Organic Letters,
Journal Year:
2024,
Volume and Issue:
unknown
Published: Nov. 19, 2024
A
chemoselective
amino-based
probe
was
designed
for
discovering
natural
products
with
covalent
binding
potential
to
lysine.
Using
this
reactivity-based
technique,
a
marine-derived
Streptomyces
strain
identified,
which
could
produce
medermycin
as
the
major
metabolite.
new
compound,
mederpyrrole
A,
derived
from
and
anthranilic
acid
through
nonenzymatic
reaction
isolated.
Medermycin
can
react
primary
amines
under
mild
conditions
generate
chimeric
possessing
naphthoquinone-pyrrole
skeleton.
It
also
covalently
bind
proteins.
Malsha D. Abeywickrama Wijewardana Sooriyaarachchi
No information about this author
et al.
Current Opinion in Structural Biology,
Journal Year:
2024,
Volume and Issue:
86, P. 102822 - 102822
Published: April 28, 2024
Protein–protein
interactions
(PPIs)
play
a
critical
role
in
cellular
signaling
and
represent
interesting
targets
for
therapeutic
intervention.
14-3-3
proteins
integrate
many
via
PPIs
are
frequently
implicated
disease,
making
them
intriguing
drug
targets.
Here,
we
review
the
recent
advances
field.
It
will
discuss
roles
within
cell,
elucidation
of
their
expansive
interactome,
complex
mechanisms
that
underpin
function.
In
addition,
significant
development
molecular
glues
target
PPIs.
particular,
it
focus
on
novel
discovery
methodologies
have
delivered
selective,
potent,
drug-like
molecules
could
open
new
avenues
precision
tools
medicines.
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.
Chemical Science,
Journal Year:
2025,
Volume and Issue:
unknown
Published: Jan. 1, 2025
A
novel
proximity-enhanced
crosslinker
using
histidine–cysteine
trapping
uncovers
a
cryptic
14-3-3/hyperphosphorylated
Tau
interaction
via
Ser356,
advancing
the
understanding
of
IDP
interactions
and
prompting
re-evaluation
14-3-3/Tau
mechanisms.
Journal of Medicinal Chemistry,
Journal Year:
2024,
Volume and Issue:
67(22), P. 20214 - 20223
Published: Nov. 12, 2024
Covalent
drugs
provide
pharmacodynamic
and
pharmacokinetic
advantages
over
reversible
agents.
However,
covalent
strategies
have
been
developed
mostly
to
target
cysteine
(Cys)
residues,
which
are
rarely
found
in
binding
sites.
Among
other
nucleophilic
residues
that
could
be
principle
used
for
the
design
of
drugs,
histidine
(His)
has
not
given
proper
attention
despite
being
an
attractive
residue
pursue
but
underexplored.
Aryl
fluorosulfates,
a
mild
electrophile
is
very
stable
biological
media,
recently
identified
as
possible
electrophiles
react
with
side
chains
Lys;
however,
limited
studies
available
on
aryl
fluorosulfates'
ability
His
residues.
We
demonstrate
incorporation
fluorosulfate
juxtaposing
can
afford
rapid
optimizations
His-covalent
As
application,
we
report
BH3
mimetics
targeting
His224
Mcl-1.
Journal of the American Chemical Society,
Journal Year:
2024,
Volume and Issue:
146(23), P. 16173 - 16183
Published: May 31, 2024
Genetically
encoding
a
proximal
reactive
warhead
into
the
protein
binder/drug
has
emerged
as
an
efficient
strategy
for
covalently
binding
to
targets,
enabling
broad
applications.
To
expand
reactivity
scope
targeting
diverse
natural
residues
under
physiological
conditions,
development
of
genetically
encoded
with
excellent
stability
and
is
highly
desired.
Herein,
we
reported
genetic
epoxide-containing
tyrosine
(EPOY)
developing
covalent
drugs.
Our
study
demonstrates
that
EPOY,
when
incorporated
nanobody
(KN035),
can
cross-link
different
side
chains
(mutations)
at
same
position
PD-L1
protein.
Significantly,
single
capable
site-specific
10
nucleophilic
was
achieved
first
time.
This
would
largely
inspire
warheads
both
small-molecule
drugs
Furthermore,
incorporate
EPOY
designed
ankyrin
repeat
(DarpinK13)
create
binders
KRAS.
KRAS
binder
holds
potential
achieve
pan-covalent
based
on
structural
similarity
among
all
oncogenic
mutants
while
avoiding
off-target
NRAS/HRAS
through
interaction
KRAS-specific
(H95
E107).
We
envision
H95
will
be
promising
pan-KRAS
inhibitors
in
future.
Chemical Reviews,
Journal Year:
2024,
Volume and Issue:
unknown
Published: Dec. 18, 2024
Molecules
that
are
able
to
induce
proximity
between
two
proteins
finding
ever
increasing
applications
in
chemical
biology
and
drug
discovery.
The
ability
introduce
an
electrophile
make
such
inducers
covalent
can
offer
improved
properties
as
selectivity,
potency,
duration
of
action,
reduced
molecular
size.
This
concept
has
been
heavily
explored
the
context
targeted
degradation
particular
for
bivalent
molecules,
but
recently,
additional
reported
other
contexts,
well
monovalent
glues.
is
a
comprehensive
review
inducers,
aiming
identify
common
trends
current
gaps
their
discovery
application.
