Advanced Science,
Journal Year:
2023,
Volume and Issue:
11(1)
Published: Nov. 7, 2023
Abstract
Cancer
immunotherapy
using
anti‐programmed
death‐ligand
1
(PD‐L1)
antibodies
has
been
used
in
various
clinical
applications
and
achieved
certain
results.
However,
such
limitations
as
autoimmunity,
tumor
hyperprogression,
overall
low
patient
response
rate
impede
its
further
application.
Mounting
evidence
revealed
that
PD‐L1
is
not
only
present
cell
membrane
but
also
cytoplasm,
exosome,
or
even
nucleus.
Among
these,
the
dynamic
spatial
heterogeneous
expression
of
tumors
mainly
responsible
for
unsatisfactory
efficacy
antibodies.
Hence,
numerous
studies
focus
on
inhibiting
degrading
to
improve
immune
response,
while
a
comprehensive
understanding
molecular
mechanisms
underlying
heterogeneity
can
fundamentally
transform
current
status
development.
Herein,
concept
creatively
introduced,
encompassing
structure
biological
functions
kinds
(including
mPD‐L1,
cPD‐L1,
nPD‐L1,
exoPD‐L1).
Then
an
in‐depth
analysis
regulatory
potential
therapeutic
targets
provided,
seeking
offer
solid
basis
future
investigation.
Moreover,
agents
summarized,
especially
small
modulators
development
directed
at
these
new
targets,
offering
novel
perspective
therapeutics
strategies.
Signal Transduction and Targeted Therapy,
Journal Year:
2022,
Volume and Issue:
7(1)
Published: April 4, 2022
Abstract
Traditional
drug
discovery
mainly
focuses
on
direct
regulation
of
protein
activity.
The
development
and
application
activity
modulators,
particularly
inhibitors,
has
been
the
mainstream
in
development.
In
recent
years,
PROteolysis
TArgeting
Chimeras
(PROTAC)
technology
emerged
as
one
most
promising
approaches
to
remove
specific
disease-associated
proteins
by
exploiting
cells’
own
destruction
machinery.
addition
PROTAC,
many
different
targeted
degradation
(TPD)
strategies
including,
but
not
limited
to,
molecular
glue,
Lysosome-Targeting
Chimaera
(LYTAC),
Antibody-based
PROTAC
(AbTAC),
are
emerging.
These
technologies
have
only
greatly
expanded
scope
TPD,
also
provided
fresh
insights
into
discovery.
Here,
we
summarize
advances
major
TPD
technologies,
discuss
their
potential
applications,
hope
provide
a
prime
for
both
biologists
chemists
who
interested
this
vibrant
field.
Chemical Society Reviews,
Journal Year:
2022,
Volume and Issue:
51(12), P. 5214 - 5236
Published: Jan. 1, 2022
Proteolysis-targeting
chimeras
(PROTACs)
are
heterobifunctional
molecules
consisting
of
one
ligand
that
binds
to
a
protein
interest
(POI)
and
another
can
recruit
an
E3
ubiquitin
ligase.
The
chemically-induced
proximity
between
the
POI
ligase
results
in
ubiquitination
subsequent
degradation
by
ubiquitin-proteasome
system
(UPS).
event-driven
mechanism
action
(MOA)
PROTACs
offers
several
advantages
compared
traditional
occupancy-driven
small
molecule
inhibitors,
such
as
catalytic
nature,
reduced
dosing
frequency,
more
potent
longer-lasting
effect,
added
layer
selectivity
reduce
potential
toxicity,
efficacy
face
drug-resistance
mechanisms,
targeting
nonenzymatic
functions,
expanded
target
space.
Here,
we
highlight
important
milestones
briefly
discuss
lessons
learned
about
targeted
(TPD)
recent
years
conjecture
on
efforts
still
needed
expand
toolbox
for
PROTAC
discovery
ultimately
provide
promising
therapeutics.
ACS Central Science,
Journal Year:
2023,
Volume and Issue:
9(7), P. 1269 - 1284
Published: July 14, 2023
Molecular
proximity
orchestrates
biological
function,
and
blocking
existing
proximities
is
an
established
therapeutic
strategy.
