Angewandte Chemie,
Год журнала:
2024,
Номер
136(47)
Опубликована: Авг. 22, 2024
Abstract
The
inhibition
of
intracellular
protein‐protein
interactions
is
challenging,
in
particular,
when
involved
interfaces
lack
pronounced
cavities.
transcriptional
co‐activator
protein
and
oncogene
β‐catenin
a
prime
example
such
challenging
target.
Despite
extensive
targeting
efforts,
available
high‐affinity
binders
comprise
only
large
molecular
weight
inhibitors.
This
hampers
the
further
development
therapeutically
useful
compounds.
Herein,
we
report
design
considerably
smaller
peptidomimetic
scaffold
derived
from
α‐helical
β‐catenin‐binding
motif
Axin.
Sequence
maturation
bicyclization
provided
stitched
peptide
with
an
unprecedented
crosslink
architecture.
binding
mode
site
were
confirmed
by
crystal
structure.
Further
derivatization
yielded
inhibitor
single‐digit
micromolar
activity
cell‐based
assay.
study
sheds
light
on
how
to
helix
mimetics
reduced
thereby
improving
their
biological
activity.
Natural Product Reports,
Год журнала:
2025,
Номер
unknown
Опубликована: Янв. 1, 2025
This
review
described
the
total
synthesis
of
naturally
occurring
cyclic
peptides
covering
2020
to
2022
paying
particular
attention
construction
their
unique
structures
via
macrocyclization.
Journal of the American Society for Mass Spectrometry,
Год журнала:
2025,
Номер
unknown
Опубликована: Май 23, 2025
Engineered
cyclic
peptides
(ECPs)
have
been
in
the
spotlight
as
novel
drug
modalities
for
challenging
therapeutic
targets.
Oral
delivery
of
engineered
benefits
from
ease
administration.
However,
one
main
hurdles
developing
orally
effective
peptide
drugs
is
their
potential
metabolic
instability
due
to
enzymatic
degradation.
To
that
end,
vitro
experiments
with
simulated
intestinal
fluid
(SIF)
used
assess
stability
gastrointestinal
tract.
Currently,
evaluations
and
biotransformation
assessments
are
performed
separately,
which
can
be
time-consuming
result
complex
data
analysis.
Presented
here
a
sample
multiplexing
strategy
address
these
challenges
by
leveraging
Thermo
Scientific
Orbitrap
Astral
mass
spectrometer
two
complementary
analyzers,
enabling
simultaneous
analysis
full
scan
analyzer
injection.
Furthermore,
we
demonstrate
10
pooled
into
injection
without
compromising
quality
decrease
instrument
run
time
improve
throughput
assay.
Macrocyclic
peptides
and
depsipeptides
are
the
emerging
class
of
a
new
modality
in
drug
discovery
research.
Tetraselide,
an
antifungal
cyclic
peptide
isolated
from
marine-derived
filamentous
fungus,
possesses
unique
amphiphilic
structural
feature
that
represents
five
consecutive
β-hydroxy-amino
acid
fatty
moieties.
Because
structure
elucidation
naturally
occurring
product
left
six
stereocenters
ambiguous,
we
implemented
bioinformatic
analyses,
chemical
degradation
study
chiral
pool
fragment
synthesis
to
identify
two
undetermined
stereochemistry.
Convergent
total
four
remaining
plausible
isomers
tetraselide
was
accomplished
via
liquid-phase
using
soluble
hydrophobic
tag
auxiliaries.
The
key
advance
involves
coupling
by
serine/threonine
ligation
reaction
head-to-tail
macrolactamization
carrier-supported
precursors
enabled
systematic
elaboration
peptides.
Ultimately,
determined
absolute
this
natural
product.
Angewandte Chemie,
Год журнала:
2024,
Номер
136(47)
Опубликована: Авг. 22, 2024
Abstract
The
inhibition
of
intracellular
protein‐protein
interactions
is
challenging,
in
particular,
when
involved
interfaces
lack
pronounced
cavities.
transcriptional
co‐activator
protein
and
oncogene
β‐catenin
a
prime
example
such
challenging
target.
Despite
extensive
targeting
efforts,
available
high‐affinity
binders
comprise
only
large
molecular
weight
inhibitors.
This
hampers
the
further
development
therapeutically
useful
compounds.
Herein,
we
report
design
considerably
smaller
peptidomimetic
scaffold
derived
from
α‐helical
β‐catenin‐binding
motif
Axin.
Sequence
maturation
bicyclization
provided
stitched
peptide
with
an
unprecedented
crosslink
architecture.
binding
mode
site
were
confirmed
by
crystal
structure.
Further
derivatization
yielded
inhibitor
single‐digit
micromolar
activity
cell‐based
assay.
study
sheds
light
on
how
to
helix
mimetics
reduced
thereby
improving
their
biological
activity.