Why masitinib could be the ‘silver bullet’ as a treatment for Covid

The news is promising and has just appeared in the prestigious magazine Science: American researchers, from a library of nearly 2,000 antiviral drugs, have selected the best candidates against Covid and have found one on which they are now optimistic, since it generated a > 99% reduction in viral load in mice. His name is masitinib.

While we are talking about preclinical phase -that is to say that it was manufactured on animals-, masitinib is already tested in humans as part of another investigation conducted in a hospital in France. We will come back to this point at the end of these lines.

Returning to the Science article (“Masitinib is a broad inhibitor of coronavirus 3CL that blocks the replication of SARS-CoV-2“, Or” Masitinib is a broad 3CL inhibitor of the coronavirus, which blocks SARS-CoV-2 replication “), is the result of scientists at the Universities of Chicago and Duke.

The work promises not only because it has confirmed a decrease in viral titers of mice up to 200 times, but because it has proven that the action to achieve this reduction can go beyond the peculiarities of the Covid variants. In other words, he would go down a different path.

What does masitinib do in its interaction with the coronavirus? It inhibits one of the enzymes of SARS, crucial for its replication: viral protease.

“This protease inhibition is the target of action of the drug. It’s called ‘protease’ because it kind of ‘cuts’ large proteins into smaller pieces,” explained the biochemist. Jorge quarleri, “Virologist” Principal Investigator of Conicet at the Institute for Biomedical Research on Retroviruses and AIDS (INBIRS).

And, true to his area of ​​expertise, Quarleri explained that “the therapy against HIV used today uses drugs that also inhibit the protease of this virus.”

From “in vitro” to “in vivo”

The document states that in addition to the reduction in viral titers, “there has been a reduction of lung inflammation”. As would be expected for a drug of this type, the authors suggest, towards the end of the article, that the action of the drug could be all the more beneficial when it is administered early.

Moreover, it is made by orally, and positive results were observed after 6 days of medication, with a dose similar to what a human would have received.

“It is clear that the utility they offer is for the acute stage of the disease “, clarified Quarleri and, still in the hypothetical plan, underlined that a possible schedule of administration could be” after the appearance of the first symptoms by the Covid or, perhaps, after having confirmed having been in close contact with a positive case ”.

In a context where the highly contagious Delta variant is progressing by leaps and bounds, generating new waves of infected, it should be noted that, in the “in vitro” phase of the trial, the scientists tested the effectiveness of the drug. against the Alpha (“ex” UK), Beta (ex South Africa) and Gamma (ex Manaus) variants.

However, Quarleri said: “protease cannot be allowed to change or mutate too much because that would make him lose the capacity to exercise his function. For this reason, viral proteases are generally a desirable target of action ”.

Of course, no matter how promising the drug is, it cannot be guaranteed that a new variant will develop “natural resistance” to the action of masitinib. In Quarleri’s words, “it remains to be seen whether the well-defined viral protease binding site of masitinib shows changes between variants.”

One by one

The “weeding” work done by these researchers is remarkable. “We looked at a library of 1,900 drugs clinically safe against OC43, a human beta-coronavirus that causes colds, and we are evaluating the main successes against SARS-CoV-2, ”they introduce in the document.

Among these, they selected “20 drugs which significantly inhibited the replication of both viruses in human cells in culture ”.

There were then 8 left, which had inhibited the activity of the main protease SARS-CoV-2 (3CLpro). And of those 8, “the most potent (according to them) was masitinib, an orally bioavailable tyrosine kinase inhibitor.”

The mouse test was done 12 hours after infection. We can assume that more “realistic” deadlines will be considered in the clinical phase, given that the onset of symptoms due to Covid can take days.

For those who are detail-minded, here is more clarification from Quarleri: “The target of action of masitinib is the so-called ‘major protease’ (and not another miner who also has an important role in replication) of the virus. This enzyme is responsible for cut a protein that the virus synthesizes during its replication within the cell.

Why are you cutting it? Because it is “like a ‘barbecued sausage’, impossible to digest. It cuts it into small proteins, which will be functional and allow the cycle of replication to continue to advance.”

Doubts and effects

Apart from the antiviral and anti-inflammatory evidence confirmed by the Science article, masitinib has been tested in humans with Covid and other pathologies, in France.

About a month ago, in fact, we learned that the AB Science laboratory, which had carried out several studies in humans with masitinib and had had to suspend them due to the detection of a potential risk of ischemic heart disease (recurrent chest pain or discomfort), finally managed to resume rehearsals, against the commitment to apply a series of security measures that have been accepted by the ANSM, mainly the French ANMAT.

These trials (now resumed without, for example, patients with a history of cardiovascular disease) include the study mentioned at the beginning of these lines, which they are conducting with people hospitalized for severe Covid (phase 2), a study in people with amyotrophic lateral sclerosis (ALS), in phase 3, and one, also in phase 3, in adults with a rare immune disorder called ‘mastocytosis’.

However, explained Quarleri, “although the authors of the Science article cite the French clinical study, they rule out that the action of the drug is due to the basis on which it is used by the French, who also combine the drug with another drug. “

Anyway, he concluded, “the French study, perhaps by ‘carambole’, will give useful information to know the action of masitinib, already in clinical phase”. The article, according to the virologist, “is an interesting first”.

PS