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A substrate-free activity-based protein profiling screen for the discovery of selective PREPL inhibitors.
[cystinuria]
Peptidases
play
vital
roles
in
physiology
through
the
biosynthesis
,
degradation
,
and
regulation
of
peptides
.
Prolyl
endopeptidase-like
(
PREPL
)
is
a
newly
described
member
of
the
prolyl
peptidase
family
,
with
significant
homology
to
mammalian
prolyl
endopeptidase
and
the
bacterial
peptidase
oligopeptidase
B
.
The
biochemistry
and
biology
of
PREPL
are
of
fundamental
interest
due
to
this
enzyme
's
homology
to
the
biomedically
important
prolyl
peptidases
and
its
localization
in
the
central
nervous
system
.
Furthermore
,
genetic
studies
of
patients
suffering
from
hypotonia
-
cystinuria
syndrome
(
HCS
)
have
revealed
a
deletion
of
a
portion
of
the
genome
that
includes
the
PREPL
gene
.
HCS
symptoms
thought
to
be
caused
by
lack
of
PREPL
include
neuromuscular
and
mild
cognitive
deficits
.
A
number
of
complementary
approaches
,
ranging
from
biochemistry
to
genetics
,
will
be
required
to
understand
the
biochemical
,
cellular
,
physiological
,
and
pathological
mechanisms
regulated
by
PREPL
.
We
are
particularly
interested
in
investigating
physiological
substrates
and
pathways
controlled
by
PREPL
.
Here
,
we
use
a
fluorescence
polarization
activity-based
protein
profiling
(
fluopol-
ABPP
)
assay
to
discover
selective
small
-molecule
inhibitors
of
PREPL
.
Fluopol-
ABPP
is
a
substrate-free
approach
that
is
ideally
suited
for
studying
serine
hydrolases
for
which
no
substrates
are
known
,
such
as
PREPL
.
After
screening
over
300
,
000
compounds
using
fluopol-
ABPP
,
we
employed
a
number
of
secondary
assays
to
confirm
assay
hits
and
characterize
a
group
of
3
-
oxo-
1
-
phenyl-
2
,
3
,
5
,
6
,
7
,
8
-
hexahydroisoquinoline-
4
-
carbonitrile
and
1
-
alkyl-
3
-
oxo-
3
,
5
,
6
,
7
-
tetrahydro-
2
H
-
cyclopenta
[
c
]
pyridine-
4
-
carbonitrile
PREPL
inhibitors
that
are
able
to
block
PREPL
activity
in
cells
.
Moreover
,
when
administered
to
mice
,
1
-
isobutyl-
3
-
oxo-
3
,
5
,
6
,
7
-
tetrahydro-
2
H
-
cyclopenta
[
c
]
pyridine-
4
-
carbonitrile
distributes
to
the
brain
,
indicating
that
it
may
be
useful
for
in
vivo
studies
.
The
application
of
fluopol-
ABPP
has
led
to
the
first
reported
PREPL
inhibitors
,
and
these
inhibitors
will
be
of
great
value
in
studying
the
biochemistry
of
PREPL
and
in
eventually
understanding
the
link
between
PREPL
and
HCS
.
Diseases
Validation
Diseases presenting
"mild cognitive deficits"
symptom
cystinuria
hydrocephalus with stenosis of the aqueduct of sylvius
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