Analytical Chemistry,
Journal Year:
2024,
Volume and Issue:
96(8), P. 3498 - 3507
Published: Feb. 16, 2024
The
development
of
small-molecular
fluorogenic
tools
for
the
chemo-selective
labeling
proteins
in
live
cells
is
important
evaluation
intracellular
redox
homeostasis.
Dynamic
imaging
human
serum
albumin
(HSA),
an
antioxidant
protein
under
oxidative
stress
with
concomitant
release
drugs
to
maintain
homeostasis,
affords
potential
opportunities
disease
diagnosis
and
treatment.
In
this
work,
we
developed
a
nonfluorogenic
prodrug
named
TPA-NAC,
by
introducing
N-acetyl-l-cysteine
(NAC)
into
conjugated
acceptor
skeleton.
Through
combined
thiol
amino
addition,
coupling
HSA
results
fluorescence
turn-on
drug
release.
It
was
reasoned
that
restricted
intramolecular
motion
probe
microenvironment
after
covalent
bonding
inhibited
nonradiative
transitions.
Furthermore,
biocompatibility
photochemical
properties
TPA-NAC
enabled
it
image
exogenous
endogenous
living
wash-free
manner.
Additionally,
released
evoked
upregulation
superoxide
dismutase
(SOD),
which
synergistically
eliminated
reactive
oxygen
species
drug-induced
liver
injury
model.
This
study
provides
insights
design
new
theranostic
fluorescent
prodrugs
treatments.
Journal of Medicinal Chemistry,
Journal Year:
2024,
Volume and Issue:
67(10), P. 7668 - 7758
Published: May 7, 2024
Covalent
inhibitors
and
other
types
of
covalent
modalities
have
seen
a
revival
in
the
past
two
decades,
with
variety
new
targeted
drugs
having
been
approved
recent
years.
A
key
feature
such
molecules
is
an
intrinsically
reactive
group,
typically
weak
electrophile,
which
enables
irreversible
or
reversible
formation
bond
specific
amino
acid
target
protein.
This
often
called
"warhead",
critical
determinant
ligand's
activity,
selectivity,
general
biological
properties.
In
2019,
we
summarized
emerging
re-emerging
warhead
chemistries
to
cysteine
acids
(Gehringer,
M.;
Laufer,
S.
A.
J.
Med.
Chem.
62,
5673−5724;
DOI:
10.1021/acs.jmedchem.8b01153).
Since
then,
field
has
rapidly
evolved.
Here
discuss
progress
on
warheads
made
since
our
last
Perspective
their
application
medicinal
chemistry
chemical
biology.
Chemical Reviews,
Journal Year:
2024,
Volume and Issue:
124(10), P. 6198 - 6270
Published: May 8, 2024
Hybrid
small-molecule/protein
fluorescent
probes
are
powerful
tools
for
visualizing
protein
localization
and
function
in
living
cells.
These
hybrid
constructed
by
diverse
site-specific
chemical
labeling
approaches
through
reactions
to
exogenous
peptide/small
tags,
enzymatic
post-translational
modifications,
bioorthogonal
genetically
incorporated
unnatural
amino
acids,
ligand-directed
reactions.
The
employed
imaging
trafficking,
conformational
changes,
bioanalytes
surrounding
proteins.
In
addition,
facilitate
visualization
of
dynamics
at
the
single-molecule
level
defined
structure
with
super-resolution
imaging.
this
review,
we
discuss
development
bioimaging
applications
based
on
hybrids.
Chemical Society Reviews,
Journal Year:
2023,
Volume and Issue:
52(3), P. 1068 - 1102
Published: Jan. 1, 2023
This
review
summarizes
chemical
tools
for
cell
engineering,
introduces
their
wide
application
in
diagnosis
and
therapy,
discusses
the
challenges
opportunities
precision
medicine.
Journal of the American Chemical Society,
Journal Year:
2023,
Volume and Issue:
145(12), P. 6741 - 6752
Published: March 16, 2023
Molecules
that
stabilize
protein–protein
interactions
(PPIs)
are
invaluable
as
tool
compounds
for
biophysics
and
(structural)
biology,
starting
points
molecular
glue
drug
discovery.
