There are few effective weapons against the coronavirus. So far, only vaccines have been proven to counter SARS-CoV-2, the virus responsible for Covid-19. An injection to be made upstream in order to be able to defend against the virus when the body meets it. Alongside vaccine research, some laboratories have embarked on the track of antiviral drugs, treatments to be taken after the first symptoms.
Molnupiravir disrupts the replication cycle of a virus
This is the case with Merck MSD which develops Molnupiravir, also known as MK-4482 / EIDD-2801. This medicine is a broad spectrum anti-viral, that is, it works on several types of viruses. It was first developed against the flu. When a virus enters a cell, it releases its RNA (ribo-nucleic acid, that is to say its genome, editor’s note) to produce new virus particles capable of infecting other cells in the body. To counter this effect, antivirals are able to disrupt the replication cycle of a virus, which slows its progression in the body and stops the spread of infection.
For this, Molnupiravir will slip a “false nucleotide“among those that make up RNA. This synthetic nucleotide (also called a”similar“) is called N4-hydroxycytidine.”This synthetic nucleotide will be integrated into the viral RNA at the time of its replication and will take the place of one of the ‘natural’ nucleotides of the virus. It will therefore be taken over by the polymerase (the enzyme in charge of synthesizing RNA, editor’s note) which confuses it with a natural nucleotide. Once incorporated, the polymerase continues to synthesize RNA with a nucleotide that is not natural. In the next round of replication, this results in mutations in the genome“, explains to Science and the Future Etienne Decroly, molecular virologist at the CNRS.
These mutations then kill the virus, which is, de facto, stopped. “The effectiveness of such a treatment depends on the effectiveness of the analog to be incorporated but also on that of the exonuclease, an enzyme which makes it possible to correct errors and which could flush out the synthetic nucleotide. If the polymerase, responsible for synthesizing RNA, is rapid and incorporates the synthetic nucleotide well, then mutations take place. But if it is too slow, then the exonuclease can come into play and come to excise the synthetic nucleotide.. “So it’s a real speed competition that is being played out.
Molnupiravir is in phase III
Good news, after the first conclusive tests, the research has just entered a phase III, with 1,500 patients according to The echoes. The two phase II trials showed that Molnupiravir effectively prevented the virus from replicating. Three dosages were tested in patients, part of which came from different French hospitals. The effect was more marked when the molecule was administered at the highest dosage within five days of the onset of the first symptoms. The molecule has therefore been shown to be more effective at the start of infection, when the viral load has not yet overwhelmed the immune system. The trial was then stopped in hospitalized people, whose condition is more serious, and only continued in patients “in the city. “
Monulpiravir is administered in the form of tablets to be taken twice a day for five days and not as an infusion like Remdesivir, repositioned him from Ebola disease, which worked with the same mechanism of DNA disruption. However, the latter is no longer recommended today. The results of the phase III clinical trial will be known in September or October and if they were to prove conclusive, Merck MSD could then consider marketing towards the end of 2021.
Two molecules in development at Pfizer
Very few laboratories have succeeded in developing interesting antiviral molecules in the fight against Covid-19. Along with Molnupiravir, Merck MDS had to give up another molecule, MK 7110, a recombinant inflammation modulator protein. After encouraging results in phase III, the American drug regulatory authority, the Food and Drug administration (FDA) had requested additional data from the laboratory. Faced with technical and regulatory uncertainties, Merck MDS preferred to abandon this option.
At the same time, other laboratories have indicated that they are working on the development of an antiviral. Pfizer’s France director, David Lepoittevin, revealed that the industrialist was developing two drugs against Covid-19 in an interview with Le Parisien. Two antivirals, one oral, the other given intravenously, and both “still at a very early stage in their development”. However, “The encouraging in vitro results of the oral form have decided us to quickly launch a clinical study on healthy adults to assess the dose and tolerance of this drug. The first results could arrive soon. The intravenous antiviral candidate is also doing it. the subject of a clinical trial in participants with Covid-19 and hospitalized “, explains David Lepoittevin. According to him, the results of these tests should soon be known.
A suppository developed by the Institut Pasteur de Lille
In France too, research on antivirals has proved fruitful. The Institut Pasteur de Lille worked on clofoctol, a molecule already used to treat nasopharyngitis. The antiviral has so far only been tested on animals. But on the mouse, the results are convincing, since the replication seems to be stopped by the molecule. The Institute has just obtained the label “National research priority“The National Medicines Safety Agency (ANSM) must now decide on an authorization to conduct trials on humans.”If all goes well, I hope that we can start the trials by the end of April or at the very beginning of May: we should know if the drug works or not against Covid-19 in humans , during the summer“enthuses Xavier Nassif, Director General of the Institut Pasteur de Lille in Capital. If the ANSM and the ethics committee give their approval, the Institut Pasteur de Lille will be able to conduct a double-blind randomized trial: one group of patients will receive the drug, which is in the form of a suppository and the other group a placebo, 600 to 700 volunteers are sought in Hauts-de-France.