Frontiers in Pharmacology,
Год журнала:
2023,
Номер
14
Опубликована: Март 21, 2023
Triple
combination
therapy
with
the
CFTR
modulators
elexacaftor
(ELX),
tezacaftor
(TEZ)
and
ivacaftor
(IVA)
has
been
qualified
as
a
game
changer
in
cystic
fibrosis
(CF).
We
provide
an
overview
of
body
literature
on
ELX/TEZ/IVA
published
between
November
2019
February
2023
after
approval
by
regulators.
Recombinant
ELX/TEZ/IVA-bound
Phe508del
exhibits
wild
type
conformation
Pharmacological Reviews,
Год журнала:
2023,
Номер
75(4), С. 789 - 814
Опубликована: Март 16, 2023
Abstract
Personalized
medicine
tailors
therapies,
disease
prevention,
and
health
maintenance
to
the
individual,
with
pharmacogenomics
serving
as
a
key
tool
improve
outcomes
prevent
adverse
effects.
Advances
in
genomics
have
transformed
pharmacogenetics,
traditionally
focused
on
single
gene-drug
pairs,
into
pharmacogenomics,
encompassing
all
"-omics"
fields
(e.g.,
proteomics,
transcriptomics,
metabolomics,
metagenomics).
This
review
summarizes
basic
principles
relevant
translation
assessing
pharmacogenomics'
central
role
converging
diverse
elements
of
personalized
medicine.
We
discuss
genetic
variations
pharmacogenes
(drug-metabolizing
enzymes,
drug
transporters,
receptors),
their
clinical
relevance
biomarkers,
legacy
decades
research
pharmacogenetics.
All
types
including
proteins,
nucleic
acids,
viruses,
cells,
genes,
irradiation,
can
benefit
from
genomics,
expanding
across
Food
Drug
Administration
approvals
therapeutics
involving
biomarkers
increase
rapidly,
demonstrating
growing
impact
pharmacogenomics.
A
beacon
for
therapeutic
approaches,
molecularly
targeted
cancer
therapies
highlight
trends
discovery
applications.
To
account
human
complexity,
multicomponent
biomarker
panels
genetic,
personal,
environmental
factors
guide
diagnosis
increasingly
artificial
intelligence
cope
extreme
data
complexities.
However,
application
encounters
substantial
hurdles,
such
unknown
validity
ethnic
groups,
underlying
bias
care,
real-world
validation.
address
science
technologies
germane
medicine,
integrated
economic,
ethical,
regulatory
issues,
providing
insights
current
status
future
direction
care.
Significance
Statement
aims
optimize
care
individual
patients
use
predictive
Pharmacogenomics
drives
guides
development
therapeutics.
addresses
large-scale
repositories
accelerating
medical
advances.
The
is
discussed,
along
hurdles
impeding
broad
implementation,
context
ethics,
economics,
affairs.
PLoS ONE,
Год журнала:
2024,
Номер
19(1), С. e0297560 - e0297560
Опубликована: Янв. 25, 2024
Variants
in
the
cystic
fibrosis
transmembrane
conductance
regulator
gene
(CFTR)
result
fibrosis-a
lethal
autosomal
recessive
disorder.
Missense
variants
that
alter
a
single
amino
acid
CFTR
protein
are
among
most
common
variants,
yet
tools
for
accurately
predicting
molecular
consequences
of
missense
have
been
limited
to
date.
AlphaMissense
(AM)
is
new
technology
predicts
pathogenicity
based
on
dual
learned
structure
and
evolutionary
features.
Here,
we
evaluated
ability
AM
predict
variants.
predicted
high
residues
overall,
resulting
false
positive
rate
fair
classification
performance
CF
from
CFTR2.org
database.
score
correlated
modestly
with
metrics
persons
including
sweat
chloride
level,
pancreatic
insufficiency
rate,
Pseudomonas
aeruginosa
infection
rate.
Correlation
was
also
modest
trafficking
folding
competency
vitro.
By
contrast,
well
channel
function
vitro-demonstrating
training
approach
learns
important
functional
information
despite
lacking
such
data
during
training.
Different
across
indicated
may
determine
if
polymorphisms
cannot
differentiate
mechanistic
effects
or
nature
pathophysiology.
Finally,
predictions
offered
utility
inform
pharmacological
response
i.e.,
theratype.
Development
approaches
biochemical
properties
therefore
still
needed
refine
targeting
emerging
precision
therapeutics.
Current Opinion in Structural Biology,
Год журнала:
2024,
Номер
84, С. 102768 - 102768
Опубликована: Янв. 11, 2024
Allostery
is
the
mechanism
by
which
information
and
control
are
propagated
in
biomolecules.
It
regulates
ligand
binding,
chemical
reactions,
conformational
changes.
An
increasing
level
of
experimental
resolution
over
allosteric
mechanisms
promises
a
deeper
understanding
molecular
basis
for
life
powerful
new
therapeutics.
In
this
review,
we
survey
literature
an
up-to-date
biological
theoretical
protein
allostery.
By
delineating
five
ways
energy
landscape
or
kinetics
system
may
change
to
give
rise
allostery,
aim
help
reader
grasp
its
physical
origins.
To
illustrate
framework,
examine
three
systems
that
display
these
forms
allostery:
inhibitors
beta-lactamases,
thermosensation
TRP
channels,
role
kinetic
allostery
function
kinases.
Finally,
summarize
growing
power
computational
tools
available
investigate
different
presented
review.
European Respiratory Journal,
Год журнала:
2024,
Номер
63(1), С. 2301959 - 2301959
Опубликована: Янв. 1, 2024
Elexacaftor-tezacaftor-ivacaftor
(ETI)
was
approved
in
2019
by
the
United
States
Food
and
Drug
Administration
(FDA)
2020
European
Medicines
Agency
(EMA)
for
people
with
cystic
fibrosis
(pwCF).
It
is
a
combination
of
small
molecules
that
bind
to
defective
transmembrane
conductance
regulator
(CFTR)
protein,
thus
allowing
rescue
CFTR
structure
function
[1].
Footnotes
This
manuscript
has
recently
been
accepted
publication
Respiratory
Journal
.
published
here
its
form
prior
copyediting
typesetting
our
production
team.
After
these
processes
are
complete
authors
have
resulting
proofs,
article
will
move
latest
issue
ERJ
online.
Please
open
or
download
PDF
view
this
article.
Conflict
interest:
Pierre-Régis
Burgel
reports
support
present
from
Association
Vaincre
la
Mucoviscidose,
Société
Française
de
Filière
Maladie
Rare
Muco
CFTR.
In
addition,
grants
Vertex
Pharmaceuticals,
GSK;
consulting
fees
Astra
Zeneca,
Chiesi,
GSK,
Insmed,
Vertex,
Viatris,
Zambon;
travel
Chiesi;
outside
submitted
work.
Isabelle
Sermet-Gaudelus
Therapeutics,
Tavanta.
Tavanta;
Durieu
Jeanne
Languepin
report
Mylan,
Anne
Guillaumot
Asten,
Boehringer
Ingelheim,
LFB,
CSL
Behring,
Roche,
Menarini;
Camille
Audousset
Zambon,
Viatris;
advisory
board
participation
Pharmaceuticals;
Raphaël
Chiron
ECFC;
Vertex;
Laurence
Weiss
Fajac
AbbVie,
Bayer,
Kither
Biotech,
leadership
role
Cystic
Fibrosis
Society;
Clémence
Martin
lecture
honoraria
AstraZeneca,
Boehringer,
GSL;
Boehringer;
All
other
nothing
disclose.