Letters in Organic Chemistry,
Год журнала:
2024,
Номер
21(11), С. 964 - 972
Опубликована: Апрель 2, 2024
Abstract:
Our
group
recently
reported
that
the
polyhydroxy
aromatic
compound
3,3′,4,4′-
biphenyltetrol
(2a)
is
a
successful
inhibitor
of
amyloid-β
peptide
(Aβ)
aggregation,
decreasing
Aβ
aggregation
by
50
%
when
present
in
equimolar
concentrations.
In
study,
several
additional
biphenyltetrols
were
prepared
and
examined
for
their
vitro
activity
against
to
investigate
effect
relative
positions
hydrogen-bond
donors
on
process.
Congo
red
spectral
shift
assays
demonstrated
that,
eight
(8)
compounds
prepared,
three
(3)
successfully
inhibited
association
monomers,
two
symmetrical
isomers,
2,2′,5,5′-biphenyltetrol
(2c),
2,2′,3,3′-biphenyltetrol
(2d),
along
with
one
unsymmetrical
isomer,
2,3′,4′,5-biphenyltetrol
(2g).
These
results,
previously
results
2a,
strongly
suggest
hydroxyl
position
affects
ability
bind
assemblies,
thus
impacting
inhibitory
efficacy.
International Journal of Molecular Sciences,
Год журнала:
2023,
Номер
24(19), С. 14850 - 14850
Опубликована: Окт. 3, 2023
The
CCT/TRiC
complex
is
a
type
II
chaperonin
that
undergoes
ATP-driven
conformational
changes
during
its
functional
cycle.
Structural
studies
have
provided
valuable
insights
into
the
mechanism
of
this
process,
but
real-time
dynamics
analyses
mammalian
chaperonins
are
still
scarce.
We
used
diffracted
X-ray
tracking
(DXT)
to
investigate
intramolecular
CCT
complex.
focused
on
three
surface-exposed
loop
regions
CCT1
subunit:
equatorial
domain
(E
domain),
E
and
intermediate
(I
domain)
juncture
near
ATP-binding
region,
apical
(A
domain).
Our
results
showed
subunit
predominantly
displayed
rotational
motion,
with
larger
mean
square
displacement
(MSD)
values
for
twist
(χ)
angles
compared
tilt
(θ)
angles.
Nucleotide
binding
had
significant
impact
dynamics.
In
absence
nucleotides,
region
between
I
could
act
as
pivotal
axis,
allowing
greater
motion
A
domain.
presence
nucleotides
wedge
weakening
role
axis
causing
adopt
more
compact
structure.
This
led
less
expanded
MSD
curves
nucleotide-absent
conditions.
change
may
help
stabilize
conformation
substrate
binding.
study
first
use
DXT
probe
molecular
at
millisecond
level.
findings
provide
new
their
in
folding
Neurobiology of Disease,
Год журнала:
2024,
Номер
unknown, С. 106775 - 106775
Опубликована: Дек. 1, 2024
The
accumulation
of
amyloid
β-proteins
(Aβ)
in
the
extracellular
space,
forming
insoluble
plaques,
is
a
primary
pathological
process
underlying
Alzheimer's
disease
(AD).
Among
various
Aβ
species
that
appear
during
aggregation,
oligomers
are
considered
most
neurotoxic
form.
However,
precise
mechanisms
their
molecular
functions
within
aggregation
cascade
have
not
been
clarified
so
far.
This
research
aimed
to
uncover
structural
and
functional
characteristics
globular-shaped
(gAβO)
under
vitro
conditions.
We
performed
thioflavin
T
(ThT)
assays
on
low-molecular-weight
(LMW)
Aβ42,
testing
different
concentrations
Aβ42
mature
fibril
(MF)
seeds
gAβO.
Fibril
formation
was
continuously
observed
using
high-speed
atomic
force
microscopy
(HS-AFM)
LMW
with
sample
Conformational
changes
aggregates
presence
gAβO
also
evaluated
circular
dichroism
spectroscopy.
results
ThT
analysis
HS-AFM
observation
indicated
promoted
while
itself
did
form
fibrous
aggregates,
indicating
would
catalytic
effects
aggregation.
showed
interaction
altered
by
amount
MF
reaction
buffers,
complex
interactions
exist
among
species.
our
present
demonstrated
significant
roles
accelerate
AD
pathogenesis.
225
<
250
words.
Letters in Organic Chemistry,
Год журнала:
2024,
Номер
21(11), С. 964 - 972
Опубликована: Апрель 2, 2024
Abstract:
Our
group
recently
reported
that
the
polyhydroxy
aromatic
compound
3,3′,4,4′-
biphenyltetrol
(2a)
is
a
successful
inhibitor
of
amyloid-β
peptide
(Aβ)
aggregation,
decreasing
Aβ
aggregation
by
50
%
when
present
in
equimolar
concentrations.
In
study,
several
additional
biphenyltetrols
were
prepared
and
examined
for
their
vitro
activity
against
to
investigate
effect
relative
positions
hydrogen-bond
donors
on
process.
Congo
red
spectral
shift
assays
demonstrated
that,
eight
(8)
compounds
prepared,
three
(3)
successfully
inhibited
association
monomers,
two
symmetrical
isomers,
2,2′,5,5′-biphenyltetrol
(2c),
2,2′,3,3′-biphenyltetrol
(2d),
along
with
one
unsymmetrical
isomer,
2,3′,4′,5-biphenyltetrol
(2g).
These
results,
previously
results
2a,
strongly
suggest
hydroxyl
position
affects
ability
bind
assemblies,
thus
impacting
inhibitory
efficacy.
