GAVO Program: A chemical library dedicated to nucleic acid components
Four French laboratories, includingthe Max Mousseron Biomolecules Institute, are joining forces in the national Gavo program to create a library unlike any other... The goal: to synthesize a large number of nucleoside and nucleotide analogues in order to test their effectiveness in combating RNA viruses, particularly SARS-CoV-2, the virus responsible for COVID-19.
"The current strategy for combating SARS-CoV-2 involves vaccination, which is a very good thing, but not everyone has access to vaccination. We must therefore continue the fight to treat and cure patients with this disease," begins Jean-Jacques Vasseur, deputy director ofthe Max Mousseron Biomolecules Institute (IBMM). At the heart of this fight are nucleosides and nucleotides. These nucleic acid components, found in 50% of antiviral drugs, are one of the main specialties of chemists at DACAN, the Department of Nucleic Acid Analogs and Components at IBMM. "We have been involved in this field for around 40 years," adds the researcher.
"Generation of original antivirals"
This recognized expertise has enabled DACAN and its two teams, ChemBioNAC and NuEP, led by Michaël Smietana and Suzanne Peyrottes respectively, to join the Gavo program. Gavo stands for "Generation of original antivirals." This project brings together a French consortium of chemists led by Jacques Lebreton, a researcher at the Ceisam laboratory in Nantes. "He contacted us following a discussion with Jacques Maddaluno, director of theCNRS Institute of Chemistry. In the context of Covid, the latter has awarded an exceptional grant of €700,000 for the creation of this consortium, which brings together Jacques Lebreton's team in Nantes,the Institute of Organic and Analytical Chemistry (ICOA) in Orléans, the Laboratory of Theoretical Physics and Chemistry (LPCT) in Nancy and, of course, our two teams at the IBMM."
Their shared goal? To discover future nucleoside-based drugs to combat SARS-CoV-2 and RNA viruses in general, but not only that. "These compounds can also be tested against certain cancer targets," explains Michaël Smietana, head of the ChemBioNAC team. "This research will enable us to build a national chemical library dedicated to nucleic acids," in other words, a bank of modified nucleosides designed to trick the inner workings of viruses. Here's how it works.
Block viral replication
The RNA segments released by viruses to replicate within the infected cell consist of a sequence of nucleotides. By incorporating a nucleoside analog, or modified nucleoside, into the virus's RNA, it is possible to block or slow down the virus's replication and thus its spread within the body. This mechanism has already been used in the design of many antiviral drugs, provided that the right nucleoside adapted to the characteristics of the targeted virus is available, as each virus uses specific enzymes to carry out its replication process.
It is the action of these enzymes, called RNA polymerases, that Gavo researchers will attempt to target by creating original molecules. "It's not a question of making natural nucleosides, nature knows how to do that very well, but of modifying them to increase their effectiveness and turn them into real drugs. There is a lot of strength in this field in France," points out Jean-Jacques Vasseur. This is particularly true at the IBMM, where research into nucleic acids and their components, initiated by Professor Jean-Louis Imbach in the 1970s and 1980s, covers the entire spectrum of nucleoside chemistry, from nucleosides to oligonucleotides. For example, telvibuvine, a synthetic nucleoside, is a drug for hepatitis B marketed since 2007 by Novartis and co-discovered by Jean-Louis Imbach and Gilles Gosselin. The Montpellier-based Virocrib platform will also participate in the program by testing these compounds on cells infected with SARS-CoV-2.
A consortium dedicated to lasting success
Scheduled to run for an initial period of three years, this program will enable the Montpellier teams to fund a one-year postdoctoral fellowship and a doctoral thesis, which will begin in September or October. "They will join our team of four permanent researchers: Suzanne Peyrottes, Christophe Mathé, Michaël Smietana, and myself. We will ,of course ,be able to draw on the lab's infrastructure, equipment, and even its human resources," explains the deputy director of the IBMM. We hope that this consortium will continue over time and even be extended to other teams at the national level, ideally including industrial partnerships."