Journal of Medicinal Chemistry,
Journal Year:
2024,
Volume and Issue:
67(22), P. 20258 - 20274
Published: Nov. 18, 2024
Macrocyclic
peptides
have
garnered
significant
attention
as
promising
drug
candidates.
However,
they
typically
face
challenges
in
achieving
and
enhancing
cell
permeability
for
access
to
intracellular
targets.
In
this
study,
we
focused
on
the
de
novo
screening
of
macrocyclic
peptide
inhibitors
against
main
protease
(Mpro)
SARS-CoV-2
identified
novel
noncovalently
bound
that
effectively
inhibit
proteolytic
activity.
High-resolution
crystal
structures
further
revealed
molecular
interactions
between
Mpro.
Subsequently,
a
specific
lacking
was
optimized
transformed
into
low-toxicity,
metabolically
stable
bicyclic
with
penetration
capacity
therapeutic
potential
SARS-CoV-2.
The
achieved
using
strategy
involved
introducing
both
structure
bridging
perfluorobiphenyl
group.
Our
study
not
only
provides
lead
inhibitor
COVID-19
but
also
offers
valuable
insights
through
strategic
modifications.
ACS Pharmacology & Translational Science,
Journal Year:
2022,
Volume and Issue:
6(1), P. 181 - 194
Published: Dec. 28, 2022
The
advent
of
SARS-CoV-2,
the
causative
agent
COVID-19,
and
its
worldwide
impact
on
global
health,
have
provided
impetus
for
development
effective
countermeasures
that
can
be
deployed
against
virus,
including
vaccines,
monoclonal
antibodies,
direct-acting
antivirals
(DAAs).
Despite
these
efforts,
current
paucity
DAAs
has
created
an
urgent
need
creation
enhanced
diversified
portfolio
broadly
acting
agents
with
different
mechanisms
action
effectively
abrogate
viral
infection.
SARS-CoV-2
3C-like
protease
(3CLpro),
enzyme
essential
replication,
is
a
validated
target
discovery
therapeutics.
In
this
report,
we
describe
structure-guided
utilization
cyclopropane
moiety
in
design
highly
potent
inhibitors
3CLpro,
SARS-CoV-1
MERS-CoV
3CLpro.
High-resolution
cocrystal
structures
were
used
to
identify
structural
determinants
associated
binding
active
site
unravel
mechanism
action.
Aldehydes
5c
11c
inhibited
replication
EC50
values
12
11
nM,
respectively.
Furthermore,
corresponding
aldehyde
bisulfite
adducts
5d
11d
equipotent
13
safety
index
(SI)
compounds
/
ranged
between
7692
9090.
Importantly,
aldehydes
potently
3CLpro
IC50
80
120
70
Likewise,
960
350
nM
790
240
Taken
together,
studies
suggest
described
herein
low
cytotoxicity
high
potency
are
promising
candidates
further
as
broad-spectrum
pathogenic
coronaviruses.
ACS Medicinal Chemistry Letters,
Journal Year:
2024,
Volume and Issue:
15(5), P. 602 - 609
Published: March 1, 2024
In
this
structure–activity
relationship
(SAR)
study,
we
report
the
development
of
dual
inhibitors
with
antiviral
properties
targeting
SARS-CoV-2
main
protease
(Mpro)
and
human
cathepsin
L
(hCatL).
The
novel
molecules
differ
in
aliphatic
amino
acids
at
P2
site
fluorine
position
on
phenyl
ring
P3
site.
identified
showed
Ki
values
within
1.61
10.72
μM
against
Mpro;
meanwhile,
ranging
from
0.004
to
0.701
toward
hCatL
were
observed.
A
great
interdependency
between
nature
side
chain
atom
was
found.
Three
dual-targeting
exhibited
activity
low
micromolar
range
CC50
>100
μM.
Docking
simulations
executed
gain
a
deeper
understanding
SAR
profile.
findings
herein
collected
should
be
taken
into
consideration
for
future
Mpro/hCatL
inhibitors.
Antimicrobial Agents and Chemotherapy,
Journal Year:
2024,
Volume and Issue:
68(10)
Published: Sept. 3, 2024
We
have
synthesized
a
novel
and
highly
selective
severe
acute
respiratory
syndrome
coronavirus
2
(SARS-CoV-2)
main
protease
peptide
mimetic
inhibitor
mimicking
the
replicase
1ab
recognition
sequence
-Val-Leu-Gln-
utilizing
cysteine
acyloxymethyl
ketone
as
electrophilic
warhead
to
target
active
site
Cys145.
Utilizing
constrained
cyclic
that
locks
conformation
between
P3
(Val)
P2
(Leu)
residues,
we
identified
fills
pocket
occupied
by
leucine
residue
sidechain
of
PF-00835231
dimethyl-3-azabicyclo-hexane
motif
in
nirmatrelvir
(PF-07321332).
This
strategy
resulted
potent
Mpro
inhibitors
without
inhibiting
essential
host
cathepsin
or
serine
proteases.
The
lead
prototype
compound
1
(MPro
IC
Journal of Medicinal Chemistry,
Journal Year:
2024,
Volume and Issue:
67(22), P. 20258 - 20274
Published: Nov. 18, 2024
Macrocyclic
peptides
have
garnered
significant
attention
as
promising
drug
candidates.
However,
they
typically
face
challenges
in
achieving
and
enhancing
cell
permeability
for
access
to
intracellular
targets.
In
this
study,
we
focused
on
the
de
novo
screening
of
macrocyclic
peptide
inhibitors
against
main
protease
(Mpro)
SARS-CoV-2
identified
novel
noncovalently
bound
that
effectively
inhibit
proteolytic
activity.
High-resolution
crystal
structures
further
revealed
molecular
interactions
between
Mpro.
Subsequently,
a
specific
lacking
was
optimized
transformed
into
low-toxicity,
metabolically
stable
bicyclic
with
penetration
capacity
therapeutic
potential
SARS-CoV-2.
The
achieved
using
strategy
involved
introducing
both
structure
bridging
perfluorobiphenyl
group.
Our
study
not
only
provides
lead
inhibitor
COVID-19
but
also
offers
valuable
insights
through
strategic
modifications.
