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.
Israel Journal of Chemistry,
Год журнала:
2024,
Номер
unknown
Опубликована: Авг. 6, 2024
Abstract
Genetic
code
expansion
aims
to
incorporate
non‐canonical
amino
acids
(ncAAs)
into
biological
systems,
enhancing
protein
functionality
or
enabling
the
in
vitro
selection
of
peptides
from
diverse
mRNA
displayed
libraries.
Typically,
genetic
has
involved
reassignment
stop
codons
ncAAs
through
orthogonal
translation
systems.
This
review
instead
focuses
on
efforts
expand
by
breaking
redundancy
sense
and
vivo.
In
vivo,
aminoacyl‐tRNA
synthetase
(AARS)/tRNA/AA
systems
are
able
compete
with
endogenous
machinery,
partial
full
codon
reassignment.
Recent
approaches,
like
genome
recoding,
offer
potential
solutions
reduce
competition.
studies
utilize
cell
extract‐based
reconstituted
allowing
precise
control
usage
via
gene
design
tRNA
addition,
making
degeneracy
easier.
these
several
unsplit
boxes
have
been
successfully
reassigned
multiple
ncAAs.
These
showcase
both
successes
challenges
achieving
orthogonality
selective
decoding
point
towards
a
future
where
64
can
encode
more
than
30
monomers,
new
advances
synthetic
biology
drug
discovery.
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.
