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A bicyclic 1-deoxygalactonojirimycin derivative as a novel pharmacological chaperone for GM1 gangliosidosis.
[gm1 gangliosidosis]
Lysosomal
β-galactosidase
(
β-
Gal
)
deficiency
causes
a
group
of
disorders
that
include
neuronopathic
GM
1
gangliosidosis
and
non-neuronopathic
Morquio
B
disease
.
We
have
previously
proposed
the
use
of
small
molecule
ligands
of
β-
Gal
as
pharmacological
chaperones
(
PCs
)
for
the
treatment
of
GM
1
gangliosidosis
brain
pathology
.
Although
it
is
still
under
development
,
PC
therapy
has
yielded
promising
preclinical
results
in
several
lysosomal
diseases
.
In
this
study
,
we
evaluated
the
effect
of
bicyclic
1
-
deoxygalactonojirimycin
(
DGJ
)
derivative
of
the
sp
(
2
)
-
iminosugar
type
,
namely
5
N
,
6
S-
(
N
'
-
butyliminomethylidene
)
-
6
-
thio-
1
-
deoxygalactonojirimycin
(
6
S-NBI-DGJ
)
,
as
a
novel
PC
for
human
mutant
β-
Gal
.
In
vitro
,
6
S-NBI-DGJ
had
the
ability
to
inhibit
the
activity
of
human
β-
Gal
in
a
competitive
manner
and
was
able
to
protect
this
enzyme
from
heat-induced
degradation
.
Computational
analysis
supported
that
the
rigid
glycone
bicyclic
core
of
6
S-NBI-DGJ
binds
to
the
active
site
of
the
enzyme
,
with
the
aglycone
N
'
-
butyl
substituent
,
in
a
precise
E
-
orientation
,
located
at
a
hydrophobic
region
nearby
.
Chaperone
potential
profiling
indicated
significant
increases
of
enzyme
activity
in
24
of
88
β-
Gal
mutants
,
including
four
common
mutations
.
Finally
,
oral
administration
of
6
S-NBI-DGJ
ameliorated
the
brain
pathology
of
GM
1
gangliosidosis
model
mice
.
These
results
suggest
that
6
S-NBI-DGJ
is
a
novel
PC
that
may
be
effective
on
a
broad
range
of
β-
Gal
mutants
.
Diseases
Validation
Diseases presenting
"oral administration"
symptom
adrenomyeloneuropathy
benign recurrent intrahepatic cholestasis
gm1 gangliosidosis
liposarcoma
neonatal adrenoleukodystrophy
phenylketonuria
primary hyperoxaluria type 1
severe combined immunodeficiency
x-linked adrenoleukodystrophy
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