Game Changer Paxlovid, First Oral Antiviral For Covid-19

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Game Changer? Paxlovid, First Oral Antiviral

For Covid-19

On December 22, 2021, the FDA granted Emergency Use Authorization (EUA)
for Pfizer's oral antiviral drug Paxlovid for the treatment of adults and pediatric
patients (12 years and older, weighing at least 40 kg or approximately 88
pounds) with mild to moderate novel coronavirus disease who test positive for
direct SARS-CoV-2 and are at high risk of developing severe COVID-19,
including hospitalization or death. The official press release states that this
is the first oral antiviral drug authorized to treat COVID-19.

Data supporting this emergency use authorization are primarily from a
randomized, double-blind, placebo-controlled clinical trial. The trial enrolled
adult patients with a confirmed positive COVID-19 diagnosis who had not yet
been hospitalized but were experiencing symptoms. None of these patients
had previously received the novel coronavirus vaccine and none had ever
been infected with COVID-19. The FDA press release noted that clinical
trial data showed that Paxlovid significantly reduced the risk of
hospitalization or all-cause mortality in patients. The proportion of
patients who experienced hospitalization or death was reduced by
approximately 88% in the Paxlovid group compared to the placebo
control group (0.8% in the treatment group and 6% in the placebo control
group). In addition, 9 patients in the placebo control group died compared to 0
in the treatment group. The safety and efficacy of Paxlovid for the treatment of
COVID-19 is currently undergoing further evaluation.

Paxlovid is a combination of Pfizer's investigational antiviral nirmatrelvir
(PF-07321332) and a low dose of ritonavir, an antiretroviral medication
traditionally used to treat HIV. Nirmatrelvir (PF-07321332) is a 3CL protease
inhibitor that disrupts the subsequent RNA replication process of the
SARS-CoV-2 by blocking the activity of the 3CL protease. Another component,

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ritonavir, allows nirmatrelvir to remain active in the body for a longer period of
time to better fight the virus.

Of the currently approved COVID-19 small molecule oral drugs, remdesivir act
on RNA-dependent RNA polymerase (RdRp) to prevent replication and

translation processes of the virus；while molnupiravir acts as a mutagenizing

agent that causes an 'error catastrophe' during viral replication.

In contrast, nirmatrelvir (PF-07321332), a SARS-CoV-2-3CL protease
inhibitor, has a slightly different mechanism of action than the previous two
drugs.

During translation, the viral RNA first synthesizes a precursor protein with a
large molecular weight, which is then processed and cleaved by a specialized
enzyme to produce a variety of mature proteins. The 3CL protease plays a key
role in this process. It is one of the key enzymes that cleaves the precursor
protein and is responsible for cutting and processing RNA in the virus' own
code.

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Theoretically, it is feasible to inhibit viral self-replication by blocking the activity
of the SARS-CoV-2 3CL protease, which prevents the protein precursor from
cleaving and forming mature virosomes.

So, what are the advantages of 3CL protease inhibitors?

First, it is highly effective. It was found that the 3CL protease has no less
than 11 protease cleavage sites on the large polyprotein 1ab, essential for the
maturation of polyprotein processing after translation from viral RNA.

Second, it is broad-spectrum. 3CL protease cleavage sites are highly
conserved in SARS-CoV-2, and natural mutations that are not drug-induced
mutations are unlikely to occur. To put it simply, the protease is similar for
different coronaviruses. One study found more than 50% similarity between
MERS virus and SARS virus, and more than 90% similarity between SARS
virus and novel coronaviruses. With multiple mutant types of novel
coronaviruses, the similarity is bound to be not too low. This also means that
the same 3CL protease is basically applicable to different novel coronaviruses.

In addition, it is highly safe. The low homology of the active central amino
acid to the human protease greatly reduces safety concerns.

From the above points, the 3CL protease inhibitor is highly competitive in the
treatment of COVID-19 infection, plus its X-ray complex structure has been
elucidated, enabling rapid drug discovery and structure optimization using
structural information. It is no wonder that some would say that it is expected to
be the GAME CHANGER of the COVID-19 epidemic.

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▶ CAS NO.67911-21-1 | Caronic anhydride

▶ CAS NO.194421-56-2 | 6,6-Dimethyl-3-Azabicyclo[3.1.0]hexane-2,4-dione

▶ CAS NO.565456-77-1 | (1R,2S,5S)-Methyl
6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride
▶ CAS NO.943516-54-9 | 6,6-Dimethyl-3-azabicyclo[3.1.0]hexane

References:
[1] Coronavirus (COVID-19) Update: FDA Authorizes First Oral Antiviral for
Treatment of COVID-19, Retrieved December 22, 2021,

Huateng Pharma https://us.huatengsci.com

from https://www.fda.gov/news-events/press-announcements/coronavirus-cov
id-19-update-fda-authorizes-first-oral-antiviral-treatment-covid-19
[2] Pfizer Receives U.S. FDA Emergency Use Authorization for Novel
COVID-19 Oral Antiviral Treatment, Retrieved December 22, 2021,
from https://www.businesswire.com/news/home/202112210
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