Biomolecules,
Journal Year:
2024,
Volume and Issue:
14(10), P. 1260 - 1260
Published: Oct. 6, 2024
The
conservation
of
the
main
protease
in
viral
genomes,
combined
with
absence
a
homologous
humans,
makes
this
enzyme
family
an
ideal
target
for
developing
broad-spectrum
antiviral
drugs
minimized
host
toxicity.
GC-376,
peptidomimetic
3CL
inhibitor,
has
shown
significant
efficacy
against
coronaviruses.
Recently,
GC-376-based
PROTAC
was
developed
to
and
induce
proteasome-mediated
degradation
dimeric
SARS-CoV-2
Signal Transduction and Targeted Therapy,
Journal Year:
2024,
Volume and Issue:
9(1)
Published: Nov. 6, 2024
Abstract
Targeted
protein
degradation
(TPD)
represents
a
revolutionary
therapeutic
strategy
in
disease
management,
providing
stark
contrast
to
traditional
approaches
like
small
molecule
inhibitors
that
primarily
focus
on
inhibiting
function.
This
advanced
technology
capitalizes
the
cell’s
intrinsic
proteolytic
systems,
including
proteasome
and
lysosomal
pathways,
selectively
eliminate
disease-causing
proteins.
TPD
not
only
enhances
efficacy
of
treatments
but
also
expands
scope
applications.
Despite
its
considerable
potential,
faces
challenges
related
properties
drugs
their
rational
design.
review
thoroughly
explores
mechanisms
clinical
advancements
TPD,
from
initial
conceptualization
practical
implementation,
with
particular
proteolysis-targeting
chimeras
molecular
glues.
In
addition,
delves
into
emerging
technologies
methodologies
aimed
at
addressing
these
enhancing
efficacy.
We
discuss
significant
trials
highlight
promising
outcomes
associated
drugs,
illustrating
potential
transform
treatment
landscape.
Furthermore,
considers
benefits
combining
other
therapies
enhance
overall
effectiveness
overcome
drug
resistance.
The
future
directions
applications
are
explored,
presenting
an
optimistic
perspective
further
innovations.
By
offering
comprehensive
overview
current
innovations
faced,
this
assesses
transformative
revolutionizing
development
setting
stage
for
new
era
medical
therapy.
Viruses,
Journal Year:
2024,
Volume and Issue:
16(3), P. 366 - 366
Published: Feb. 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.
Communications Medicine,
Journal Year:
2025,
Volume and Issue:
5(1)
Published: April 26, 2025
Effective
antiviral
therapy
is
lacking
for
most
viral
infections,
and
when
available,
frequently
compromised
by
the
selection
of
resistance.
Targeted
protein
degraders
could
provide
an
avenue
to
more
effective
antivirals,
able
overcome
The
aim
this
study
was
determine
whether
adaptation
SARS-CoV-2
main
protease
(Mpro,
also
described
as
chymotrypsin-like
(3CLpro)
or
non-structural
5
(Nsp5))
inhibitors
into
leads
increased
activity,
including
activity
against
resistant
virus.
We
adapted
clinically
approved
Mpro
inhibitor
nirmatrelvir
a
panel
degraders.
Size-matched
non-degrading
controls
were
synthesised
discriminate
degradation
from
inhibition
activity.
Degrader
confirmed
using
inducible
Mpro-HiBiT
tag
expressing
cell
line.
Antiviral
both
wildtype
nirmatrelvir-resistant
virus
performed
infection
susceptible
lines.
Here
we
show
three
compounds,
derived
utilising
VHL
IAP
ubiquitin
ligase
recruiters,
capable
degrading
in
concentration,
time
proteasome
dependent
fashion.
These
compounds
degrade
mutant
Mpro.
potent
these
possesses
enhanced
multiple
strains
compared
controls.
This
work
demonstrates
feasibility
generating
inhibitors,
confirms
that
possess
higher
potency
virus,
size
matched
enzymatic
inhibitors.
findings
further
support
development
targeted
drugs,
which
may
lead
therapies
future.
Journal of Medicinal Chemistry,
Journal Year:
2024,
Volume and Issue:
67(11), P. 8791 - 8816
Published: May 22, 2024
The
spread
of
the
influenza
virus
has
caused
devastating
pandemics
and
huge
economic
losses
worldwide.
Antiviral
drugs
with
diverse
action
modes
are
urgently
required
to
overcome
challenges
viral
mutation
drug
resistance,
targeted
protein
degradation
strategies
constitute
excellent
candidates
for
this
purpose.
Herein,
first
polymerase
acidic
(PA)
using
small-molecule
degraders
developed
by
hydrophobic
tagging
(HyT)
technology
effectively
combat
was
reported.
SAR
results
revealed
that
compound
Chemical Biology & Drug Design,
Journal Year:
2024,
Volume and Issue:
104(5)
Published: Nov. 1, 2024
Cereblon
(CRBN),
a
member
of
the
E3
ubiquitin
ligase
complex,
has
gained
significant
attention
as
therapeutic
target
in
cancer.
CRBN
regulates
degradation
various
proteins
cancer
progression,
including
transcription
factors
and
signaling
molecules.
PROTACs
(proteolysis-targeting
chimeras)
are
novel
approach
that
uses
cell's
system
to
remove
disease-causing
selectively.
CRBN-dependent
work
by
tagging
harmful
for
destruction
through
ubiquitin-proteasome
system.
This
strategy
offers
several
advantages
over
traditional
protein
inhibition
methods,
potential
overcome
drug
resistance.
Recent
progress
developing
CRBN-based
shown
promising
preclinical
results
both
hematologic
malignancies
solid
tumors.
Additionally,
have
enhanced
our
understanding
CRBN's
role
cancer,
potentially
serving
biomarkers
patient
stratification
predicting
responses.
In
this
review,
we
delineate
mechanisms
action
(CRBN-PROTACs),
summarize
recent
advances
clinical
applications,
provide
perspective
on
future
development.
Bulletin of the Korean Chemical Society,
Journal Year:
2025,
Volume and Issue:
unknown
Published: Jan. 6, 2025
Abstract
Targeted
protein
degradation
(TPD)
is
a
relatively
novel
drug
discovery
strategy
that
could
help
break
through
the
limitations
of
traditional
small
molecule
inhibitors.
While
TPD
mostly
utilizes
diverse
E3
ligases
to
incorporate
ubiquitin‐proteasome
system
(UPS),
cereblon
(CRBN)
be
considered
one
most
successfully
adopted
ligases.
Thus,
expanding
scope
CRBN
ligands
has
received
tremendous
attention
overcome
related
issues,
such
as
selectivity
and
druggability.
In
this
study,
design
synthesis
benzosultam‐based
have
been
explored
by
replacement
lactam
in
lenalidomide
with
sultam.
The
sultam‐based
showed
binding
affinities
2‐20
times
stronger
than
lenalidomide,
presumably
from
additional
hydrogen
bonds
generated
extra
oxygen
atom
sultam
group,
supported
docking
studies.
This
research
highlights
potential
benzosultam
new
tool
for
CRBN‐mediated
strategies.
