Chemistry - A European Journal,
Journal Year:
2024,
Volume and Issue:
unknown
Published: Dec. 11, 2024
The
incorporation
of
fluorinated
amino
acids
into
proteins
provides
new
opportunities
to
study
biomolecular
structure-function
relationships
in
an
elegant
manner.
available
strategies
incorporate
the
majority
are
not
site-specific
or
imply
important
structural
modifications.
Here,
we
present
a
chemical
biology
approach
for
three
commercially
Cγ-modified
fluoroprolines
that
has
been
validated
using
non-pathogenic
version
huntingtin
exon-1
(HttExon-1).
19F,
1H
and
15N
NMR
shifts
measured
multiple
variants
HttExon-1
indicated
trans/cis
ratio
was
strongly
dependent
on
fluoroproline
variant
sequence
context.
By
isotopically
labelling
rest
protein,
have
shown
extent
spectroscopic
perturbations
neighbouring
residues
depends
number
fluorine
atoms
stereochemistry
at
Cγ,
as
well
isomeric
form
fluoroproline.
We
rationalized
these
observations
by
means
extensive
molecular
dynamics
simulations,
indicating
observed
atomic
shift
correlate
with
distance
effect
remains
very
local.
These
results
validate
excellent
strategy
monitor
intra-
intermolecular
interactions
disordered
proline-rich
proteins.
Synthesis,
Journal Year:
2025,
Volume and Issue:
unknown
Published: March 5, 2025
Abstract
The
development
of
non-canonical
amino
acids
is
pivotal
to
peptide
engineering,
enabling
the
design
molecules
with
novel
structural
features,
improved
activities,
and
optimized
metabolic
profiles.
Among
these,
heteroaromatic
γ-amino
have
attracted
significant
attention
for
their
ability
mimic
native
folds
while
accessing
conformational
spaces.
In
this
study,
chemical
diversity
was
expanded
by
introducing
two
new
monomers,
ATC*
AOC*,
designed
around
a
thiazole
an
oxazole
scaffold,
respectively.
These
analogues,
characterized
tunable
substitution
patterns
precise
stereochemical
control
significantly
expand
well-established
ATC
family.
Communications Chemistry,
Journal Year:
2025,
Volume and Issue:
8(1)
Published: March 12, 2025
The
unique
role
of
proline
in
modulating
protein
folding
and
recognition
makes
it
an
attractive
target
for
substitution
to
generate
new
proteomimetics.
design,
synthesis,
conformational
analysis
non-canonical
surrogates
can
also
aid
parsing
the
prolyl
stereoelectronic
effects
on
structure.
We
recently
described
synthesis
dehydro-δ-azaproline
(ΔaPro),
a
novel
unsaturated
analogue
featuring
planar
dehydropyrazine
ring.
When
incorporated
into
host
sequences,
this
backbone
N-aminated
surrogate
forms
acylhydrazone
bond
with
unusually
high
trans
rotamer
bias
low
isomerization
barrier.
Here,
we
used
CD,
NMR
spectroscopy,
MD
simulations
evaluate
impact
ΔaPro
within
polyproline
II
(PPII)
loop
regions
avian
pancreatic
polypeptide
(aPP).
residue
strongly
favors
PPII
conformation
stabilizes
aPP
tertiary
fold
when
at
select
positions
miniprotein.
A
variant
three
substitutions
was
found
significantly
enhance
thermal
stability
wild-type
despite
compromising
dimerization.
Our
results
suggest
that
proline-rich
folds
relies
more
torsional
preferences
than
ring
puckering
informs
strategies
incorporation
thermally
stable
functional
Proline
plays
important
mediating
stability,
however,
noncanonical
analogues
is
not
well
understood.
authors
report
(aPP)
aPP.
Future Medicinal Chemistry,
Journal Year:
2025,
Volume and Issue:
unknown, P. 1 - 15
Published: May 12, 2025
The
pyrrolidine
moiety,
a
five-membered
saturated
nitrogen-containing
heterocycle,
emerged
as
crucial
pharmacophore
in
medicinal
chemistry
due
to
its
distinctive
physicochemical
properties,
including
hydrophilicity,
basicity,
and
structural
rigidity.
Extensive
modifications
of
derivatives
yielded
novel
compounds
with
pronounced
antidiabetic
anticancer
activities.
investigation
pyrrolidine-based
molecules
demonstrated
that
substitutions
at
the
N1,
3rd,
5th
positions
offer
significant
opportunities
for
optimizing
biological
activity
enhancing
target-specific
interactions.
synthesis
has
been
explored
literature;
however,
structural,
target
interaction
analysis,
pharmacological
aspects
warranted
development
targeted
small
molecule
versatile
agents
are
lacking.
review
addresses
this
gap
by
emphasizing
developments
via
highlighting
their
activities,
offering
comprehensive
perspective
on
therapeutics.
investigated
features
underscore
dual
functionality
drugs
managing
disorders,
such
diabetes
cancer,
share
common
pathological
mechanisms,
inflammation,
oxidative
stress,
metabolic
dysregulation.
This
overlap
catalyzed
multifunctional
capable
targeting
pathways
integral
both
conditions,
providing
promising
avenue
therapeutic
innovation.
The Journal of Organic Chemistry,
Journal Year:
2024,
Volume and Issue:
89(24), P. 18159 - 18178
Published: Dec. 10, 2024
A
series
of
novel
spirocyclic
α-proline
building
blocks
with
a
spiro
conjunction
in
position
3
the
pyrrolidine
ring
was
prepared
to
employ
two
convenient
and
practical
synthetic
approaches.
Both
alternative
routes
utilize
simple
readily
available
starting
materials─cyclic
ketones
esters─and
comprise
6
7
steps,
respectively.
The
methodologies
feature
distinct
advantages,
using
routine
organic
chemistry
transformations,
are
suitable
for
producing
multigram
amounts
target
prolines.
approach
also
became
valuable
pyroglutamic
acids.
