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, 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.
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, from https://www.fda.gov/news-events/press-announcements/coronavirus-covid-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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