Screening, identification and characterization of antivirals against Respiratory virus

The COVID-19 crisis has exposed our lack of preparedness to respond quickly to emerging infections with high pandemic potential. The development of vaccines and therapeutic antibodies has reduced the dramatic consequences of the COVID-19 pandemic. However, we cannot anticipate when and which other (respiratory) virus will emerge in the future. Developing effective therapies takes time. Having access to immediately available antivirals during the initial phase of an epidemic will be instrumental in controlling the spread of a new emerging virus and thus reducing the risk of it evolving into a pandemic phase. We must develop ambitious research programs in order to better face new health crises. The objective of the ANTIVIRESPIR program is to ambitiously resize the national Virocrib infrastructure to complement its expertise, models and logistics in order to synthesize, screen, identify and characterize innovative antivirals against infectious Respiratory virus, at risk of emergence, and which can be immediately used during a new epidemic/pandemic linked to the adaptation to humans of a new viral strain. Ideally, new antivirals should have a broad spectrum of activity by targeting different viruses from the same family or even different families and this is what this consortium will aim to identify and validate in a continuum of preclinical models in vitro and in vivo. The unique and complementary expertise of each of the teams and technological platforms involved in the ANTIVIRESPIR program is optimal for the chemical synthesis, identification, characterization and pre-clinical evaluation of new broad-spectrum antivirals capable of fighting emerging or re-emerging viral infections. This consortium includes researchers involved in phenotypic screening approaches with access to unique chemical libraries: it is composed of medicinal chemists, virologists, biologists and immunologistes expert in the development and use of pre-clinical in vitro and in vivo models. Considering the major risk of emergence of new Respiratory virus, in particular due to pollution, population increase and global warming, this program will focus on Respiratory virus represented by Coronavirus, Influenza and Pneumovirus (respiratory virus syncytial, metapneumovirus). The versatility of the consortium's resources will thus be able to respond quickly to other emerging or re-emerging viral infections caused by other viruses such as arboviruses which are classified on the PEPR-MIE priority list. To achieve these objectives, we will develop new tools for the phenotypic screening of unique chemical libraries (from ChemBioFrance and GAVO consortium's chemists). The strains will then be validated in in vitro physiological models, including bronchial air-liquid epithelia (HAE) and other stem cell-derived lung organoids (iALI), customizable and genetically modifiable. The targets of antiviral compounds will be identified by selection of resistance mutations to these compounds (direct antivirals) and by cellular transcriptomic analysis (host-targeting immunomodulators). These antiviral targets will also be characterized using a virus-like particle system to better understand the mechanisms of action of the antivirals selected on the stages from viral entry to assembly. Their effectiveness can thus be optimized by chemists, and combinations can also be considered. Finally, animal models will be optimized and used for preclinical validation of the most promising compounds with immunophenotyping. In conclusion, with the establishment of this consortium and the tools it provides, we will be able to offer a rapid intervention force in the context of new health crises linked to the emergence of viral infections.