Development of succinate-based analogues and formulations against influenza virus infection

Introduction

One of the top global causes of death worldwide is respiratory viral infections. Among these, influenza virus-related infections cause deadly epidemics and pandemics. Each year, seasonal influenza infects more than 1 billion people (i.e. ∼20% of the world's population) and results in approximately 500,000 deaths. Vaccination efficacy can be impaired by viral intrinsic antigenic drift and the efficiency of drugs targeting directly influenza viruses is largely disputed. Hence, the development of innovative options is required to better treat influenza. In that regard, we recently demonstrated the antiviral activity of succinate (EMBO J., 2022) as well as of “C2”, two host metabolites. In this project, our objectives are to synthesize succinate-derived drugs against influenza viruses, select the best candidates and test them in vitro and in vivo, and finally formulate them into dry powders for direct lung delivery.

Methods

A series of compounds are synthesized by a structure-activity relationship strategy. Various chemical modifications will be introduced in the “hit” compound in the aim to identify analogues with high activity and good druggability.

Results

A preliminary screening of a short series of commercially available analogues using human bronchial epithelial cells led to the identification of three new active compounds (coined “S1”, “S10” and “S11”). All have an antiviral and anti-inflammatory effect more potent than the natural metabolites succinate and C2. In an in vivo model of influenza pneumonia, mice treated at day 2 post-infection with these analogues resisted better than non-treated or C2-treated animals to a lethal dose of influenza virus (survival rate: 85%, 0%, and 50% respectively).

Conclusion

Our study will pave the way for the development of appropriate “drug-and-devices” that will help to administer these succinate analogues directly into the respiratory tract. This project is funded through an ANR program.