Inclusive Pattern Generation Protocols to Decode Thiol-Mediated Uptake
ACS Central Science,
Год журнала:
2024,
Номер
10(5), С. 1033 - 1043
Опубликована: Апрель 17, 2024
Thiol-mediated
uptake
(TMU)
is
an
intriguing
enigma
in
current
chemistry
and
biology.
While
the
appearance
of
cell-penetrating
activity
upon
attachment
cascade
exchangers
(CAXs)
has
been
observed
by
many
increasingly
being
used
practice,
molecular
basis
TMU
essentially
unknown.
The
objective
this
study
was
to
develop
a
general
protocol
decode
dynamic
covalent
networks
that
presumably
account
for
TMU.
Uptake
inhibition
patterns
obtained
from
removal
exchange
partners
either
protein
knockdown
or
alternative
inhibitors
are
aligned
with
original
generated
CAX
transporters
functions
(here
cell
motility).
These
inclusive
reveal
four
most
significant
CAXs
known
today
enter
cells
along
three
almost
orthogonal
pathways.
Epidithiodiketopiperazines
(ETP)
preferably
integrins
disulfide
isomerases
(PDIs),
benzopolysulfanes
(BPS)
different
PDIs,
PDIA3,
asparagusic
acid
(AspA),
antisense
oligonucleotide
phosphorothioates
(OPS)
transferrin
receptor
can
be
activated
PDIs
their
respective
inhibitors.
findings
provide
solid
understand
use
enable
prevent
entry
into
cells.
Язык: Английский
Chemoselective Reagents for the Traceless Bioreversible Modification of Native Proteins
Bioconjugate Chemistry,
Год журнала:
2024,
Номер
35(9), С. 1300 - 1308
Опубликована: Авг. 29, 2024
Nature
utilizes
bioreversible
post-translational
modifications
(PTMs)
to
spatiotemporally
diversify
protein
function.
Mimicking
Nature's
approach,
chemists
have
developed
a
variety
of
chemoselective
regents
for
traceless,
modification
native
proteins.
These
strategies
found
utility
in
the
development
reversible
covalent
inhibitors
and
degraders
as
well
synthesis
functional
conjugates
delivery
into
cells.
This
Viewpoint
provides
snapshot
such
tools,
which
currently
cover
Cys,
Ser,
Thr,
Lys,
Asp,
Glu
residues
N
terminus.
Additionally,
we
explore
how
reagents,
originally
by
research
communities
with
differing
objectives,
can
be
utilized
synergistically.
Looking
forward,
discuss
need
developing
reagents
labeling
His,
Tyr,
Arg,
Trp,
Asn,
Gln,
Met
C-terminus
installation
dynamic
PTMs.
Finally,
broaden
applicability
these
point
out
importance
modular
release
scaffolds
tunable
times
responsiveness
multiple
endogenous
triggers.
We
anticipate
that
this
will
catalyze
further
technological
breakthroughs
rapidly
evolving
field.
Язык: Английский
Mammalian Esterase Activity: Implications for Peptide Prodrugs
Biochemistry,
Год журнала:
2024,
Номер
unknown
Опубликована: Окт. 3, 2024
As
a
traceless,
bioreversible
modification,
the
esterification
of
carboxyl
groups
in
peptides
and
proteins
has
potential
to
increase
their
clinical
utility.
An
impediment
is
lack
strategies
quantify
esterase-catalyzed
hydrolysis
rates
for
esters
esterified
biologics.
We
have
developed
continuous
Förster
resonance
energy
transfer
(FRET)
assay
esterase
activity
based
on
peptidic
substrate
protease,
Glu-C,
that
cleaves
glutamyl
peptide
bond
only
if
side
chain
free
acid.
Using
pig
liver
(PLE)
human
carboxylesterases,
we
validated
with
substrates
containing
simple
(
Язык: Английский
Selenium‐Centered Cascade Exchangers and Conformational Control Unlock Unique Patterns of Thiol‐Mediated Cellular Uptake
ChemistryEurope,
Год журнала:
2024,
Номер
2(5)
Опубликована: Авг. 2, 2024
Abstract
Dynamic‐covalent
electrophiles
called
cascade
exchangers
(CAXs)
can
reversibly
engage
cell‐surface
thiols.
Conjugates
between
CAXs
and
molecular
or
even
protein‐sized
cargos
deliver
these
into
cells
by
thiol‐mediated
uptake
(TMU);
free
also
hinder
TMU
presumably
competing
for
thiol
exchange
sites.
So
far,
three
orthogonal
networks
of
cellular
partners
have
been
identified
to
participate
in
TMU,
centering
on
the
transferrin
receptor,
integrins,
protein
disulfide
isomerases.
This
study
introduces
cyclic
selenenylsulfides
as
a
new
CAX
type,
with
polarised
reactivity
that
brings
important
differences
from
known
diselenide
CAXs.
Additionally,
this
methods
modulate
activity
employing
remote
functional
groups
tune
ring
re‐closure
rates,
e.
g.
via
thiolate
de/stabilization
hydrogen
bonding
ion
pairing.
Differently
all
known,
Se‐centred
two
different
(integrins
preferred,
PDIA3
tolerated).
When
free,
remotely
tuned
were
strong
inhibitors
most
systems,
but
again
brought
novel
feature:
they
increased
tetrel‐centred
Michael
acceptor
CAXs,
making
them
first
we
know
accelerate
TMU.
We
conclude
Se‐
share
partner
hinders
which
may
be
target
improving
delivery
drugs.
The
unique
patterns
generated
Se‐centered
closure
motifs
support
will
prove
valuable
tool
help
decode
achieve
chemical
control
over
entry
level.
Язык: Английский
Asparagusic Golgi Trackers
JACS Au,
Год журнала:
2024,
Номер
4(10), С. 3759 - 3765
Опубликована: Авг. 20, 2024
Thiol-mediated
uptake
(TMU)
is
thought
to
occur
through
dynamic
covalent
cascade
exchange
networks.
Here
we
show
that
the
accounting
for
TMU
of
asparagusic
acid
derivatives
(AspA)
ends
in
Golgi
apparatus
(G)
and
shifts
from
disulfide
thioester
with
palmitoyl
transferases
as
final
partner.
As
a
result,
AspA
combined
pH-sensitive
fluoresceins,
red-shifted
silicon-rhodamines,
or
mechanosensitive
flipper
probes
selectively
labels
fluorescence
microscopy
images
living
fixed
cells.
trackers
work
without
cellular
engineering
excel
speed,
simplicity,
generality,
compatibility
G/ER
cis/trans
discrimination,
morphological
changes,
anterograde
vesicular
trafficking,
superresolution
imaging
by
stimulated
emission
depletion
microscopy.
flippers
particular
can
image
membrane
order
tension
and,
if
desired,
at
plasma
during
TMU.
Язык: Английский