By
contrast,
strengthening
or
creating
neoproximity
with
chemistry
enables
modulation
of
processes
high
selectivity
has
the
potential
to
substantially
expand
target
space.
A
plethora
proximity-based
modalities
proteins
via
diverse
approaches
have
recently
emerged,
opening
opportunities
for
biopharmaceutical
innovation.
This
Outlook
outlines
mechanisms
molecules
based
on
induced
proximity,
including
protein
degraders,
blockers,
stabilizers,
inducers
post-translational
modifications,
agents
cell
therapy,
discusses
challenges
that
field
must
address
mature
unlock
translation
in
biology
medicine.
Journal of the American Chemical Society,
Journal Year:
2022,
Volume and Issue:
144(48), P. 21831 - 21836
Published: Nov. 23, 2022
As
effective
ways
to
regulate
protein
levels,
targeted
degradation
technologies
have
attracted
great
attention
in
recent
years.
Here,
we
established
a
novel
integrin-facilitated
lysosomal
(IFLD)
strategy
degrade
extracellular
and
cell
membrane
proteins
using
bifunctional
compounds
as
molecular
degraders.
By
conjugation
of
target
protein-binding
ligand
with
an
integrin-recognition
ligand,
the
resulting
degrader
proved
be
highly
efficient
induce
internalization
subsequent
or
integrin-
lysosome-dependent
manner.
demonstrated
development
BMS-L1-RGD,
which
is
programmed
death-ligand
1
(PD-L1)
validated
both
vitro
vivo,
IFLD
expands
toolbox
for
regulation
secreted
membrane-associated
thus
has
potential
applied
chemical
biology
drug
discovery.
Chemical Reviews,
Journal Year:
2023,
Volume and Issue:
123(12), P. 7782 - 7853
Published: May 15, 2023
The
high
selectivity
and
affinity
of
antibodies
toward
their
antigens
have
made
them
a
highly
valuable
tool
in
disease
therapy,
diagnosis,
basic
research.
A
plethora
chemical
genetic
approaches
been
devised
to
make
accessible
more
"undruggable"
targets
equipped
with
new
functions
illustrating
or
regulating
biological
processes
precisely.
In
this
Review,
addition
introducing
how
naked
various
antibody
conjugates
(such
as
antibody-drug
conjugates,
antibody-oligonucleotide
antibody-enzyme
etc.)
work
therapeutic
applications,
special
attention
has
paid
chemistry
tools
helped
optimize
the
outcome
(i.e.,
enhanced
efficacy
reduced
side
effects)
facilitate
multifunctionalization
antibodies,
focus
on
emerging
fields
such
targeted
protein
degradation,
real-time
live-cell
imaging,
catalytic
labeling
decaging
spatiotemporal
control
well
engagement
inside
cells.
With
advances
modern
biotechnology,
well-designed
derivatives
via
size
miniaturization
together
efficient
delivery
systems
emerged,
which
gradually
improved
our
understanding
important
paved
way
pursue
novel
for
potential
treatments
diseases.
Angewandte Chemie International Edition,
Journal Year:
2023,
Volume and Issue:
62(11)
Published: Jan. 17, 2023
Abstract
Proteolysis
targeting
chimeras
(PROTACs)
technology
is
an
emerging
approach
to
degrade
disease‐associated
proteins.
Here,
we
report
carbon‐dot
(CD)‐based
PROTACs
(CDTACs)
that
membrane
proteins
via
the
ubiquitin‐proteasome
system.
CDTACs
can
bind
programmed
cell
death
ligand
1
(PD‐L1),
recruit
cereblon
(CRBN)
induce
PD‐L1
ubiquitination,
and
them
with
proteasomes.
Fasting‐mimicking
diet
(FMD)
also
used
enhance
cellular
uptake
proteasome
activity.
More
than
99
%
or
90
of
in
CT26
B16‐F10
tumor
cells
be
degraded
by
CDTACs,
respectively.
Furthermore,
activate
stimulator
interferon
genes
(STING)
pathway
trigger
immune
responses.
