Angewandte Chemie International Edition,
Год журнала:
2023,
Номер
62(13)
Опубликована: Фев. 3, 2023
Abstract
Bispecific
chimeras
bridging
cell
membrane
proteins
with
lysosome‐trafficking
receptors
(LTRs)
provide
an
effective
therapeutic
approach
through
lysosomal
degradation
of
disease‐relevant
targets.
Here,
we
report
a
novel
dendronized
DNA
chimera
(DENTAC)
strategy
that
uses
dendritic
to
engage
surface
scavenger
(SRs)
as
LTR.
Using
bioorthogonal
strain‐promoted
alkyne‐azide
cycloaddition
conjugate
the
protein
binder,
resulting
DENTAC
is
able
traffic
target
into
lysosome
for
elimination.
We
demonstrated
utility
by
degrading
oncogenic
nucleolin
(NCL)
and
epidermal
growth
factor
receptor
(EGFR).
The
anti‐cancer
application
NCL‐targeting
was
validated
in
mouse
xenograft
model
lung
cancer.
This
work
thus
presents
new
avenue
rapid
development
potent
degraders
against
proteins,
also
broad
research
prospects.
Chemical Society Reviews,
Год журнала:
2024,
Номер
53(7), С. 3253 - 3272
Опубликована: Янв. 1, 2024
This
review
delineates
emerging
technologies
for
targeted
protein
degradation
that
directly
involve
lysosomes
or
proteasomes.
It
explores
their
unique
features,
advantages,
and
limitations,
offering
perspectives
on
future
therapeutic
applications.
Angewandte Chemie International Edition,
Год журнала:
2024,
Номер
63(18)
Опубликована: Фев. 19, 2024
The
cell
membrane
is
a
crucial
component
of
cells,
protecting
their
integrity
and
stability
while
facilitating
signal
transduction
information
exchange.
Therefore,
disrupting
its
structure
or
impairing
functions
can
potentially
cause
irreversible
damage.
Presently,
the
tumor
recognized
as
promising
therapeutic
target
for
various
treatment
methods.
Given
extensive
research
focused
on
membranes,
it
both
necessary
timely
to
discuss
these
developments,
from
materials
design
specific
biomedical
applications.
This
review
covers
treatments
based
functional
targeting
membrane,
ranging
well-known
membrane-anchoring
photodynamic
therapy
recent
lysosome-targeting
chimaeras
protein
degradation.
diverse
mechanisms
are
introduced
in
following
sections:
phototherapy,
self-assembly
situ
biosynthesis
degradation
proteins
by
chimeras.
In
each
section,
we
outline
conceptual
general
derived
numerous
studies,
emphasizing
representative
examples
understand
advancements
draw
inspiration.
Finally,
some
challenges
future
directions
membrane-targeted
our
perspective.
aims
engage
multidisciplinary
readers
encourage
researchers
related
fields
advance
fundamental
theories
practical
applications
membrane-targeting
agents.
Journal of the American Chemical Society,
Год журнала:
2023,
Номер
145(44), С. 24272 - 24283
Опубликована: Окт. 30, 2023
Targeted
degradation
of
the
cell-surface
and
extracellular
proteins
via
endogenous
lysosomal
pathways,
such
as
lysosome-targeting
chimeras
(LYTACs),
has
recently
emerged
an
attractive
tool
to
expand
scope
chemical
biology.
Herein,
we
report
a
series
recombinant
genetically
fused
insulin-like
growth
factor
2
(IGF2),
which
termed
iLYTACs,
that
can
be
conveniently
obtained
in
high
yield
by
standard
cloning
bacterial
expression
matter
days.
We
showed
both
type-I
IGF2
was
suitable
affibody
or
nanobody
capable
binding
specific
protein
target,
type-II
iLYTAC
(or
IGF2-Z),
IgG-binding
Z
domain
served
universal
antibody-binding
adaptor,
could
used
for
effective
targeting
various
membrane-bound
proteins-of-interest.
