Molecular & Cellular Virology

Illustration depicting the different stages (entry, replication, assembly, and secretion) of the CoV and HEV life cycles.
The activities and areas of interest of both research groups are highlighted in red boxes.

Elucidating the function and regulation of the Hepatitis E Virus (HEV) replicase

As a positive single-stranded RNA virus, HEV replicates its genome by RNA-dependent RNA synthesis. To take on this essential step of its lifecycle, HEV encodes a multidomain protein, termed ORF1. The number of ORF1 domains as well as their organization and functions remain debated. Our project aims at elucidating the function and regulation of ORF1, making use of efficient cellular models to study HEV lifecycle developed in our team since 2015. Today, no specific treatment against HEV is available and the search for active molecules against this emerging virus is highly needed. We also aim at identifying new potent antiviral molecules that specifically inhibit the replication step of HEV by screening plant extracts and chemical compound libraries. Understanding the mechanisms of action of anti-replicative molecules either on the virus replicase itself or on cellular effectors that are crucial for the virus to establish its replication process is another of our essential goal.

Project leader : Cécile-Marie Aliouat-Denis

Deciphering key mechanisms of the Hepatitis E Virus (HEV) life cycle and identifying novel antiviral molecules

Hepatitis E virus (HEV) is a major cause of acute viral hepatitis worldwide. Although HEV infection is generally self-limiting, it can result in mortality rates of up to 30% in pregnant women and may progress to chronic infection in immunocompromised individuals. To date, no specific antiviral treatment or universally available vaccine exists to combat HEV infection. HEV is a quasi-enveloped, positive-sense RNA virus that expresses three open reading frames (ORFs): ORF1 encodes the viral replicase, ORF2 encodes the capsid protein, and ORF3 encodes a small protein involved in virion morphogenesis and egress. While our understanding of the HEV life cycle has significantly advanced in recent years, many fundamental aspects of HEV biology remain unresolved.

Our research program aims to elucidate key mechanisms governing the HEV life cycle and to identify novel antiviral molecules. To this end, we investigate HEV replication and assembly processes, with a particular focus on the ORF1 replicase and the biogenesis of the ORF2 capsid protein. We seek to determine how and where HEV replication complexes are formed and regulated, as well as which host cell components are exploited to create a permissive environment for viral replication. We have previously demonstrated that the ORF2 capsid protein is produced in multiple forms with distinct functions during the viral life cycle. Building on these findings, we now aim to decipher the molecular mechanisms underlying the generation of these ORF2 variants and to define their specific roles. In parallel, we are developing molecular tools to study viral proteins and are conducting antiviral screens using plant extracts and chemical compound libraries to identify new inhibitors of HEV replication.

Project leader : Laurence Cocquerel

Understanding viral replication through the identification of new targets for bio-inspired antivirals

Our goal is to better understand the replication mechanisms of coronaviruses by identifying new antiviral drugs of natural origin. Few naturally occurring molecules, whose structures are structurally unique and more complex than synthetic molecules, have been studied for their antiviral properties. In recent years, however, there has been growing interest in natural molecules as a source of inspiration for drug design. We hypothesize that, due to their unique structures, they could inhibit viral infection and reveal as yet unidentified viral or cellular factors. Our previous work on the hepatitis C virus has led to the identification of new natural inhibitors, including EGCG, delphinidin, and dehydrojuncusol, and we have been able to determine their mechanisms of action (Calland et al Hepathology 2012; Calland et al. J. Virol 2015; Sahuc et al. J. Virol 2019). Our more recent work on human coronaviruses (HCoVs) has also led to the identification of a natural antiviral with photodependent virucidal activity, pheophorbide A (Meunier et al. AAC 2022) and a new replication inhibitor, hyperforin, from St John’s wort (Raczkiewicz et al. Front. Microbiol 2024).
The current projects are focused on a new series of natural molecules, prenylated derivatives of phloroglucinol, that are new coronavirus replication inhibitors. These interdisciplinary projects in collaboration with Pr Céline Rivière (phytochemist, UMRt BioEcoAgro Univ. Lille), and Dr Mourad Elhabiri (medicinal chemist, LIMA UMR 7042, Strasbourg) aim to :

• Determine the mechanism of action and identify viral or cellular targets of these new compounds to get insight in coronavirus replication pathway.
• Establish preclinical studies in different models to be able to propose these new compounds for future coronavirus therapy.

Project leader : Karin Séron