Advanced Materials,
Journal Year:
2025,
Volume and Issue:
unknown
Published: May 22, 2025
Abstract
The
ability
of
cytokine
receptors
to
mediate
the
internalization
targets
in
lysosomes
positions
them
as
specific
and
effective
effectors
for
protein
degradation
strategies.
However,
challenges
remain,
including
potential
unintended
activation
cell‐proliferation‐related
receptors,
well
limitations
programmability
structural
flexibility
degradators.
In
this
work,
a
CXCR7‐targeting
chimera
(AP‐CRTAC)
that
functions
CXCR7
inducer
by
covalently
linking
membrane
protein‐targeting
aptamer
with
mutant‐CXCL12
mimic
peptide
is
developed.
This
selectively
binds
without
activating
CXCR4.
AP‐CRTAC,
which
incorporates
various
forms
from
DNA,
RNA,
or
even
bispecific
aptamers,
has
shown
significant
efficacy
degrading
one
more
proteins
mutants
on
cell
surface.
Moreover,
AP‐CRTAC
constructed
2′
F‐pyrimidine‐modified
RNA
targeting
EGFR
effectively
degrades
mutations.
Notably,
enhances
sensitivity
L858R/T790M/C797S
triple
mutant
lung
cancer
cells,
are
resistant
current
EGFR‐targeted
therapies,
third‐generation
inhibitor
osimertinib
both
vitro
vivo
settings.
research
introduces
an
engineered
high
specificity
targeted
surface
proteins,
while
minimizing
unwanted
side
effects.
Bioanalysis,
Journal Year:
2025,
Volume and Issue:
unknown, P. 1 - 16
Published: Feb. 3, 2025
Undruggable
targets
account
for
roughly
85%
of
human
disease-related
and
represent
a
category
therapeutic
that
are
difficult
to
tackle
with
traditional
methods,
but
their
considerable
clinical
importance.
These
generally
defined
by
planar
functional
interfaces
the
absence
efficient
ligand-binding
pockets,
making
them
unattainable
conventional
pharmaceutical
strategies.
The
advent
oligonucleotide-based
proteolysis-targeting
chimeras
(PROTACs)
has
instilled
renewed
optimism
in
addressing
these
challenges.
PROTACs
facilitate
targeted
degradation
undruggable
entities,
including
transcription
factors
(TFs)
RNA-binding
proteins
(RBPs),
via
proteasome-dependent
mechanisms,
thereby
presenting
novel
approaches
diseases
linked
targets.
This
review
offers
an
in-depth
examination
recent
progress
integration
PROTAC
technology
oligonucleotides
target
traditionally
proteins,
emphasizing
design
principles
mechanisms
action
innovative
PROTACs.
ABSTRACT
Targeted
protein
degradation
(TPD)
is
a
rapidly
emerging
and
potentially
transformative
therapeutic
modality.
However,
the
large
majority
of
>600
known
ubiquitin
ligases
have
yet
to
be
exploited
as
TPD
effectors
by
proteolysis-targeting
chimeras
(PROTACs)
or
molecular
glue
degraders
(MGDs).
We
report
here
chemical–genetic
platform,
Site-specific
Ligand
Incorporation-induced
Proximity
(SLIP),
identify
actionable
(“PROTACable”)
sites
on
any
potential
effector
in
intact
cells.
SLIP
uses
genetic
code
expansion
(GCE)
encode
copper-free
“click”
ligation
at
specific
site
cells,
enabling
situ
formation
covalent
PROTAC-effector
conjugate
against
target
interest
(POI).
Modification
drives
targeted
protein,
establishing
these
for
TPD.
Using
SLIP,
we
systematically
screened
dozens
across
E3
E2
enzymes
from
diverse
classes,
identifying
multiple
novel
PROTACable
which
are
competent
adds
powerful
approach
proximity-induced
pharmacology
(PIP)
toolbox,
future
ligand
discovery
fully
enable
TPD,
other
PIP
modalities.
bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2025,
Volume and Issue:
unknown
Published: March 13, 2025
Traditional
phenotypic
drug
discovery
platforms
have
suffered
from
poor
scalability
and
a
lack
of
mechanistic
understanding
newly
discovered
probes.
To
address
this,
we
created
Endo-
GeneScreen
(EGS),
high-throughput
enabled
screening
platform
that
identifies
bioactive
small
molecules
capable
regulating
endogenous
protein
expression
encoded
by
any
preselected
target
gene
within
biologically
appropriate
context.