Thus,
FMD
treatment
effectively
inhibit
growth
tumors.
Compared
small‐molecule‐based
PROTACs,
offer
several
advantages,
such
as
efficient
protein
degradation,
targeted
accumulation,
system
activation,
vivo
detection.
Theranostics,
Journal Year:
2023,
Volume and Issue:
13(5), P. 1520 - 1544
Published: Jan. 1, 2023
Immunotherapy
has
achieved
great
success
recently
and
opened
a
new
avenue
for
anti-tumor
treatment.
Programmed
cell
death
1/programmed
ligand
1
(PD-1/PD-L1)
are
typical
immune
checkpoints
that
transmit
coinhibitory
signals,
muting
the
host
immunity.
Monoclonal
antibodies
block
PD-1/PD-L1
axis
have
benefited
many
patients
with
different
tumor
diseases.
However,
objective
response
rate
is
still
unsatisfactory.
In
this
review,
we
summarize
three
strategies
targeting
PD-L1
based
on
forms
of
various
regulating
mechanisms
to
enhance
therapeutic
effect,
including
blockade
interaction
between
PD-1,
downregulation
expression
degradation
mature
PD-L1.
Thereinto,
describe
variety
materials
been
designed
target
PD-L1,
antibodies,
nanoparticle,
peptide,
aptamer,
RNA,
small
molecule.
Additionally,
list
drugs
regulation
capacity
used
in
clinical
ongoing
studies
explore
other
alternatives
besides
anti-PD-L1
monoclonal
antibodies.
Moreover,
discuss
associated
opportunities
cancer
combination
therapy
modalities
such
as
chemotherapy,
radiotherapy,
photodynamic
(PDT)
photothermal
(PTT),
these
conventional
or
emerging
capable
increasing
cells
by
altering
microenvironment
(TME),
would
display
synergistic
effect.
At
last,
give
brief
summary
outlook
regarding
research
status
future
prospect
immunotherapy.
Chemistry - A European Journal,
Journal Year:
2023,
Volume and Issue:
29(20)
Published: Jan. 19, 2023
Bioorthogonal
chemistry
involves
selective
biocompatible
reactions
between
functional
groups
that
are
not
normally
present
in
biology.
It
has
been
used
to
probe
biomolecules
living
systems,
and
advanced
biomedical
strategies
such
as
diagnostics
therapeutics.
In
this
review,
the
challenges
opportunities
encountered
when
translating
vitro
bioorthogonal
approaches
vivo
settings
presented,
with
a
focus
on
methods
deliver
reaction
components.
These
include
metabolic
bioengineering,
active
targeting,
passive
simultaneously
strategies.
The
suitability
of
ligation
bond
cleavage
for
applications
is
critically
appraised,
practical
considerations
optimum
scheduling
regimen
pretargeting
discussed.
Finally,
we
our
own
perspectives
area
identify
what,
view,
key
must
be
overcome
maximise
impact
these
approaches.
ACS Nano,
Journal Year:
2023,
Volume and Issue:
17(7), P. 6150 - 6164
Published: March 21, 2023
The
selective
removal
of
misfolded,
aggregated,
or
aberrantly
overexpressed
protein
plays
an
essential
role
in
maintaining
protein-dominated
biological
processes.
In
parallel,
the
precise
knockout
abnormal
proteins
is
inseparable
from
accurate
identification
within
complex
environments.
Guided
by
these
precepts,
small
molecules,
antibodies,
are
commonly
used
as
recognition
tools
for
developing
targeted
degradation
(TPD)
technology.
Indeed,
TPD
has
shown
tremendous
prospects
chronic
diseases,
rare
cancer
research,
and
other
fields.
Meanwhile,
aptamers
short
RNA
DNA
oligonucleotides
that
can
bind
to
target
with
high
specificity
strong
affinity.
Accordingly,
actively
designing
constructing
this
perspective,
we
provide
a
brief
introduction
technology
its
current
progress,
summarize
application
challenges.
Recent
advances
aptamer-based
reviewed,
together
corresponding
challenges
outlooks.