Orally Bioavailable RORγ/DHODH Dual Host-Targeting Small Molecules with Broad-Spectrum Antiviral Activity
Alexandra Herrmann,
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Christian Gege,
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Christina Wangen
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et al.
Antiviral Research,
Journal Year:
2024,
Volume and Issue:
unknown, P. 106008 - 106008
Published: Sept. 1, 2024
Language: Английский
RORγt inhibitors in clinical development for the treatment of autoimmune diseases: challenges and opportunities
Expert Opinion on Therapeutic Patents,
Journal Year:
2025,
Volume and Issue:
unknown
Published: March 20, 2025
Nuclear
receptor
retinoid-related
orphan
gamma-t
(RORγt)
is
a
major
transcription
factor
for
Th17
cell
differentiation
and
IL-17
production.
RORγt
has
been
considered
as
promising
drug
target
the
treatment
of
IL-17-mediated
inflammatory
diseases.
Numerous
small
molecule
inhibitors
have
discovered,
more
than
twenty
advanced
to
clinical
trials.
However,
none
these
compounds
yet
achieved
market
approval.
This
manuscript
summarizes
development
22
clinical-stage
inhibitors,
including
their
structures,
patent
applications,
trial
status,
based
on
publications
patents
available
up
November
2024.
The
discovery
was
an
exciting
field
molecular
treatments,
which
gone
through
boom
period
in
past
ten
years.
some
leading
recently
failed
trials
due
lack
efficacy
or
having
safety
concerns,
although
few
candidates
targeting
are
still
preclinical
studies.
Realizing
challenge,
researchers
started
develop
different
approaches
such
dual
exploring
new
indications,
utilizing
potential
value
inhibitors.
Language: Английский
Cyclin-Dependent Kinase 8 Represents a Positive Regulator of Cytomegalovirus Replication and a Novel Host Target for Antiviral Strategies
Debora Obergfäll,
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Markus Wild,
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Mona Sommerer
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et al.
Pharmaceutics,
Journal Year:
2024,
Volume and Issue:
16(9), P. 1238 - 1238
Published: Sept. 23, 2024
Background.
Cyclin-dependent
kinase
8
(CDK8)
is
a
multifaceted
regulator
and
represents
catalytic
component
of
the
transcriptional
Mediator
complex.
CDK8
activity,
on
one
hand,
increases
elongation
by
recruitment
Mediator/super
complexes,
but,
other
negatively
regulates
CDK7-controlled
initiation
through
inactivating
cyclin
H
phosphorylation.
Recently,
these
combined
properties
have
also
suggested
its
rate-limiting
importance
for
herpesviral
replication.
Objectives.
In
this
paper,
we
focused
human
cytomegalovirus
(HCMV)
addressed
question
whether
pharmacological
inhibition
or
knock-down
may
affect
viral
replication
efficiency
in
cell
culture
models.
Methods.
A
number
animal
herpesviruses,
as
well
non-herpesviruses,
were
used
to
analyze
models,
assess
antiviral
efficacy
inhibitors.
Results.
Using
clinically
relevant
inhibitors
(CCT-251921,
MSC-2530818,
BI-1347),
HCMV
was
found
strongly
reduced
even
at
nanomolar
drug
concentrations.
The
EC50
values
consistent
three
different
strains
(i.e.,
AD169,
TB40,
Merlin)
analyzed
two
types
primary
fibroblasts
astrocytoma
cells),
drugs
comprised
low
level
cytotoxicity.
findings
highlighted
following:
(i)
pronounced
vitro
SI
anti-HCMV
activity
obtained
with
inhibitors;
(ii)
confirmation
CDK8–siRNA
knock-down;
(iii)
CDK8-dependent
reduction
immediate
early,
late
protein
levels;
(iv)
main
late-stage
replication;
(v)
several
mechanistic
aspects,
which
point
strong
impact
progeny
production
release,
but
lack
relevance
entry
nuclear
egress;
(vi)
significant
synergy
combinations
against
host
vCDK/pUL97
(maribavir);
(vii)
finally,
broad-spectrum
seen
comparison
selected
α-,
β-,
γ-,
non-herpesviruses.
Conclusions.
summary,
novel
data
provide
evidence
positive
efficiency,
moreover,
suggest
exploitability
an
target
strategies
host-directed
development.
Language: Английский
Discovery of 1-(Phenylsulfonyl)-1,2,3,4-tetrahydroquinoline Derivative as Orally Bioavailable and Safe RORγt Inverse Agonists for Potential Treatment of Rheumatoid Arthritis
Journal of Medicinal Chemistry,
Journal Year:
2024,
Volume and Issue:
67(22), P. 20315 - 20342
Published: Nov. 15, 2024
The
retinoic
acid
receptor-related
orphan
receptor
γt
(RORγt)
is
a
key
regulator
of
Th17
cells,
associated
with
autoimmune
diseases,
making
it
significant
drug
target.
Herein,
we
designed
and
synthesized
1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinoline
derivatives,
improving
upon
GSK2981278
to
enhance
bioavailability.
Of
which,
Language: Английский
Facile Synthesis of New Antiviral Fluoro-Quinazolines Enabled by Merging Domino Reactions
Svetlana B. Tsogoeva,
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Sascha Kohlbauer,
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Honglin Xia
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et al.
Synthesis,
Journal Year:
2024,
Volume and Issue:
unknown
Published: Nov. 12, 2024
Abstract
Quinazolines,
particularly
fluoro-quinazolines,
represent
important
structural
motifs
in
bioactive
molecules
and
pharmaceuticals.
Despite
several
known
synthetic
routes,
the
efficient
synthesis
of
fluorine-containing
quinazolines
remains
a
challenge.
Herein,
straightforward
sustainable
fluorine-substituted
using
domino
sequences
is
reported.
The
obtained
novel
fluoro-quinazoline
compounds
exhibit
significant
vitro
activity
against
human
cytomegalovirus
(HCMV),
expanding
library
potential
antiviral
drug
compounds.
Our
finding
outlays
toolkit
for
fluoro-quinazolines
introduces
new
agents
HCMV
therapy.
Language: Английский