As
proof-of-concept,
EGS
successfully
identified
candidates
up-regulate
neuronal
Syngap1,
causes
neurodevelopmental
disorder
when
haploinsufficient.
For
example,
SR-1815,
previously
unknown
undescribed
kinase
inhibitor,
alleviated
major
cellular
consequences
Syngap1
loss-of-function
restoring
normal
SynGAP
levels
dampening
hyperactivity
haploinsufficient
neurons.
Moreover,
demonstrate
assays
accelerate
preclinical
development
facilitate
mode-of-action
deconvolution
studies.
Thus,
first-in-class
molecule
probes
promote
biological
precision
therapeutic
development.
Chemical Communications,
Journal Year:
2025,
Volume and Issue:
unknown
Published: Jan. 1, 2025
The
synthesis
of
a
library
minimal-backbone,
cell-permeable,
clickable
pseudopeptide
Pin1
ligands
with
potential
applications
in
drug
development
and
biochemical
studies
is
reported.
ligands'
affinity
constants
were
evaluated
using
NMR.
lead
compound
4b,
demonstrated
effective
cell
permeability,
inhibitory
activity,
an
antiproliferative
effect
on
multiple
myeloma
line.
Pharmaceuticals,
Journal Year:
2025,
Volume and Issue:
18(3), P. 419 - 419
Published: March 16, 2025
Hepatitis
B
virus
(HBV)
is
an
important
global
public
health
issue.
The
World
Health
Organization
(WHO)
2024
Global
Report
estimated
that
the
prevalence
of
people
living
with
HBV
infection
254
million,
incidence
1.2
million
new
infections
yearly.
Previous
studies
have
shown
natural
compounds
antiviral
inhibition
potentials.
In
silico
methods
such
as
molecular
docking,
virtual
screening,
pharmacophore
modeling,
quantitative
structure–activity
relationship
(QSAR),
and
dynamic
simulations
been
successfully
applied
in
identifying
bioactive
strong
binding
energies
treatment
targets.
COVID-19
pandemic
necessitated
importance
repurposing
already
approved
drugs
using
methods.
This
study
aimed
at
unveiling
benefits
techniques
a
potential
alternative
compounds’
drug
discovery
for
therapy.
Relevant
articles
from
PubMed,
Google
Scholar,
Web
Science
were
retrieved
analyzed.
Furthermore,
this
comprehensively
reviewed
literature
containing
identified
essential
proteins.
Notably,
hesperidin,
quercetin,
kaempferol,
myricetin,
flavonoids
hepatitis
surface
antigen
(HBsAg).
investigation
reveals
offer
understanding
mechanisms
action,
reveal
previously
overlooked
viral
targets
(including
PreS1
Domain
HBsAg
cccDNA
(Covalently
Closed
Circular
DNA)
regulators,
facilitate
creation
specific
inhibitors.
integration
silico,
vitro,
vivo
insights
further
highlight
Moreover,
combination
compounds,
approach,
improves
chances
personalized
precision
medicine
treatment.
Therefore,
we
recommend
strategies
combine
vivo,
approaches
to
effective
drugs.
Journal of Medicinal Chemistry,
Journal Year:
2025,
Volume and Issue:
unknown
Published: March 26, 2025
Developing
proteolysis-targeting
chimeras
(PROTACs)
is
well
recognized
through
target
protein
degradation
(TPD)
toward
promising
therapeutics.
While
a
variety
of
diseases
are
driven
by
aberrant
ubiquitination
and
critical
proteins
with
protective
functions,
stabilization
(TPS)
rather
than
TPD
emerging
as
unique
therapeutic
modality.
Deubiquitinase-targeting
(DUBTACs),
class
heterobifunctional
stabilizers
consisting
deubiquitinase
(DUB)
protein-of-interest
(POI)
targeting
ligands
conjugated
linker,
can
rescue
such
from
elimination.
DUBTACs
stabilize
the
levels
POIs
in
DUB-dependent
manner,
removing
ubiquitin
polyubiquitylated
degraded
proteins.
induce
new
interaction
between
POI
DUB
forming
POI-DUBTAC-DUB
ternary
complex.
Herein,
benefits
TPS
approaches
for
human
introduced,
recent
advances
developing
summarized.
Relevant
challenges,
opportunities,
future
perspectives
also
discussed.