A
concise
asymmetric
synthesis
of
clickable
enantiomeric
pyrrolidines
was
achieved
using
Crabbé-Ma
allenation.
The
synthesized
iminosugars
were
grafted
by
copper–free
strain-promoted
alkyne-azide
cycloaddition
onto
phosphorus
dendrimers.
hexavalent
and
dodecavalent
evaluated
as
β‑glucocerebrosidase
inhibitors.
level
inhibition
suggests
that
monofluorocyclooctatriazole
group
may
contribute
to
the
affinity
for
protein
leading
potent
multivalent
Docking
studies
carried
out
rationalize
these
results.
Then,
clusters
pharmacological
chaperones
in
Gaucher
patients’
fibroblasts.
An
increase
activity
observed
with
at
concentrations
low
1
µM
0.1
µM,
respectively.
These
iminosugar
constitute
first
example
acting
against
disease.
International Journal of Molecular Sciences,
Год журнала:
2023,
Номер
24(10), С. 9105 - 9105
Опубликована: Май 22, 2023
Mutations
in
the
GBA1
gene,
encoding
lysosomal
enzyme
glucocerebrosidase
(GCase),
cause
Gaucher
disease
(GD)
and
are
most
common
genetic
risk
factor
for
Parkinson's
(PD).
Pharmacological
chaperones
(PCs)
being
developed
as
an
alternative
treatment
approach
GD
PD.
To
date,
NCGC00241607
(NCGC607)
is
one
of
promising
PCs.
Using
molecular
docking
dynamics
simulation
we
identified
characterized
six
allosteric
binding
sites
on
GCase
surface
suitable
Two
were
energetically
more
preferable
NCGC607
located
nearby
to
active
site
enzyme.
We
evaluated
effects
activity
protein
levels,
glycolipids
concentration
cultured
macrophages
from
(n
=
9)
GBA-PD
5)
patients
well
induced
human
pluripotent
stem
cells
(iPSC)-derived
dopaminergic
(DA)
neurons
patient.
The
results
showed
that
increased
(by
1.3-fold)
levels
1.5-fold),
decreased
4.0-fold)
derived
also
enhanced
1.5-fold)
with
N370S
mutation
(p
<
0.05).
In
iPSC-derived
DA
by
1.1-fold
1.7-fold
Thus,
our
could
bind
confirmed
its
efficacy
patients.
Molecules,
Год журнала:
2024,
Номер
29(2), С. 453 - 453
Опубликована: Янв. 17, 2024
Gaucher
disease
(GD)
is
a
rare
genetic
metabolic
disorder
characterized
by
dysfunction
of
the
lysosomal
glycoside
hydrolase
glucocerebrosidase
(GCase)
due
to
mutations
in
gene
GBA1,
leading
cellular
accumulation
glucosylceramide
(GlcCer).
While
most
current
research
focuses
on
primary
accumulated
material,
lesser
attention
has
been
paid
secondary
storage
materials
and
their
reciprocal
intertwining.
By
using
novel
approach
based
flow
cytometry
fluorescent
labelling,
we
monitored
changes
directly
fibroblasts
derived
from
GD
patients
carrying
N370S/RecNcil
homozygous
L444P
or
R131C
with
respect
wild
type.
In
fibroblasts,
detected
not
only
GlcCer
but
also
considerable
increase
GM1
storage,
comparable
one
observed
infantile
affected
gangliosidosis.
addition,
ability
trivalent
trihydroxypiperidine
iminosugar
compound
(CV82),
which
previously
showed
good
pharmacological
chaperone
activity
GCase
enzyme,
reduce
levels
was
tested.
Interestingly,
treatment
different
concentrations
CV82
led
significant
reduction
without
significantly
affecting
levels.
The
selective
against
enzyme
β-Galactosidase
responsible
for
catabolism
ganglioside.
GM1-ganglioside
level
cannot
be
therefore
ascribed
direct
action
suggesting
that
decrease
rather
related
other
unknown
mechanisms
follow
GCase.
conclusion,
this
work
indicates
tracking
storages
can
represent
key
step
better
understanding
pathways
involved
severity
GD,
underlying
importance
developing
drugs
able
both
storage-material
accumulations
GD.
Nature Communications,
Год журнала:
2024,
Номер
15(1)
Опубликована: Апрель 18, 2024
Genetic
variation
in
human
populations
can
result
the
misfolding
and
aggregation
of
proteins,
giving
rise
to
systemic
neurodegenerative
diseases
that
require
management
by
proteostasis.
