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Hitting the virus where it hurts most: the two new antivirals against SARS-CoV-2

We have vaccines, we have rapid diagnostic tests, there are already some treatments (drug combinations, anti-inflammatories, cytokine inhibitors, monoclonal antibodies). Antivirals were missing. There were already many under study, specifically 264.

Finding an effective drug against a virus is not easy , or at least not as easy as developing an antibiotic. Unlike bacteria, all viruses are obligate intracellular parasites, pirates of cells. They always multiply inside, using the cellular machinery.

In reality, viruses are synthesized by the cell, using the cell’s replication system to make copies of its genome and the cell’s protein synthesis system to make their own. Therefore, the vast majority of the enzymes and mechanisms that the virus uses to multiply are from the cell . For this reason, finding a drug that blocks the multiplication of the virus is very difficult: many of them have side effects, because they also affect the cellular machinery. You can block the multiplication of the virus, but you can also damage a cellular function. And that also has consequences for the host of the virus.

However, in the biological cycle of the virus within the cell there is also some step or stage that depends directly on enzymes or proteins of the virus. By reading the genes of the virus, the cell synthesizes its proteins and some of them are involved in its own multiplication and are essential for the virus to complete its cycle. If we know in detail what this cycle of the virus is like inside the cell, some drugs can be designed that specifically block viral replication without altering or damaging other cellular functions. And that is what is being investigated.

These days, two new antivirals against SARS-CoV-2 have been made public in separate press releases: molnupiravir and paxlovid. How do they work and where do they work against the virus?

Molnupiravir, a viral RNA polymerase inhibitor

Molnupiravir is an inhibitor of one of those viral enzymes essential for replication, the viral RNA polymerase that copies the virus genome. This antiviral was designed decades ago by Emory University (USA) and is being developed by the pharmaceutical company Merck (other names for this compound are EIDD-2801 and MK-4482). It had already been tested before when the 2009 flu pandemic.

Molnupiravir is the brand name for N4-hydroxycytidine (NHC), an analog of the nucleoside cytidine, one of the components of RNA (in biology, an analog is a compound that has the same function as another). Cytidine is formed when cytosine, one of the five nitrogenous bases that are part of nucleic acids, binds with a ribose sugar ring.

In the presence of N4-hydroxycytidine, during virus replication, the RNA polymerase enzyme incorporates this compound instead of cytidine. This ultimately means introducing a change, a mutation in the new copy of viral RNA. This mutation is not recognized by the virus’s own error correction system, which is why the N4-hydroxycytidine analogs continue to be incorporated. Mutations accumulate and the virus enters a phase of lethal mutagenesis, and its multiplication is prevented. The replication cycle of the virus is blocked.

Molnupiravir is actually a prodrug, a substance that is administered in an inactive form and is metabolized in vivo, within the body, where it is transformed into the active drug.

Its activity had been tested in vitro, in the laboratory, to inhibit the multiplication of other viruses with an RNA genome, such as Ebola, influenza (flu), chikungunya and other coronaviruses. In 2020, the proof of concept against SARS-CoV-2 was published in Nature: molnupiravir was capable of inhibiting the replication and transmission of the virus in ferrets.

Now, in a press release (we will have to wait for the scientific publication), the results of a phase III clinical trial (called MoVe-OUT) have been made public. It has been tested in 700 patients from 17 countries, all adults with COVID-19, unvaccinated, high-risk and not hospitalized.

Various doses of molnupiravir were tested over 5 days given orally. Half of the patients were the control group, the placebo without medication. Of the group administered molnupiravir, 7.3% required hospitalization (28 of 385). Of the placebo group, it was 14.1% (53 of 377). This is 50% effective in reducing hospitalization and death from covid-19 .

For ethical reasons (with such a percentage of efficacy it is not ethical to continue with the placebo group) the trial has been stopped and authorization has already been requested from the regulatory agencies, for its emergency use.

The results also show that the drug is effective against the variants of concern and the side effects, for the moment, are mild or moderate .

Perhaps one of your problems is the price: it seems that the treatment will be around 600 euros . In addition, it has been shown to be effective if administered in the first days of infection , which will require early diagnosis.

Its possible cytotoxic effect (toxic to our own cells) has also been questioned, but it seems that this depends on the half-life of the compound within our organism. We will have to continue studying it.

Paxlovid, an inhibitor of one of the viral proteases

The other antiviral that has requested authorization is paxlovid, from the pharmaceutical company Pfizer. This drug had already been tested years ago against SARS, intravenously. In this case, it is an inhibitor of one of the SARS-CoV-2 proteases, called 3CL.

During the replication of the virus, the cell synthesizes the virus its proteins, in the form of polyproteins, which are then processed, cut by enzymes of the virus itself, the 3CL and PL proteases. These viral enzymes are essential to cut polyproteins into smaller proteins so that they are functional.

If we inhibit or block these proteases, the virus blocks their replication. Protease inhibitors are used to inhibit the replication of other viruses, such as HIV or hepatitis C virus. In this case, 1,219 unvaccinated adults participated in the clinical trial.

Treatment with paxlovid lasted 5 days and was combined with another protease inhibitor, ritonavir, which has been used against HIV. The effect of paxlovid was thus found to be longer lasting. In patients treated with paxlovid and ritonavir, only 0.8% required hospitalization and none died. In the placebo group, 7% were hospitalized and 10 died.

This is 89% effective in reducing hospitalization and death . Paxlovid was also effective against different variants of concern.

One more tool against the pandemic

These antivirals are not going to replace vaccines , but they do represent a new tool to control the pandemic and avoid hospitalizations, the most serious cases and deaths, if they are administered early.

They are the first to be developed that are administered orally, which is an advantage. The monoclonal antibody-based therapies that are also being developed block the surface proteins of the virus and prevent it from entering cells, but they are very expensive treatments (can reach 2,000 euros per dose) and are administered intravenously.

However, the price can be another obstacle in this case because the price of the treatment appears to be around 600 euros (Pfizer has announced that it is giving up the patent on its drug so that it can be produced at low cost).

We will have to wait for scientific publications, we will have to see what possible side effects they may have when the number of people in the trials increases and if new resistance of the virus to these antivirals, new variants or mutants capable of escaping these inhibitors appears.

We have vaccines, we have rapid diagnostic systems (PCR, antigen tests), we have antivirals. All the science to fight this pandemic. We keep moving forward, let’s be optimistic.

Ignacio López-Goñi, Professor of Microbiology, University of Navarra.

This article was originally published on The Conversation. Read the original.

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