ORF8
is
an
asymmetric-homodimer
SARS-COV-2
accessory
protein
implicated
in
excesive
human
inflammation
causing
numerous
deaths.
There
no
approved
drug
targeting
ORF8,
nor
it
known
whether
any
anti-ORF8
drugs
could
reduce
inflammation.
Computationally
combining
ligand
co-evolution
of
parent
molecules
with
affinity-consensus
docking,
children
candidates
for
docking
to
cavities
were
generated.
Targeting
the
homodimer
interface
highest
affinity
scaffolds,
hundreds
grandchildren
predicting
nanoMolar
affinities,
unique
high
specificities
and
low
toxicity
risks
Although
remaining
hypothetical
without
experimental
confirmation,
this
constitute
a
new
methodological
attempt
search
drug-like
interfere
SARS-COV-2-dependent
excessive
iScience,
Год журнала:
2024,
Номер
27(6), С. 109992 - 109992
Опубликована: Май 17, 2024
Highlights•Pre-COVID
memory
selectively
recognize
peptides
conserved
between
SARS-CoV-2
and
sCoV•Post-infection
responses
display
no
biases
toward
epitopes
or
proteins•The
CD4
T
cell
response
magnitude
to
is
host-specific
across
viral
proteinsSummaryThe
studies
reported
here
focus
on
the
impact
of
pre-existing
immunity
first
encounter
with
SARS-CoV-2.
They
leverage
PBMC
samples
from
plasma
donors
collected
after
a
infection,
prior
vaccine
availability
compared
emergence
Analysis
specificity
entire
proteome
revealed
that
recognition
SARS-CoV-2-derived
by
cells
pandemic
are
enriched
for
reactivity
non-structural
proteins
endemic
CoV
strains.
However,
primary
infection
structural
proteins.
We
observed
little
evidence
preferential
recall
seasonal
CoV,
finding
confirmed
through
use
curated
SARS-unique
peptides.
Our
data
suggest
elicited
primarily
established
naive
pool.Graphical
abstract
Viruses,
Год журнала:
2024,
Номер
16(7), С. 1008 - 1008
Опубликована: Июнь 22, 2024
SARS-CoV-2
is
a
highly
pathogenic
respiratory
virus
that
successfully
initiates
and
establishes
its
infection
at
the
mucosa.
However,
little
known
about
how
antagonizes
host’s
mucosal
immunity.
Recent
findings
have
shown
marked
reduction
in
expression
of
polymeric
Ig
receptor
(pIgR)
COVID-19
patients.
This
maintains
homeostasis
by
transporting
dimeric
IgA
(dIgA)
pentameric
IgM
(pIgM)
across
epithelial
cells
to
neutralize
invading
pathogens.
By
studying
interaction
between
pIgR
proteins,
we
discovered
viral
accessory
protein
Open
Reading
Frame
8
(ORF8)
potently
downregulates
this
downregulation
activity
ORF8
correlates
with
ability
interact
pIgR.
Importantly,
ORF8-mediated
diminishes
binding
dIgA
or
pIgM,
proteins
variants
concern
preserve
function
downregulating
pIgR,
indicating
importance
conserved
pathogenesis.
We
further
observed
secreted
binds
cell
surface
but
does
not
trigger
cellular
internalization
ORF8,
which
requires
These
suggest
role
immune
evasion.
ORF8
is
an
asymmetric-homodimer
SARS-COV-2
accessory
protein
implicated
in
excesive
human
inflammation
causing
numerous
deaths.
There
no
approved
drug
targeting
ORF8,
nor
it
known
whether
any
anti-ORF8
drugs
could
reduce
inflammation.
Computationally
combining
ligand
co-evolution
of
parent
molecules
with
affinity-consensus
docking,
children
candidates
for
docking
to
cavities
were
generated.
Targeting
the
homodimer
interface
highest
affinity
scaffolds,
hundreds
grandchildren
predicting
nanoMolar
affinities,
unique
high
specificities
and
low
toxicity
risks
Although
remaining
hypothetical
without
experimental
confirmation,
this
constitute
a
new
methodological
attempt
search
drug-like
interfere
SARS-COV-2-dependent
excessive
