Molnupiravir Works by Inducing Mutations in SARS-CoV-2

Researchers have shown that the antiviral drug molnupiravir, currently in clinical trials as a COVID treatment, works by inducing mutations in SARS-CoV-2 which prevent the coronavirus from replicating further.

Since the onset of the corona pandemic, researchers have been developing various vaccines and drugs to varying degrees of success. Previous studies have shown why the antiviral drug remdesivir, the first one approved against COVID, has a rather weak effect on the virus. “Remdesivir does interfere with the [viral] polymerase while doing its work, but only after some delay. And the drug does not fully stop the enzyme,” said Max Planck Director Patrick Cramer. 

Molnupiravir was originally developed to treat influenza and in preliminary clinical trials, the compound is promising against SARS-CoV-2. “Knowing that a new drug is working is important and good. However, it is equally important to understand how molnupiravir works at the molecular level in order to gain insights for further antiviral development,” explained Cramer. “According to our results, Molnupiravir acts in two phases.”

Induced RNA mutations halt replication
Molnupiravir, an orally available drug, becomes activated through metabolisation in the body. When it enters the cell, it is converted into RNA-like building blocks. In the first phase, viral RNA polymerase incorporates the building blocks into the virus’ own RNA. However, unlike remdesivir, which merely slows the viral RNA polymerase, molnupiravir does not interfere with its copying functions. Instead, in the second phase, the RNA-like building blocks connect with the building blocks of the viral genetic material. “When the viral RNA then gets replicated to produce new viruses, it contains numerous errors, so-called mutations. As a result, the pathogen can no longer reproduce,” explained Florian Kabinger, a doctoral student in Cramer’s department.
Molnupiravir also appears to do this for other viruses “The compound could potentially be used to treat a whole spectrum of viral diseases,” said Höbartner, a professor of chemistry at the University of Würzburg. “Molnupiravir has a lot of potential.” 
Currently, molnupiravir is in phase III studies, where it is being tested on a large number of patients and is being evaluated for safety. The US government has already secured 1.7 million doses, at a cost of US$1 billion. However, working out at a cost of nearly US$600 per dose, it will not be cheap.

The researchers published their findings in Nature Structural & Molecular Biology.

Source: Max Planck Institute

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