Targeted degradation of membrane and extracellular proteins with LYTACs
Acta Pharmacologica Sinica,
Год журнала:
2024,
Номер
unknown
Опубликована: Авг. 5, 2024
Язык: Английский
Evolution of Alzheimer’s Disease Therapeutics: From Conventional Drugs to Medicinal Plants, Immunotherapy, Microbiotherapy and Nanotherapy
Pharmaceutics,
Год журнала:
2025,
Номер
17(1), С. 128 - 128
Опубликована: Янв. 17, 2025
Alzheimer's
disease
(AD)
represents
an
escalating
global
health
crisis,
constituting
the
leading
cause
of
dementia
among
elderly
and
profoundly
impairing
their
quality
life.
Current
FDA-approved
drugs,
such
as
rivastigmine,
donepezil,
galantamine,
memantine,
offer
only
modest
symptomatic
relief
are
frequently
associated
with
significant
adverse
effects.
Faced
this
challenge
in
line
advances
understanding
pathophysiology
neurodegenerative
condition,
various
innovative
therapeutic
strategies
have
been
explored.
Here,
we
review
novel
approaches
inspired
by
advanced
knowledge
underlying
pathophysiological
mechanisms
disease.
Among
alternatives,
immunotherapy
stands
out,
employing
monoclonal
antibodies
to
specifically
target
eliminate
toxic
proteins
implicated
AD.
Additionally,
use
medicinal
plants
is
examined,
synergistic
effects
components
may
confer
neuroprotective
properties.
The
modulation
gut
microbiota
also
addressed
a
peripheral
strategy
that
could
influence
neuroinflammatory
degenerative
processes
brain.
Furthermore,
potential
emerging
approaches,
microRNAs
regulate
key
cellular
nanotherapy,
which
enables
precise
drug
delivery
central
nervous
system,
analyzed.
Despite
promising
these
strategies,
incidence
continues
rise.
Therefore,
it
proposed
achieving
effective
treatment
future
require
integration
combined
maximizing
different
interventions.
Язык: Английский
Insights From Protein Frustration Analysis of BRD4-Cereblon Degrader Ternary Complexes Show Separation of Strong from Weak Degraders
RSC Medicinal Chemistry,
Год журнала:
2025,
Номер
unknown
Опубликована: Янв. 1, 2025
Strong
ligand
directed
degraders
stabilize
the
hydrophobic
residue
burial
between
E3
ligase
and
target
protein
to
be
degraded.
Weak
destabilize
ternary
complex
through
multiple
mechanisms.
Язык: Английский
Insights From Protein Frustration Analysis of BRD4-Cereblon Degrader Ternary Complexes Show Separation of Strong from Weak Degraders
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2025,
Номер
unknown
Опубликована: Фев. 10, 2025
Abstract
PROteolysis
TArgeting
Chimeras
(PROTACs),
also
known
as
Ligand-Directed
Degraders
(LDDs),
are
an
innovative
class
of
small
molecules
that
leverage
the
ubiquitin-proteasome
system
to
induce
degradation
target
proteins.
Structure
based
design
methods
not
readily
applicable
for
designing
LDDs
due
dynamic
nature
ternary
complexes.
This
study
investigates
properties
five
LDD-mediated
BRD4-Cereblon
complexes,
focusing
on
challenges
evaluating
linker
efficiency
difficulty
in
identifying
suitable
computational
metrics
correlate
well
with
cooperativity
or
propensity
LDDs.
We
uncovered
protein
frustration,
a
concept
originally
developed
understand
folding,
calculated
residues
protein-protein
interface
complexes
recapitulate
strength
Our
findings
indicated
hydrophobic
among
highly
frustrated
pairs,
and
they
crucial
distinguishing
strong
degraders
from
weak
ones.
By
analyzing
frustration
patterns,
we
identified
key
interactions
critical
effectiveness
complex.
These
insights
provide
practical
guidelines
prioritizing
more
efficient
degraders,
paving
way
development
next-generation
improved
therapeutic
potential.
