RNA Biology,
Journal Year:
2023,
Volume and Issue:
20(1), P. 525 - 538
Published: Aug. 1, 2023
Precursor
mRNA
(pre-mRNA)
splicing
is
an
essential
step
in
human
gene
expression
and
carried
out
by
a
large
macromolecular
machine
called
the
spliceosome.
Given
spliceosome's
role
shaping
cellular
transcriptome,
it
not
surprising
that
mutations
machinery
can
result
range
of
diseases
disorders
(spliceosomopathies).
This
review
serves
as
introduction
into
main
features
pre-mRNA
humans
how
changes
function
its
components
lead
to
ranging
from
blindness
cancers.
Recently,
several
drugs
have
been
developed
interact
directly
with
this
change
outcomes
at
either
single
or
transcriptome-scale.
We
discuss
mechanism
action
perturb
unique
ways.
Finally,
we
speculate
on
what
future
may
hold
emerging
area
spliceosomopathies
spliceosome-targeted
treatments.
Journal of Medicinal Chemistry,
Journal Year:
2022,
Volume and Issue:
65(21), P. 14261 - 14275
Published: Oct. 25, 2022
Hydrogen-bond
donors
are
seen
to
cause
more
problems
for
drug
designers
than
hydrogen-bond
acceptors.
Most
of
the
polarity
in
drug-like
compounds
comes
from
acceptors
since
they
typically
exceed
number
and
heavily
solvated
on
an
individual
basis.
The
implications
this
imbalance
optimization
permeability
aqueous
solubility
discussed.
A
factor
that
should
be
considered
ligand
recognition
by
targets
is
presence
a
donor
generally
implies
acceptor
also
present
(but
not
vice
versa).
Frustrated
solvation
secondary
electrostatic
interactions
result
aligned
acceptors,
design
opportunities
presented
these
phenomena
based
oxygen,
nitrogen
carbon
compared
as
target
elements,
halogen-
chalcogen-bond
discussed
equivalents.
Journal of the American Chemical Society,
Journal Year:
2022,
Volume and Issue:
144(49), P. 22622 - 22632
Published: Nov. 30, 2022
Proteolysis
Targeting
Chimeras
(PROTACs)
are
attractive
therapeutic
modalities
for
degrading
disease-causing
proteins.
While
many
PROTACs
have
been
developed
numerous
protein
targets,
current
small-molecule
PROTAC
approaches
cannot
target
undruggable
proteins
that
do
not
binders.
Here,
we
present
a
novel
approach,
termed
bridged
PROTAC,
which
utilizes
binder
of
the
protein's
binding
partner
to
recruit
complex
into
close
proximity
with
an
E3
ubiquitin
ligase
Applying
this
strategy,
discovered
MS28,
first-in-class
degrader
cyclin
D1,
lacks
binder.
MS28
effectively
degrades
faster
degradation
kinetics
and
superior
efficiency
than
CDK4/6,
through
recruiting
CDK4/6-cyclin
D1
von
Hippel–Lindau
ligase.
also
suppressed
proliferation
cancer
cells
more
CDK4/6
inhibitors
degraders.
Altogether,
strategy
could
provide
generalizable
platform
targeting
Nature Structural & Molecular Biology,
Journal Year:
2023,
Volume and Issue:
30(9), P. 1380 - 1392
Published: Aug. 7, 2023
The
ribosome
is
a
major
target
for
clinically
used
antibiotics,
but
multidrug
resistant
pathogenic
bacteria
are
making
our
current
arsenal
of
antimicrobials
obsolete.
Here
we
present
cryo-electron-microscopy
structures
17
distinct
compounds
from
six
different
antibiotic
classes
bound
to
the
bacterial
at
resolutions
ranging
1.6
2.2
Å.
improved
resolution
enables
precise
description
antibiotic-ribosome
interactions,
encompassing
solvent
networks
that
mediate
multiple
additional
interactions
between
drugs
and
their
target.
Our
results
reveal
high
structural
conservation
in
binding
mode
antibiotics
with
same
scaffold,
including
ordered
water
molecules.
