The work of Aurélie Chazot and her collaborators is highlighted by CNRS Biologie and relayed by the press, congratulations!
Covid-19 and hepatitis C: a key discovery for effective drug treatments
Scientists have deciphered the activation pathway of bemnifosbuvir, a drug candidate initially in development to treat hepatitis C virus (HCV). The findings of the research team, led by CNRS scientists, unlock new opportunities to boost the efficacy of this type of drug against other RNA viruses, such as the ones that cause Covid-19 and dengue fever.
When taken in pill form, bemnifosbuvir – like all antivirals in the same family – must undergo a series of changes inside infected cells before it acquires the form needed to prevent a virus from multiplying4 . Scientists have discovered that five different enzymes drive this series of changes. They used X-ray crystallization techniques to study the three-dimensional structure of these enzymes and their surfaces interacting with the drug. Scientists also converged to the chemical parts in bemnifosbuvir behind its enhanced efficacy in liver cells. This discovery is a step towards improving the drug potency in other infected organs, such as the lungs in the case of Covid-19.
The findings, published in PLOS Biology on August 27, are expected to expand control over the nucleotide analogue activation pathway and encourage the development of novel compounds expanding effectiveness against other RNA viruses. Similarly, it will facilitate accurate prediction of which cell-type activate which antiviral drug candidate. Scientists can also use this new knowledge to limit clinical trials to animal models that in fact have the enzymes needed to activate this type of drug.
The bemnifosbuvir molecule, here being activated in its “AT-8003” form (enlargement in the right box), is represented in colored sticks. Here it interacts with the human enzyme “HINT1”, responsible for increased effectiveness of the drug in the liver.
© François Ferron, Bruno Canard et al., PLOS Biology
Bibliography
The activation cascade of the broad-spectrum antiviral bemnifosbuvir characterized at atomic resolution. Aurélie Chazot, Claire Zimberger, Mikael Feracci, Adel Moussa, Steven Good, Jean-Pierre Sommadossi, Karine Alvarez, François Ferron and Bruno Canard. PLOS Biology, 27 August 2024.
DOI : https://doi.org/10.1371/journal.pbio.3002743
Contact
Bruno Canard
CNRS Researcher
François Ferron
CNRS Researcher
Aurélie Meilhon
CNRS Press Officer
Published on August 30, 2024