Язык: Английский
Green procedures for synthesizing potential hNMDA receptor allosteric modulators through reduction and one-pot reductive acetylation of nitro(hetero)arenes using a superparamagnetic Fe3O4@APTMS@Cp2ZrClx (x = 0, 1, 2) nanocatalyst
Nanoscale Advances,
Год журнала:
2025,
Номер
unknown
Опубликована: Янв. 1, 2025
In
this
research,
we
have
developed
diverse
strategies
for
synthesizing
potential
h
NMDA
receptor
allosteric
modulators
through
reduction
and
one-pot
reductive
acetylation
of
nitro(hetero)arenes
using
a
mesoporous
zirconocene-containing
nanocatalyst.
Язык: Английский
Preparation and characterization of ASDs improves the solubility and dissolution performance of a PROTAC drug
Journal of Drug Delivery Science and Technology,
Год журнала:
2025,
Номер
unknown, С. 106837 - 106837
Опубликована: Март 1, 2025
Язык: Английский
Integrating Proteolysis‐Targeting Chimeras (PROTACs) with Delivery Systems for More Efficient and Precise Targeted Protein Degradation
Macromolecular Rapid Communications,
Год журнала:
2025,
Номер
unknown
Опубликована: Апрель 4, 2025
Targeted
protein
degradation
(TPD)
using
the
proteolysis-targeting
chimeras
(PROTACs)
is
emerging
as
a
revolutionary
technology,
offering
potential
strategy
for
cancer
treatment
by
inducing
of
overexpressed
oncogenic
proteins
in
tumors.
PROTACs
function
recruiting
E3
ligases
and
utilizing
ubiquitin-proteasome
pathway
(UPS)
to
catalyze
target
proteins.
Compared
traditional
small
molecules
inhibitors,
exhibit
enhanced
selectivity,
ability
overcome
drug
resistance,
traditionally
deemed
"undruggable".
However,
poor
water
solubility
low
cellular
permeability
significantly
limit
their
pharmacokinetic
properties,
while
systemic
toxicity
may
hinder
clinical
application.
To
address
these
limitations,
strategies
that
integrate
with
delivery
systems
are
gaining
attention.
This
review
summarizes
latest
advancements
various
enhance
vivo
efficacy
reduce
off-target
effects
PROTACs,
including
prototype
nanoparticles,
covalent
modification-based
prodrug
strategies,
innovative
multi-headed
designs,
microneedle
systems,
discussing
design
principles
associated
challenges.
The
combination
potent
multifunctional
holds
promise
accelerating
translation
improving
therapeutic
treatment.
Язык: Английский
PROTACs in platelets: emerging antithrombotic strategies and future perspectives
Current Opinion in Hematology,
Год журнала:
2024,
Номер
unknown
Опубликована: Окт. 21, 2024
Purpose
of
review
Proteolysis-targeted
chimeras
(PROTACs)
are
heterobifunctional
compounds
that
selectively
target
proteins
for
degradation
and
an
emerging
therapeutic
modality
to
treat
diseases
such
as
cancer
neurodegenerative
disorders.
This
will
widen
the
area
application
by
highlighting
ability
PROTACs
remove
from
anucleate
platelets
evaluate
their
antithrombotic
potential.
Recent
findings
Proteomic
biochemical
studies
demonstrated
human
possess
Ubiquitin
Proteasomal
System
well
E3
ligase
cereblon
(CRBN)
therefore
may
be
susceptible
PROTAC-mediated
protein
degradation.
confirmed
CRBN
ligand-based
targeting
generic
tyrosine
kinases,
Btk
and/or
Fak
lead
efficacious
selective
in
platelets.
Downregulation
Btk,
a
key
player
involved
signalling
thrombosis,
but
not
haemostasis,
resulted
impaired
in-vitro
thrombus
formation.
Summary
Platelets
targeted
have
limited
resynthesise
proteins,
ensuring
long-term
downregulation
proteins.
Therefore,
serve
additional
research
tool
study
platelet
function
offer
new
potential
prevent
thrombosis.
Future
should
focus
on
enhancing
cell
specificity
avoid
on-target
side
effects
other
blood
cells.
Язык: Английский