GAVO program: A chemical library dedicated to nucleic acid constituents
Four French laboratories, including theInstitut des biomolécules Max Mousseron, have joined forces in the national Gavo program to create a library like no other... The aim: to synthesize a large number of nucleoside and nucleotide analogues in order to test their efficacy in the fight against RNA viruses, and more specifically against Sars-Cov-2, responsible for Covid-19.
" The current strategy for combating Sars-Cov-2 is through vaccination, and that's a very good thing, but not everyone has access to it. We must therefore continue the fight to treat and cure patients suffering from this disease ", says Jean-Jacques Vasseur, Deputy Director of theInstitut des biomolécules Max Mousseron (IBMM). At the heart of this battle are nucleosides and nucleotides. These constituents of nucleic acids, present in 50% of anti-viral drugs, are one of the major specialties of the chemists at IBMM's DACAN (Department of Nucleic Acid Analogues and Constituents). " We've been involved in this field for some forty years," adds the researcher.
"Generating original anti-virals
This recognized expertise has enabled DACAN and its two teams, ChemBioNAC and NuEP, headed by Michaël Smietana and Suzanne Peyrottes respectively, to join the Gavo program. Gavo stands for " Generation of original anti-virals ". This project brings together a consortium of French chemists around 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 granted an exceptional subsidy of 700,000 euros for the creation of this consortium, which brings together Jacques Lebreton's team in Nantes, theInstitut de Chimie Organique et Analytique (ICOA) in Orléans, the Laboratoire de Physique et Chimie Théoriques (LPCT) in Nancy and, of course, our two teams at IBMM".
Their common goal? To discover future nucleoside-based drugs to combat Sars-Cov-2 and RNA viruses in general, but not only. These compounds can also be tested against certain cancer targets," explains Michaël Smietana, head of the ChemBioNAC team. This research will provide us with a national chemical library dedicated to nucleic acids ", in other words, a bank of nucleosides modified to deceive the intimate mechanisms of viruses. Here's how it works.
Block viral replication
The RNA segments released by viruses to replicate within the infected cell are made up of a succession of nucleotides. By incorporating a nucleoside analogue - in other words, a modified nucleoside - into the RNA of the virus, we can block or slow down replication of the virus, and thus its propagation within the organism. This mechanism has already been used in the design of many antivirals, provided that the right nucleoside is available to match the characteristics of the targeted virus, since each uses its own specific enzymes to carry out the replication process.
It's the action of these enzymes, known as RNA polymerases, that Gavo's researchers are going to target by manufacturing original molecules. "It's not a question of making natural nucleosides, which nature knows how to do very well, but of modifying them in order to increase their efficacy and turn them into real drugs. There's a lot of strength in this field in France," points out Jean-Jacques Vasseur. Particularly at IBMM, where the work on nucleic acids and their components initiated by Professor Jean-Louis Imbach in the 1970s and 80s, covers the whole spectrum from nucleosides to oligonucleotides. For example, telvibuvine, a synthetic nucleoside, is a drug against hepatitis B marketed since 2007 by Novartis and co-discovered by Jean-Louis Imbach and Gilles Gosselin. The Montpellier-based Virocrib platform will also be involved in the program, testing these compounds on cells infested with Sars-Cov-2.
A consortium destined to last
Scheduled for an initial period of three years, this program will enable Montpellier teams to finance a post-doc for one year and a doctoral thesis starting next September or October. " They will join our team of four permanent researchers: Suzanne Peyrottes, Christophe Mathé, Michaël Smietana and myself. Of course, we'll be able to draw on the lab's infrastructure, equipment and even human resources," explains IBMM's deputy director. We hope that this consortium will continue over time, and even be extended to other teams at national level, ideally including industrial partnerships ".