These
heterobifunctional
iLYTACs
are
fully
encoded
produced
on
large
scale
from
conventional
E.
coli
systems
without
any
form
modification.
In
current
study,
successfully
facilitated
cell
uptake,
localization,
efficient
disease-relevant
targets
different
mammalian
lines,
including
EGFR,
PD-L1,
CD20,
α-synuclein.
The
antitumor
properties
were
further
validated
mouse
xenograft
model.
Overall,
represent
general
modular
strategy
convenient
selective
targeted
degradation,
thus
expanding
potential
applications
LYTACs
related
techniques.
Nature Communications,
Год журнала:
2024,
Номер
15(1)
Опубликована: Фев. 23, 2024
Abstract
Targeted
degradation
of
proteins
has
emerged
as
a
powerful
method
for
modulating
protein
homeostasis.
Identification
suitable
degraders
is
essential
achieving
effective
degradation.
Here,
we
present
non-covalent
degrader
construction
strategy,
based
on
modular
supramolecular
co-assembly
system
consisting
two
self-assembling
peptide
ligands
that
bind
cell
membrane
receptors
and
the
interest
simultaneously,
resulting
in
targeted
The
developed
lysosome-targeting
co-assemblies
(LYTACAs)
can
induce
lysosomal
extracellular
IL-17A
PD-L1
several
scavenger
receptor
A-expressing
lines.
IL-17A-degrading
been
applied
an
imiquimod-induced
psoriasis
mouse
model,
where
it
decreases
levels
skin
lesion
alleviates
psoriasis-like
inflammation.
Extending
to
asialoglycoprotein
receptor-related
degradation,
LYTACAs
have
demonstrated
versatility
potential
streamlining
proteins.
Proceedings of the National Academy of Sciences,
Год журнала:
2024,
Номер
121(13)
Опубликована: Март 21, 2024
Lysosome-targeting
chimeras
(LYTACs)
are
a
promising
therapeutic
modality
to
drive
the
degradation
of
extracellular
proteins.
However,
early
versions
LYTAC
contain
synthetic
glycopeptides
that
cannot
be
genetically
encoded.
Here,
we
present
our
designs
for
fully
encodable
(GELYTAC),
making
tool
compatible
with
integration
into
cells
targeted
delivery
at
diseased
sites.
To
achieve
this,
replaced
glycopeptide
portion
LYTACs
protein
insulin-like
growth
factor
2
(IGF2).
After
showing
initial
efficacy
wild-type
IGF2,
increased
potency
GELYTAC
using
directed
evolution.
Subsequently,
demonstrated
engineered
construct
not
only
secretes
from
HEK293T
but
also
human
primary
T-cells
uptake
various
targets
receiver
cells.
Immune
secrete
thus
represent
avenue
spatially
selective
degradation.
Journal of the American Chemical Society,
Год журнала:
2024,
Номер
146(26), С. 17728 - 17737
Опубликована: Июнь 20, 2024
Targeted
protein
degradation
technology
holds
great
potential
in
biomedicine,
particularly
treating
tumors
and
other
protein-related
diseases.
Research
on
intracellular
using
molecular
glues
PROTAC
is
leading,
while
research
the
of
membrane
proteins
extracellular
through
lysosomal
pathway
still
preclinical
stage.
The
scarcity
useful
targets
an
immense
limitation
to
technological
advancement,
making
it
essential
explore
novel,
potentially
effective
approaches
for
targeted
degradation.
Here,
we
employed
glucose
transporter
Glut1
as
innovative
lysosome-targeting
receptor
devised
Glut1-Facilitated
Lysosomal
Degradation
(GFLD)
strategy.
We
synthesized
ligands
via
reversible
addition-fragmentation
chain
transfer
(RAFT)
polymerization
acquired
antibody-glycooligomer
conjugates
bioorthogonal
reactions
molecules,
utilized
management
PD-L1
high-expressing
triple-negative
breast
cancer.
a
exhibits
advancement
broader
array
medications
future.