Water
molecules
visualized
within
sites
preordered,
become
presence
drug
physically
displaced
on
binding.
Insight
into
RNA-ligand
will
facilitate
development
new
antimicrobial
agents,
as
well
other
RNA-targeting
therapies.
Chemical Reviews,
Journal Year:
2024,
Volume and Issue:
124(3), P. 929 - 1033
Published: Jan. 29, 2024
RNA-based
therapies
have
catalyzed
a
revolutionary
transformation
in
the
biomedical
landscape,
offering
unprecedented
potential
disease
prevention
and
treatment.
However,
despite
their
remarkable
achievements,
these
encounter
substantial
challenges
including
low
stability,
susceptibility
to
degradation
by
nucleases,
prominent
negative
charge,
thereby
hindering
further
development.
Chemically
modified
platforms
emerged
as
strategic
innovation,
focusing
on
precise
alterations
either
RNA
moieties
or
associated
delivery
vectors.
This
comprehensive
review
delves
into
platforms,
underscoring
significance
augmenting
performance
translational
prospects
of
therapeutics.
It
encompasses
an
in-depth
analysis
various
chemically
that
been
instrumental
propelling
therapeutics
toward
clinical
utility.
Moreover,
scrutinizes
rationale
behind
diverse
chemical
modification
techniques
aiming
at
optimizing
therapeutic
efficacy
molecules,
facilitating
robust
management.
Recent
empirical
studies
corroborating
enhancement
through
modifications
are
highlighted.
Conclusively,
we
offer
profound
insights
transformative
impact
drugs
delineates
prospective
trajectories
for
future
development
integration.
Molecular Cell,
Journal Year:
2023,
Volume and Issue:
83(22), P. 3953 - 3971
Published: Oct. 5, 2023
tRNA
function
is
based
on
unique
structures
that
enable
mRNA
decoding
using
anticodon
trinucleotides.
These
interact
with
specific
aminoacyl-tRNA
synthetases
and
ribosomes
3D
shape
sequence
signatures.
Beyond
translation,
tRNAs
serve
as
versatile
signaling
molecules
interacting
other
RNAs
proteins.
Through
evolutionary
processes,
fragmentation
emerges
not
merely
random
degradation
but
an
act
of
recreation,
generating
shorter
called
tRNA-derived
small
(tsRNAs).
tsRNAs
exploit
their
linear
sequences
newly
arranged
for
unexpected
biological
functions,
epitomizing
the
"renovatio"
(from
Latin,
meaning
renewal,
renovation,
rebirth).
Emerging
methods
to
uncover
full
tRNA/tsRNA
modifications,
combined
techniques
study
RNA
integrate
AI-powered
predictions,
will
comprehensive
investigations
products
new
interaction
potentials
in
relation
functions.
We
anticipate
these
directions
herald
a
era
understanding
complexity
advancing
pharmaceutical
engineering.
Scientific Reports,
Journal Year:
2024,
Volume and Issue:
14(1)
Published: April 2, 2024
High
throughput
screening
(HTS)
is
routinely
used
to
identify
bioactive
small
molecules.
This
requires
physical
compounds,
which
limits
coverage
of
accessible
chemical
space.
Computational
approaches
combined
with
vast
on-demand
libraries
can
access
far
greater
space,
provided
that
the
predictive
accuracy
sufficient
useful
Through
largest
and
most
diverse
virtual
HTS
campaign
reported
date,
comprising
318
individual
projects,
we
demonstrate
our
AtomNet®
convolutional
neural
network
successfully
finds
novel
hits
across
every
major
therapeutic
area
protein
class.
We
address
historical
limitations
computational
by
demonstrating
success
for
target
proteins
without
known
binders,
high-quality
X-ray
crystal
structures,
or
manual
cherry-picking
compounds.
show
molecules
selected
model
are
drug-like
scaffolds
rather
than
minor
modifications
Our
empirical
results
suggest
methods
substantially
replace
as
first
step
small-molecule
drug
discovery.
