A Race For Better 3CL Inhibitors to Cure COVID-19: Copies vs. Innovators

Developed by Pfizer, Paxlovid™ is the latest COVID-19 treatment making headlines. In December, the Food and Drug Administration (FDA) granted Paxlovid™ an emergency use authorization for certain adults and pediatric patients at high risk for severe disease, after clinical trial results demonstrating 89% reduction in the risk of hospitalization and death for patients with certain risk factors. Paxlovid is also cheaper than many other COVID-19 drugs, and it is expected to work against the Omicron variant. 

Paxlovid™ is an antiviral therapy consisting of two different generic medications packaged together to offer a three-pill dose. Two of the pills are nirmatrelvir, the inhibitor of 3C-like protease, a key enzyme that is required in order for the coronavirus to make functional virus particles. Nirmatrelvir disrupts the ability of SARS-CoV-2 virus, released from the infected cells, to enter uninfected cells in the body, thereby stopping the infection. The third pill is ritonavir, a drug that was once used to treat HIV/AIDS, but is serving as a “booster” in the composition of Paxlovid™. The role of ritonavir is to shut down nirmatrelvir’s metabolism in the liver, so that it doesn’t get removed from the body too quickly -- before the therapeutic effect is achieved. 

While Paxlovid is not the only pill available to treat COVID-19 -- for example, the FDA also granted an emergency authorization to molnupiravir (Lagevrio) developed by Merck -- it is currently the most efficacious. Molnupiravir, for instance, has only a 30% reduction in the risk for hospitalization and death from COVID-19. Orally prescribed Paxlovid is also more convenient compared to another well-known COVID-19 drug, remdesivir, which is administered by intravenous injection.

With all the apparent benefits, Paxlovid is still not a perfect remedy against the COVID-19 pandemic. After Paxlovid entered markets in late 2021, researchers noticed a puzzling trend. In some people taking the drug and getting cured rapidly, symptoms and detectable virus reappeared days later -- as was the case with President Joe Biden. The strange phenomenon, dubbed ‘Paxlovid rebound’, was found to be surprisingly common in people who take Paxlovid as a treatment. According to one study, more than one-quarter of the Paxlovid recipients rebounded, based on levels of SARS-CoV-2, compared with just one of the 25 untreated people. Moreover, people with Paxlovid rebound had high levels of virus for several days, as if they had new acute infections. 

Another unpleasant issue with Paxlovid is the so-called ‘Paxlovid mouth’. About 5.6% of people who took Paxlovid to treat COVID-19 infection reported dysgeusia, which is a change in the taste in one's mouth. Some people reported a bitter or metallic taste shortly after taking their first set of pills, while others reported much worse taste characteristics. The reason for “Paxlovid mouth” is likely ritonavir, a part of the drug that is used to boost levels of antiviral medicines. Ritonavir has a known association with dysgeusia. Fortunately, the bad taste goes away upon discontinuation of the treatment. Considering the benefits Paxlovid provides, this side effect seems to be an acceptable trade-off, but its absence would have made the whole treatment approach a more pleasant one. 

Finally, there is an increasing concern about resistance mutations in SARS-CoV-2’s protease with a potential to render Paxlovid less efficient/inefficient, and some circulating variants of the coronavirus already have them. 

Yet, Paxlovid so far remains the lead treatment for COVID-19 and the mechanism on which it works – inhibiting the 3CL Protease – remains one of the most promising avenues of treatment for COVID-19 and related variants.   

The Promise of 3CL Protease Inhibitors

Similar to other coronaviruses, the SARS-CoV-2 RNA genome encodes four major structural proteins: spike (S), nucleocapsid (N), membrane (M), and envelope (E). In addition, the virus genome encodes sixteen non-structural proteins required during various steps of the virus replication cycle. These proteins interact with the host cellular machinery of our body, utilizing it for replication to keep infecting more cells. In theory, any SARS-CoV-2 encoded protein may represent a . However, a lot of practical efforts were directed towards targeting 3CL protease (3CLpro, also known as main protease), one of the non-structural coronavirus proteins. Because of its essential role in processing the polyproteins that are translated from the viral RNA and essential for viral replication, and absence of human homologue, 3CLpro is for antiviral drug discovery. The inhibitors of 3CLpro are also most likely less toxic to cells of our body.