Development of Selective Nanomolar Cyclic Peptide Ligands as GBA1 Enzyme Stabilizers
RSC Chemical Biology,
Год журнала:
2025,
Номер
unknown
Опубликована: Янв. 1, 2025
The
stabilisation
of
recombinant
glycosidases
by
exogenous
ligands,
known
as
pharmacological
chaperones
or
enzyme
stabilisers,
has
recently
garnered
great
clinical
interest.
This
strategy
can
prevent
degradation
in
the
blood,
reducing
required
dosages
and
extending
IV
injection
intervals,
thereby
side
effects,
improving
patient
lifestyles
treatment
costs.
While
this
therapeutic
approach
been
successfully
implemented
for
treating
Pompe
Fabry
diseases,
studies
Gaucher
disease
using
alone
combination
with
replacement
therapy
(ERT)
have
limited,
no
small
molecule
yet
approved
condition.
Developing
such
therapies
requires
selective
effective
reversible
GBA1
ligands.
Here,
we
describe
development
a
new
class
macrocyclic
peptide
ligands
random
nonstandard
peptides
integrated
discovery
(RaPID)
technology,
demonstrate
their
ability
to
bind
stabilise
rhGBA1
plasma
at
nanomolar
concentrations.
These
cyclic
do
not
inhibit
endogenous
cells
due
poor
cell
permeability
but
extracellular
plasma,
presenting
significant
potential
combinatorial
ERT-pharmacological
chaperone
disease.
Язык: Английский
RaPID discovery of cell-permeable helical peptide inhibitors con-taining cyclic β-amino acids against SARS-CoV-2 main protease
RSC Chemical Biology,
Год журнала:
2025,
Номер
unknown
Опубликована: Янв. 1, 2025
The
ribosomal
synthesis
of
a
helical
peptide
library
containing
structurally
constrained
cyclic
β-amino
acid
at
every
third
position
and
its
application
for
the
RaPID
selection
against
SARS-CoV-2
main
protease
(M
pro
)
inhibitors.
Язык: Английский
Translation of Deoxyribonucleic Acid into Synthetic Alpha Helical Peptides for Darwinian Evolution
JACS Au,
Год журнала:
2024,
Номер
4(10), С. 4013 - 4022
Опубликована: Окт. 2, 2024
DNA-encoded
libraries
connect
the
phenotypes
of
synthetic
molecules
to
a
DNA
barcode;
however,
most
do
not
tap
into
potential
Darwinian
evolution.
Herein,
we
report
DNA-templated
synthesis
(DTS)
architecture
make
peptides
that
are
stabilized
α-helical
conformations
via
head-to-tail
supramolecular
cyclization.
Using
pilot
library
targeting
MDM2,
show
repeated
screening
can
amplify
binder
from
lowest
abundance
in
ranking
correlates
binding
affinity.
The
study
also
highlights
need
design
such
chemistry
avoids
biases
heterogeneous
yield
DTS.
Язык: Английский
Disulfide-Directed Multicyclic Peptides with N-Terminally Extendable α-Helices for Recognition and Activation of G Protein-Coupled Receptors
Journal of the American Chemical Society,
Год журнала:
2024,
Номер
unknown
Опубликована: Дек. 17, 2024
Many
peptide
hormones
adopt
long
α-helical
structures
upon
interacting
with
their
cognate
receptors
but
often
exhibit
flexible
conformations
when
unbound.
Strategies
that
can
stabilize
α-helices
without
disrupting
binding
to
are
still
lacking,
which
hinders
progress
in
biological
applications
and
drug
development.
Here,
we
present
an
approach
combines
rational
design
library
screening
create
identify
a
unique
disulfide-directed
multicyclic
(DDMP)
scaffold,
could
effectively
N-terminally
extendable
while
displaying
exceptional
efficiency
disulfide
pairing
oxidative
folding.
This
DDMP
scaffold
was
then
utilized
for
stabilizing
the
structure
of
glucagon-like
peptide-1
(GLP-1),
resulting
potent
GLP-1
receptor
(GLP-1R)
agonist
significantly
improved
α-helicity
proteolytic
stability.
By
incorporating
external
into
preserve
native
N-terminal
allowing
extensive
evolution
C-terminal
disulfide-rich
domain
enhancing
target
binding,
as
demonstrated
by
generation
DDMP-stabilized
(g1:Ox).
The
cryo-electron
microscopy
g1:Ox-GLP-1R
complex
heterotrimeric
G
Язык: Английский