GRAPHIC: V. ALTOUNIAN/SCIENCEscience.org SCIENCElighting it only for people at increased risk
of severe COVID-19.
Pfizer’s pill works differently, blocking
an enzyme central to SARS-CoV-2’s replica-
tion cycle (see graphic, below). Company
scientists designed a version of the com-
pound back in 2003 to inhibit a protease
in the coronavirus that causes severe acute
respiratory syndrome (SARS), a cousin of
SARS-CoV-2. But then the SARS outbreak
abated and Pfizer shelved the product. Last
year, the company discovered the compound
could stop SARS-CoV-2. An early version was
tested intravenously, and Pfizer subsequently
crafted an easier to deliver tablet.
The treatment also includes a decades-old
generic HIV drug called ritonavir that helps
stave off enzymes that break down the pro-
tease inhibitor. In the trial, patients took six
pills a day, two of Pfizer’s antiviral and one
ritonavir in the morning, and the same regi-
men at night.
Having more than one oral antiviral for
COVID-19 may preserve both drugs’ effec-
tiveness. Viruses often evolve resistance
to individual medications. But hitting
multiple molecular targets in SARS-CoV-
should make it harder for the pathogen to
escape. “Resistance is all a question of prob-
abilities,” says Celia Schiffer, a structural
biologist at the University of Massachusetts
Chan Medical School. When a virus is faced
with two different drugs, “it’s just much less
probable that there would be changes that
can evade both simultaneously.”
Other protease inhibitors for SARS-CoV-
are racing through clinical trials. “We need
multiple approaches,” says Mark Denison, a
virologist at Vanderbilt University. “I don’t
care what your drug is, coronaviruses are ca-
pable of developing resistance to it.”
Antiviral treatment also needs to be de-
livered fast, notes David Ho, a virologist
and longtime AIDS physician at Columbia
University—within the first week or less of
COVID-19 symptoms. After that, the disease
often enters “an inflammatory phase, where
antiviral intervention makes no difference,”
he points out. In parts of the United States
and some other countries, SARS-CoV-2 test-
ing remains spotty and results can take days
to come, which could delay treatment.
There’s concern, too, about whether oral
antivirals will be accessible to low- and
middle-income countries. Merck says its
5-day pill regimen will cost about $700 in
the United States, and Pfizer has suggested
its pricing will be similar. Both companies,
however, are pledging to make their anti-
virals affordable for countries unable to pay
that rate. Merck has granted a royalty-free
license to a nonprofit organization, allowing
for cheaper manufacturing and distribution,
and Pfizer has said it will charge many coun-
tries a lower, not-for-profit price.
Mitjà hailed both the Merck and Pfizer re-
sults, noting that in his adopted country of
Papua New Guinea, only 1% of the population
is fully vaccinated against COVID-19 and the
disease continues to wreak havoc. For now,
he’s just hoping the country can get these
new antivirals to its population, at a cost it
can afford. jViral RNA
Ribosomes
Polyprotein chainsSARS-CoV-Host cell membraneTranslation of
viral proteins
2ProteolysisViral proteinsMain protease3Transcription and
translation of structural
and accessory proteins5Assembly, packaging,
and release
61 Attachment and entrymolnupiravir (Merck)RNA replicationRdRpNSPReplication
transcription complex4Circulating RNAPF-
(Pfizer)Two drugs, two targets
As SARS-CoV-2 replicates, Pfizer’s pill inhibits a
viral protease that creates other proteins needed by
the virus. Merck’s compound introduces disruptive
mutations when the virus copies its genome.
800 12 NOVEMBER 2021 • VOL 374 ISSUE 6569A
s the world has learned to its cost,
the Delta variant of the pandemic
coronavirus is more than twice as
infectious as previous strains. But
just what drives Delta’s ability to
spread so rapidly hasn’t been clear.
Now, a new lab strategy that makes it pos-
sible to safely study the effects of mutations
in SARS-CoV-2 variants has delivered one
answer: a little-noticed mutation in Delta
that allows the virus to stuff more of its ge-
netic code into host cells, thus boosting the
chances that each infected cell will spread
the virus to another cell.
That discovery, published last week
in Science , is “a big deal,” says Michael
Summers, a structural biologist at the Uni-
versity of Maryland, Baltimore County—and
not just because it helps explain Delta’s rav-
ages. The new system, developed by Nobel
Prize winner Jennifer Doudna of the Uni-
versity of California (UC), Berkeley, and
colleagues, is a powerful tool for under-
standing SARS-CoV-2 variants and explor-
ing how future variants might affect the
pandemic, he says. “The system she has
developed allows you to look at any muta-
tion and its influence on key parts of viral
replication. ... That can now be studied in a
much easier way by a lot more scientists.”
Researchers analyzing how mutations
in the coronavirus’ genome affect its activ-
ity have concentrated on the spike protein,
which studs the virus’ surface and allows it
to invade human cells. That’s partly because,
short of deliberately mutating the virus and
testing it—research that requires high-level
biosafety facilities—the best tool for probing
individual mutations has been what’s called
a “pseudovirus,” a construct made from a dif-
ferent virus. But those constructs can only
express spike, not SARS-CoV-2’s other three
structural proteins.New tool points
to mutation
behind Delta’s
infectiousness
“Viruslike particles” open
the way to easier study of
viral mutations, proteins
COVID-By Meredith WadmanNEWS | IN DEPTH