CNRS scientists have deciphered the activation process of bemnifosbuvir, prescribed to treat hepatitis C, which could be capable of defeating SARS-CoV-2.
- Bemnifosbuvir, used in the treatment of hepatitis C, requires “undergoing a series of modifications in infected cells to obtain the form that will allow it to inhibit the multiplication of the virus.”
- For this, the drug needs a minimum set of 5 different cellular enzymes.
- This discovery opens the way to a possible improvement in the drug’s effectiveness in other organs affected by the infection.
Bemnifosbuvir is an oral medication originally developed by the American company Altea Pharmaceuticals to treat hepatitis C. In February 2022, CNRS researchers had indicated that this treatment was a promising candidate for fighting SARS-CoV-2. “It acts as a viral RNA chain terminator, stopping the synthesis of viral genomes, and its chemical structure slows down the rate of its excision by the nsp14 site by about 5 times. It also blocks an essential activity located in the first domain of the polymerase, making the acquisition of viral resistance more difficult.” In plain language, the drug stops the replication of the virus responsible for Covid-19 by simultaneously targeting the RdRp and NiRAN active sites.
A series of modifications of bemnifosbuvir are dependent on five different enzymes
In a new study, published in the journal Plos Biologythe same scientists wanted to describe the activation process of bemnifosbuvir in order to increase its effectiveness against RNA viruses, including those responsible for Covid-19, influenza and dengue fever. Once ingested in pill form, the drug needs to “undergo a series of modifications in infected cells before obtaining the form that will allow it to inhibit the multiplication of the virus.” Through their observations, the team found that these transformations could not occur without five different enzymes. Using crystallography techniques, they were able to describe at the atomic level the three-dimensional structure of these enzymes and their areas of interaction with the treatment. The authors also identified the chemical motif of bemnifosbuvir responsible for its enhanced effectiveness in liver cells.
RNA viruses: towards more effective drug versions?
According to the scientists, these results will make it possible to improve control of the drug activation chain and to develop more effective versions against different RNA viruses. “It will also make it possible to accurately predict which families of viruses the drug will be active on and which antivirals it will be complementary to. Thanks to this new knowledge, researchers will also be able to restrict clinical trials to animal models that have the enzymes necessary for activating this type of drug.”