Here,
we
define
role
GRP94,
endoplasmic
reticulum
Hsp90
chaperone
paralog,
managing
alpha-1-antitrypsin
deficiency
on
a
residue-by-residue
basis
using
Gaussian
process
regression-based
machine
learning
profile
spatial
covariance
relationships
dictate
protein
folding
arising
from
sequence
variants
population.
Covariance
analysis
suggests
for
ATPase
activity
GRP94
controlling
N-
C-terminal
cooperative
responsible
correction
liver
lung-disease
phenotypes
deficiency.
process-based
profiling
provides
standard
model
built
covariant
principles
evaluate
proteostasis
components
guiding
information
flow
genome
proteome
response
genetic
variation,
potentially
allowing
us
intervene
onset
progression
complex
multi-system
diseases.
Abstract
Genetic
variants
of
GBA1
can
cause
the
lysosomal
storage
disorder
Gaucher
disease
and
are
among
highest
genetic
risk
factors
for
Parkinson's
(PD).
encodes
enzyme
beta‐glucocerebrosidase
(GCase),
which
orchestrates
degradation
glucosylceramide
(GluCer)
in
lysosome.
Recent
studies
have
shown
that
GluCer
accelerates
α
‐synuclein
aggregation,
exposing
GCase
deficiency
as
a
major
factor
PD
pathology
promising
target
treatment.
This
study
investigates
interaction
three
disease‐associated
(p.E326K,
p.N370S,
p.L444P)
with
their
transporter,
integral
membrane
protein
2
(LIMP‐2).
Overexpression
LIMP‐2
HEK
293T
cells
boosts
abundance
wt,
E326K,
N370S
increases/rescues
enzymatic
activity
wt
E326K
variant.
Using
novel
purification
approach,
co‐purification
untagged
complex
His‐tagged
from
cell
supernatant
293F
is
achieved,
confirming
functional
binding
trafficking
these
variants.
Furthermore,
single
helix
ectodomain
exploited
to
design
lysosome‐targeted
peptide
enhances
patient‐derived
control
fibroblasts.
These
findings
reveal
an
allosteric
activator
GCase,
suggesting
possible
therapeutic
potential
targeting
this
interaction.
International Journal of Applied Pharmaceutics,
Год журнала:
2024,
Номер
unknown, С. 15 - 22
Опубликована: Июль 7, 2024
Natural
cyclic
oligosaccharides
called
cyclodextrins
(CDs)
improve
the
bioavailability
of
drugs
by
formation
inclusion
complexes
involving
small
and
macromolecules
poorly
soluble
compounds
in
water.
CDs
act
as
a
solubilizer
targeting
agent
for
with
low
water
solubility,
enabling
them
to
effectively
target
specific
cells.
Where
water-soluble
interact
hydrophobic
cavity
enhance
their
solubility.
are
effective
drug
delivery
agents
because
essential
function
processing
complex
carriers.
Various
ligands
can
be
utilized
modify
surface
cyclodextrin
actively
drugs.
It
is
possible
consider
it
have
amphiphilic
characteristics
enduring
chemical
transformation
long
aliphatic
chains,
variety
produce
nanoparticles
without
usage
surfactants.
CD-nanocarriersact
cargo
solubilizers
receptors
present
cells
release
drug.
many
applications,
including
reduction
drug-induced
gastrointestinal
discomfort,
avoiding
interactions
between
drug-drug
drug-excipient,
transforming
products
that
liquid
into
microcrystalline
solid
powders.
Because
biocompatibility
biodegradability,
outstanding
properties
make
particularly
useful
pharmaceutical
cosmetic
industries.
ACS Chemical Neuroscience,
Год журнала:
2025,
Номер
unknown
Опубликована: Март 13, 2025
Intrinsically
disordered
proteins
(IDPs)
are
highly
flexible
molecules
often
linked
to
the
onset
of
incurable
diseases.
Despite
their
great
therapeutic
potential,
IDPs
considered
as
undruggable
because
they
lack
defined
binding
pockets,
which
constitute
basis
drug
discovery
approaches.
However,
small
that
interact
with
intrinsically
state
α-synuclein,
protein
Parkinson's
disease
(PD),
were
recently
identified
and
shown
act
chemical
chaperones.
Glucocerebrosidase
(GCase)
is
an
enzyme
crucially
involved
in
PD,
since
mutations
code
for
GCase
among
most
frequent
genetic
risk
factors
PD.
Following
"dual-target"
approach,
stating
one
carefully
designed
molecule
can,
principle,
interfere
more
than
target,
we
a
pharmacological
chaperone
interacts
monomeric
form
α-synuclein.
This
result
opens
novel
avenues
be
explored
search
on
dual
targets,
particular,
challenging
targets
such
IDPs.
