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Innovative strategies to treat protein misfolding in inborn errors of metabolism: pharmacological chaperones and proteostasis regulators.
[phenylketonuria]
To
attain
functionality
,
proteins
must
fold
into
their
three
-dimensional
native
state
.
The
intracellular
balance
between
protein
synthesis
,
folding
,
and
degradation
is
constantly
challenged
by
genetic
or
environmental
stress
factors
.
In
the
last
ten
years
,
protein
misfolding
induced
by
missense
mutations
was
demonstrated
to
be
the
seminal
molecular
mechanism
in
a
constantly
growing
number
of
inborn
errors
of
metabolism
.
In
these
cases
,
loss
of
protein
function
results
from
early
degradation
of
missense-induced
misfolded
proteins
.
Increasing
knowledge
on
the
proteostasis
network
and
the
protein
quality
control
system
with
distinct
mechanisms
in
different
compartments
of
the
cell
paved
the
way
for
the
development
of
new
treatment
strategies
for
conformational
diseases
using
small
molecules
.
These
comprise
proteostasis
regulators
that
enhance
the
capacity
of
the
proteostasis
network
and
pharmacological
chaperones
that
specifically
bind
and
rescue
misfolded
proteins
by
conformational
stabilization
.
They
can
be
used
either
alone
or
in
combination
,
the
latter
to
exploit
synergistic
effects
.
Many
of
these
small
molecule
compounds
currently
undergo
preclinical
and
clinical
pharmaceutical
development
and
two
have
been
approved
:
saproterin
dihydrochloride
for
the
treatment
of
phenylketonuria
and
tafamidis
for
the
treatment
of
transthyretin
-related
hereditary
amyloidosis
.
Different
technologies
are
exploited
for
the
discovery
of
new
small
molecule
compounds
that
belong
to
the
still
young
class
of
pharmaceutical
products
discussed
here
.
These
compounds
may
in
the
near
future
improve
existing
treatment
strategies
or
even
offer
a
first
-time
treatment
to
patients
suffering
from
nowadays-untreatable
inborn
errors
of
metabolism
.
Diseases
Validation
Diseases presenting
"amyloidosis"
symptom
cadasil
fabry disease
familial mediterranean fever
hereditary cerebral hemorrhage with amyloidosis
lymphangioleiomyomatosis
phenylketonuria
systemic capillary leak syndrome
triple a syndrome
waldenström macroglobulinemia
This symptom has already been validated
