide
researchers
in
designing
more
broad-spectrum
antiviral
molecules
mimicking
nirmatrelvir,
which
assist
fighting
other
infectious
viruses.
also
help
prepare
future
epidemics
or
pandemics.
Journal of Chemical Research,
Год журнала:
2025,
Номер
49(2)
Опубликована: Март 1, 2025
The
repercussions
of
the
COVID-19
pandemic
caused
by
severe
acute
respiratory
syndrome
coronavirus
2
(SARS-CoV-2)
are
catastrophic,
and
world
has
yet
to
achieve
full
recovery.
Several
inhibitors
targeting
SARS-CoV-2
main
protease
experiencing
diminished
efficacy
owing
resistance-inducing
mutations.
current
situation
implies
that
quest
find
potent
resilient
drugs
overcome
resistance
must
be
a
continuous
effort.
Here,
multiple
receptor
virtual
screening
molecular
dynamics
(MD)
simulation
techniques
were
employed
identify
novel
binders
from
an
integrated
small-molecule
database
as
leads
for
discovery,
design,
development
antivirals
immune
protease.
was
initially
screened
separately
against
five
structures
with
different
substrate-binding
site
conformations
using
GOLD
program,
after
which
fitness
score
control
compound
used
cutoff
create
shortlist
potential
hits
in
each
case.
Then,
21
compounds
at
intersection
all
shortlists
selected
hits.
subjected
MD
simulations,
identifying
four
capable
remaining
bound
up
100
ns.
Analysis
mode
binding
interactions
between
revealed
fit
better
into
conserved
subpockets
than
interact
important
amino
acid
residues.
Conjointly,
energy,
toxicity
analysis
results
further
demonstrated
promising
augment
fight
resistance.
Scientific Reports,
Год журнала:
2024,
Номер
14(1)
Опубликована: Авг. 21, 2024
Natural
language-based
generative
artificial
intelligence
(AI)
has
become
increasingly
prevalent
in
scientific
research.
Intriguingly,
capabilities
of
pre-trained
transformer
(GPT)
language
models
beyond
the
scope
natural
tasks
have
recently
been
identified.
Here
we
explored
how
GPT-4
might
be
able
to
perform
rudimentary
structural
biology
modeling.
We
prompted
model
3D
structures
for
20
standard
amino
acids
and
an
α-helical
polypeptide
chain,
with
latter
incorporating
Wolfram
mathematical
computation.
also
used
interaction
analysis
between
anti-viral
nirmatrelvir
its
target,
SARS-CoV-2
main
protease.
Geometric
parameters
generated
typically
approximated
close
experimental
references.
However,
modeling
was
sporadically
error-prone
molecular
complexity
not
well
tolerated.
Interaction
further
revealed
ability
identify
specific
acid
residues
involved
ligand
binding
along
corresponding
bond
distances.
Despite
current
limitations,
show
capacity
AI
basic
atomic-scale
accuracy.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Март 13, 2024
Abstract
Non-structural
protein
10
(nsp10)
and
non-structural
16
(nsp16)
are
part
of
the
RNA
synthesis
complex,
which
is
crucial
for
replication
severe
acute
respiratory
syndrome
coronavirus
2
(SARS-CoV-2).
Nsp16
exhibits
2’-
O
-methyltransferase
activity
during
viral
messenger
capping
active
in
a
heterodimeric
complex
with
enzymatically
inactive
nsp10.
It
has
been
shown
that
inactivation
nsp10-16
interferes
severely
replication,
making
it
highly
promising
drug
target.
As
information
on
ligands
binding
to
(nsp10-16)
still
scarce,
we
screened
site
potential
drug-like
fragment-like
compounds
using
X-ray
crystallography.
The
set
234
consists
derivatives
natural
substrate
S
-adenosyl
methionine
(SAM)
adenine
derivatives,
some
have
described
previously
as
methyltransferase
inhibitors
nsp16
binders.
A
docking
study
guided
selection
many
these
compounds.
Here
report
structures
binders
SAM
two
them,
toyocamycin
sangivamycin,
present
additional
crystal
presence
second
substrate,
Cap0-analog/Cap0-RNA.
identified
hits
were
tested
solution
antiviral
cell
culture.
Our
data
provide
important
structural
various
molecules
bind
can
be
used
novel
starting
points
selective
inhibitor
designs.
Vaccines,
Год журнала:
2023,
Номер
11(9), С. 1472 - 1472
Опубликована: Сен. 10, 2023
Coronavirus
disease
2019
(COVID-19)
is
a
worldwide
public
health
and
economic
threat,
virus
variation
amplifies
the
difficulty
in
epidemic
prevention
control.
The
structure
of
severe
acute
respiratory
syndrome
coronavirus
2
(SARS-CoV-2)
has
been
studied
extensively
now
well
defined.
S
protein
most
distinguishing
feature
terms
infection
immunity,
mediating
entrance
inducing
neutralizing
antibodies.
its
essential
components
are
also
promising
target
to
develop
vaccines
antibody-based
drugs.
Therefore,
key
site
mutation
gene
high
interest.
Among
them,
RBD,
NTD,
furin
cleavage
sites
mutable
regions
with
serious
consequences
for
SARS-CoV-2
biological
characteristics,
including
infectivity,
pathogenicity,
natural
vaccine
efficacy,
antibody
therapeutics.
We
aware
that
this
outbreak
may
not
be
last.
narrative
review,
we
summarized
viral
prevalence
condition,
discussed
specific
amino
acid
replacement
associated
immune
challenges
attempted
sum
up
some
control
strategies
by
reviewing
literature
on
previously
published
research
about
assist
clarifying
pathway
developing
countermeasures
against
such
viruses
as
soon
possible.
