how new antivirals fight SARS-CoV-2 infection

By Gary Dagorn

Posted today at 2:00 p.m., updated at 3:08 p.m.

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DecryptionsAlong with Paxlovid, from Pfizer, authorized on January 21 by the HAS, several types of antivirals are being developed to treat symptomatic Covid-19. Here’s how they work.

Friday January 21, the High Authority for Health (HAS) gave the green light to the marketing of Paxlovid, from Pfizer, the first treatment once morest the coronavirus which should be available outside a hospital environment for people at risk suffering from Covid-19. 19 symptomatic.

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This is a first in the history of the pandemic, since, since January 2020, the only known way to fight the disease is to treat the most serious symptoms in hospital: we try to regulate the the body’s immune response and to breathe oxygen into the lungs, which are attacked by both the virus and the inflammation. Until recent months, no drug had shown antiviral efficacy once morest the virus. This momentary failure hardly surprised the scientific community, which knows full well that it is much more difficult to target and fight a virus than a bacterium.

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But in recent months, several antiviral molecules have shown clear activity once morest SARS-CoV-2, and raise real hopes of treating symptomatic cases of Covid-19 more easily and in greater numbers.

Here we have tried to explain how these drugs work inside cells.

Protease inhibitors

Example : Paxlovid, developed by Pfizer; pasitinib tested by AB Science. Novartis also says it is working on a protease inhibitor once morest all human coronaviruses.

This is a fairly well-known and long-used type of antiviral treatment. The principle is to prevent the virus from replicating, and therefore from infecting more cells. For this, the drug will target and neutralize a crucial viral protein for the coronavirus: its protease. Let’s see how it works in practice:

Step 1

When Sars-CoV-2 infects a human cell, it fuses its outer membrane with that of the cell: the contents of the virus, its RNA, is then released inside the cell.

2nd step

The first action of the virus will be to have one of its genes, ORF1ab, translated by ribosomes, the cell’s “factories” that allow genes to be translated into proteins.

Step 3

By “reading” the ORF1ab gene, the ribosomes make a large chain of proteins called Pp1ab: these are actually several proteins stuck together, but as long as they are “welded” these proteins cannot do their job, they are inactive.

Step 4

In this chain, one of the proteins stuck together, the protease, activates and releases itself. Its role is then to “extricate” the proteins present in the chain by cutting it so that each can play its role: replicating the virus genome, making new virions and neutralizing the cell’s immune defences.

Step 5

This is where the protease inhibitor comes into play: when the protease is “released”, the drug will attach itself to it and prevent it from continuing its work; the virus proteins are not cut, they remain inactive.

Step 6

From then on, Sars-CoV-2 can no longer make copies of its genome or of itself: the virus population drops and the infection dies out.

Mutagenic ribonucleotides

Example : Molnupiravir, developed by Ridgeback Therapeutics, with help from Merck.

This type of antiviral is a little more complex. Its strategy is similar to that of protease inhibitors, since it attacks the replication of the virus, but in a different way: instead of strictly preventing it, it inserts errors in the copy of the virus genome to make dysfunctional viruses, and therefore inoperative. Let’s see how it works:

Step 1

When the virus begins its replication, it uses the ribosomes of its host cell to make them produce the famous chain of proteins, as we have already seen. This is then “cut” by the protease, and the multitude of proteins produced begin to “work”.

2nd step

Part of these proteins will assemble to form a system capable of reading the rest of the RNA and duplicating it. It is called the replicase-transcriptase complex.

Step 3

This is where the drug comes into play. This will “integrate” the replication machine and will scramble the copy of the RNA: it will introduce into it information that can be interpreted in two different ways instead of just one. This ambiguity then causes “copy errors” and therefore mutations.

Step 4

These serial mutations, by producing dysfunctional copies of the virus, will be lethal for it: badly copied, it will become incapable of replicating itself, or quite simply of penetrating human cells. It then loses its pathogenic power, and ends up disappearing, engulfed by the immune defenses of the human body.

Monoclonal antibodies

Example : Sotrovimab, developed by GSK; REGN-COV2, developed by Regeneron Pharmaceuticals and Roche; Bamlanivimab, developed by AbCellera Biologics and Eli Lilly.

Although not strictly speaking an antiviral, monoclonal antibodies can be effective once morest certain viruses. Used since the mid-1980s as anticancer drugs or once morest certain autoimmune diseases, these antibodies are produced in series in the laboratory using modified B lymphocytes and are called “monoclonal” because they only recognize a single antigen, a single target, which was previously chosen by the researchers. In this case, these monoclonal antibodies are designed to recognize the tip of the surface protein of SARS-CoV-2, the one that comes into contact with human cells to allow it to infect them. Demonstration:

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