However,
identifying
initial
PPI
stabilizing
matter
is
highly
challenging,
chemical
optimization
labor-intensive.
Inspired
by
crosslinking
reversible
covalent
fragment-based
discovery,
we
developed
an
approach
term
"molecular
locks"
to
rapidly
access
glue-like
compounds.
These
dual-covalent
small
molecules
reversibly
react
with
a
nucleophilic
amino
acid
on
each
of
the
partner
proteins
dynamically
crosslink
protein
complex.
The
between
hub
14-3-3
estrogen-related
receptor
γ
(ERRγ)
was
used
pharmacologically
relevant
case
study.
Based
focused
library
dual-reactive
molecules,
compound
developed.
Biochemical
assays
X-ray
crystallographic
studies
validated
ternary
complex
formation
overall
stabilization
via
dynamic
crosslinking.
lock
selective
specific
14-3-3/ERRγ
complex,
over
other
complexes.
This
selectivity
driven
interplay
reactivity
recognition
composite
binding
interface.
long
lifetime
locks
enabled
even
in
presence
several
competing
clients
higher
intrinsic
affinities.
enables
systematic,
selective,
potent
complexes
support
Chemical Reviews,
Journal Year:
2025,
Volume and Issue:
unknown
Published: Jan. 7, 2025
The
term
"undruggable"
refers
to
proteins
or
other
biological
targets
that
have
been
historically
challenging
target
with
conventional
drugs
therapeutic
strategies
because
of
their
structural,
functional,
dynamic
properties.
Drugging
such
undruggable
is
essential
develop
new
therapies
for
diseases
where
current
treatment
options
are
limited
nonexistent.
Thus,
investigating
methods
achieve
drugging
an
important
challenge
in
medicinal
chemistry.
Among
the
numerous
methodologies
drug
discovery,
covalent
modification
has
emerged
as
a
transformative
strategy.
attachment
diverse
functional
molecules
provides
powerful
platform
creating
highly
potent
and
chemical
tools
well
ability
provide
valuable
information
on
structures
dynamics
targets.
In
this
review,
we
summarize
recent
examples
biomolecules
development
therapeutics
overcome
discovery
challenges
highlight
how
contribute
toward
particular,
focus
use
chemistry
drugs,
identification,
screening,
artificial
modulation
post-translational
modifications,
cancer
specific
chemotherapies,
nucleic
acid-based
therapeutics.
Journal of the American Chemical Society,
Journal Year:
2023,
Volume and Issue:
145(6), P. 3346 - 3360
Published: Feb. 4, 2023
Electrophiles
for
covalent
inhibitors
that
are
suitable
in
vivo
administration
rare.
While
acrylamides
prevalent
FDA-approved
drugs,
chloroacetamides
considered
too
reactive
such
purposes.
We
report
sulfamate-based
electrophiles
maintain
chloroacetamide-like
geometry
with
tunable
reactivity.
In
the
context
of
BTK
inhibitor
ibrutinib,
sulfamate
analogues
showed
low
reactivity
comparable
potency
protein
labeling,
vitro,
and
cellular
kinase
activity
assays
were
effective
a
mouse
model
CLL.
second
example,
we
converted
chloroacetamide
Pin1
to
potent
selective
acetamide
improved
buffer
stability.
Finally,
show
acetamides
can
be
used
ligand-directed
release
(CoLDR)
chemistry,
both
generation
"turn-on"
probes
as
well
traceless
site-specific
labeling
proteins.
Taken
together,
this
chemistry
represents
promising
addition
list
targeting.
Chemical Society Reviews,
Journal Year:
2023,
Volume and Issue:
52(16), P. 5485 - 5515
Published: Jan. 1, 2023
In
this
review,
we
highlight
bifunctional
modalities
that
perform
functions
other
than
degradation
and
have
great
potential
to
revolutionize
disease
treatment,
while
also
serving
as
important
tools
in
basic
research
explore
new
aspects
of
biology.
