Journal of the American Chemical Society,
Год журнала:
2024,
Номер
unknown
Опубликована: Дек. 26, 2024
Triple-negative
breast
cancer
(TNBC)
poses
significant
treatment
challenges
due
to
its
high
metastasis,
heterogeneity,
and
poor
biomarker
expression.
The
N-terminus
of
an
octapeptide
NAPVSIPQ
(NAP)
was
covalently
coupled
a
carboxylic
acid
derivative
Ru(2,2′-bipy)32+
(Rubpy)
synthesize
N-stapled
short
peptide-Rubpy
conjugate
(Ru-NAP).
This
photosensitizer
(PS)
utilized
treat
TNBC
through
microtubule
(MT)
targeted
chemotherapy
photodynamic
therapy
(PDT).
Ru-NAP
formed
more
elaborate
molecular
aggregates
with
fibrillar
morphology
as
compared
NAP.
A
much
higher
binding
affinity
over
NAP
toward
β-tubulin
(KRu-NAP:
(6.8
±
0.55)
×
106
M–1;
KNAP:
(8.2
1.1)
104
M–1)
observed
stronger
electrostatic
interactions
between
the
MT
average
linear
charge
density
∼85
e/nm
cationic
Rubpy
part
Ru-NAP.
also
supported
by
docking,
simulation,
appropriate
imaging
studies.
promoted
serum
stability,
specific
E-site
βIII-tubulin
followed
disruption
network,
effective
singlet
oxygen
generation
in
cells
(MDA-MB-231),
causing
cell
cycle
arrest
G2/M
phase
triggering
apoptosis.
Remarkably,
MDA-MB-231
were
sensitive
noncancerous
human
embryonic
kidney
(HEK293
cells)
when
exposed
light
(LightIC50Ru-NAP[HEK293]:
17.2
2.5
μM,
LightIC50Ru-NAP[MDA-MB-231]:
32.5
7.8
nM,
DarkIC50Ru-NAP[HEK293]:
>
80
DarkIC50Ru-NAP[MDA-MB-231]:
2.9
0.5
μM).
effectively
inhibited
tumor
growth
xenograft
models
nude
mice.
Our
findings
provide
strong
evidence
that
has
potential
therapeutic
role
treatment.
Journal of Medicinal Chemistry,
Год журнала:
2025,
Номер
unknown
Опубликована: Апрель 23, 2025
There
is
an
urgent
need
for
the
development
of
safe
and
effective
modalities
treatment
diseases
owing
to
drug
resistance,
undesired
side
effects,
poor
clinical
outcomes.
Combining
cell-targeting
efficient
cell-killing
properties,
peptide-drug
conjugates
(PDCs)
have
demonstrated
superior
efficacy
compared
with
peptides
payloads
alone.
However,
innovative
molecular
designs
PDCs
are
essential
further
improving
targeting
precision,
protease
resistance
stability,
cell
permeability,
overall
efficacy.
Several
strategies
been
developed
address
these
challenges,
such
as
multivalency
approaches,
bispecific
targeting,
long-acting
PDCs.
Other
novel
strategies,
including
overcoming
biological
barriers,
conjugating
functional
payloads,
macropinocytosis,
also
shown
promise.
This
perspective
compiles
most
recent
enhancing
PDC
efficacy,
highlights
key
advancements
in
PDC,
provides
insights
on
future
directions
Abstract
The
modification
of
biomolecules,
particularly
peptides,
has
garnered
considerable
attention
from
researchers,
effectively
serving
as
a
connection
between
chemistry
and
biology.
peptides
can
facilitate,
among
others,
the
generation
peptide
drugs,
antibody–drug
conjugates,
probes
for
molecular
imaging.
Herein,
we
have
carefully
curated
reactions
chemical
transformations
bioactive
sequences
equipped
with
histidine
amino
acids
that
are
conducive
biological
applications.
This
Account
also
highlights
strategies
might
capture
imagination
both
researchers
synthetic
chemists.
1
Introduction
2
Histidine
Modification
in
Bioactive
Peptides
Proteins
3
Remote
Protein
Adjacent
to
4
Conclusions
Future
Directions
ACS Medicinal Chemistry Letters,
Год журнала:
2024,
Номер
16(1), С. 109 - 115
Опубликована: Дек. 12, 2024
Selective
targeting
of
cancer
cells
via
overexpressed
cell-surface
receptors
is
a
promising
strategy
to
enhance
chemotherapy
efficacy
and
minimize
off-target
side
effects.
In
this
study,
we
designed
peptide
31
(YHWYGYTPERVI)
target
the
epidermal
growth
factor
receptor
(EGFR)
in
triple-negative
breast
(TNBC)
cells.
Peptide
internalized
by
TNBC
through
EGFR-mediated
endocytosis
shares
sequence
structural
similarities
with
human
EGF
(hEGF),
natural
EGFR
ligand.
Unlike
hEGF,
does
not
induce
cell
migration
A
novel
conjugate
doxorubicin
(Dox)
retains
selectivity
for
exhibits
significant
toxicity
comparable
that
unconjugated
Dox.
Importantly,
shows
no
toward
normal
epithelial
up
high
concentration
(25
μM).
Thus,
serves
as
versatile
ligand
developing
conjugates
EGFR-positive
cancers.
Journal of the American Chemical Society,
Год журнала:
2024,
Номер
unknown
Опубликована: Дек. 26, 2024
Triple-negative
breast
cancer
(TNBC)
poses
significant
treatment
challenges
due
to
its
high
metastasis,
heterogeneity,
and
poor
biomarker
expression.
The
N-terminus
of
an
octapeptide
NAPVSIPQ
(NAP)
was
covalently
coupled
a
carboxylic
acid
derivative
Ru(2,2′-bipy)32+
(Rubpy)
synthesize
N-stapled
short
peptide-Rubpy
conjugate
(Ru-NAP).
This
photosensitizer
(PS)
utilized
treat
TNBC
through
microtubule
(MT)
targeted
chemotherapy
photodynamic
therapy
(PDT).
Ru-NAP
formed
more
elaborate
molecular
aggregates
with
fibrillar
morphology
as
compared
NAP.
A
much
higher
binding
affinity
over
NAP
toward
β-tubulin
(KRu-NAP:
(6.8
±
0.55)
×
106
M–1;
KNAP:
(8.2
1.1)
104
M–1)
observed
stronger
electrostatic
interactions
between
the
MT
average
linear
charge
density
∼85
e/nm
cationic
Rubpy
part
Ru-NAP.
also
supported
by
docking,
simulation,
appropriate
imaging
studies.
promoted
serum
stability,
specific
E-site
βIII-tubulin
followed
disruption
network,
effective
singlet
oxygen
generation
in
cells
(MDA-MB-231),
causing
cell
cycle
arrest
G2/M
phase
triggering
apoptosis.
Remarkably,
MDA-MB-231
were
sensitive
noncancerous
human
embryonic
kidney
(HEK293
cells)
when
exposed
light
(LightIC50Ru-NAP[HEK293]:
17.2
2.5
μM,
LightIC50Ru-NAP[MDA-MB-231]:
32.5
7.8
nM,
DarkIC50Ru-NAP[HEK293]:
>
80
DarkIC50Ru-NAP[MDA-MB-231]:
2.9
0.5
μM).
effectively
inhibited
tumor
growth
xenograft
models
nude
mice.
Our
findings
provide
strong
evidence
that
has
potential
therapeutic
role
treatment.
