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

We have vaccines, we have rapid diagnostic tests, there are already some treatments (combinations of drugs, anti-inflammatories, cytokine inhibitors, monoclonal antibodies). Antivirals were lacking. There were already many under study, specifically 264.
BIO Covid-19 Therapeutic Development Tracker.
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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 cellular machinery.
In reality, viruses are synthesized by the cell, using the cell replication system to make copies of its genome and the cell’s protein synthesis system to make its own. Therefore, the vast majority of the enzymes and mechanisms that the virus uses to multiply are from the cell. Therefore, 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 has consequences for the host of the virus as well.
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 intervene in its own multiplication and are essential for the virus to complete its cycle. If we know in detail what that virus cycle is like inside the cell, some drugs can be designed that specifically block viral replication without altering or damaging other cellular functions. And that’s what we’re still looking into.
These days two new antivirals against SARS-CoV-2 have been made public in press releases: molnupiravir and paxlovid. How do they work and where do they act against the virus?
Wikimedia Commons / Vega Alonso, CC BY-SA
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 genome of the virus. This antiviral was designed decades ago by Emory University (USA) and is being developed by the pharmaceutical company Merck (other names of this compound are EIDD-2801 and MK-4482). It had already been tested before when the 2009 flu pandemic.
Molnupiravir is the trade name for N4-hydroxycitidine (NHC), an analogue of the nucleoside cytidine, one of the components of RNA (in biology, one analogue 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, is joined with a ring of ribose sugar.
In the presence of N4-hydroxycytidine, during virus replication, the enzyme RNA polymerase 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 error correction system of the virus itself, so N4-hydroxycitidine analogues continue to be incorporated. Mutations accumulate and the virus enters a phase of lethal mutagenesis, and its multiplication is prevented. The virus replication cycle is blocked.
Molnupiravir is actually a prodrug, a substance that is administered inactive form and 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 RNA genome, such as Ebola, influenza (influenza), chikungunya and other coronaviruses. In 2020, the proof of concept against SARS-CoV-2 had been published in Nature: molnupiravir was able to inhibit the replication and transmission of the virus in ferrets.
Now, in a press release (we will have to wait for 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.
Several doses of molnupiravir were tested for 5 days administered orally. Half of the patients were in the control group, the placebo without medication. Of the group given molnupiravir, 7.3% required hospitalization (28 out of 385). Of the gruFor placebo, it was 14.1% (53 out 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 unethical 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 variants of concern and the side effects, at the moment, are mild or moderate.
Perhaps one of its problems is the price: it seems that the treatment will be around 600 euros. In addition, it has been seen to be effective if administered the first few 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. It will have to be studied further.
Paxlovid, an inhibitor of one of the viral proteases
The other antiviral that has applied for 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 proteases of SARS-CoV-2, the so-called 3CL.
During the replication of the virus, the cell synthesizes its proteins to the virus, in the form of polyproteins, which are then processed, cut by enzymes of the virus itself, the proteases 3CL and PL. These viral enzymes are essential to cut polyproteins into smaller proteins and thus be functional.
If we inhibit or block those proteases, the virus blocks it from replicating. Protease inhibitors are used to inhibit the replication of other viruses, such as HIV or the hepatitis C virus. In this case, the clinical trial involved 1,219 unvaccinated adults.
Treatment with paxlovid lasted 5 days and was combined with another protease inhibitor, ritonavir, which has been used against HIV. It was found that this way the effect of paxlovid was more durable. In patients treated with paxlovid and ritonavir, only 0.8% required hospitalization and none died. In the placebo group, 7% were hospitalized and ten 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 will not replace vaccines, but they do represent a new tool to control the pandemic and avoid hospitalizations, the most serious cases and deaths, if administered early.
They are the first that have been developed that are administered orally, which is an advantage. The monoclonal antibody-based therapies that are also being developed block the virus’ surface proteins and prevent it from entering cells, but they are very expensive treatments (they can reach €2,000 a dose) and are administered intravenously.
However, the price can be another obstacle in this case because the price of the treatment seems to be around 600 euros (Pfizer has announced that it renounces the patent of 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 appear.
We have vaccines, we have rapid diagnostic systems (PCR, antigen test), we have antivirals. All the science to fight this pandemic. We keep moving forward, let’s be optimistic.

A version of this article was published on the author’s blog, microBIO.

Ignacio López-Goñi, Professor of Microbiology, University of Navarra
This article was originally published on The Conversation. Read the original.

Original source in Spanish