Biology subjects

Mathez, G.

Publications and source records attributed to Mathez, G..

3 recordsLinked to original sources

bioRxiv2025

A pan-respiratory virus attachment inhibitor with high potency in human airway models and in vivo

Respiratory viruses can cause severe infections, including bronchiolitis and pneumonia, often leading to hospitalization or death. Due to their ease of transmission, they are also scrutinized for their pandemic potential. No broad-spectrum antiviral is currently available. However most respiratory viruses use sialic acid or heparan sulfates as attachment receptors. Here, we report the identification of a pan-respiratory antiviral strategy based on mimicking both glycans. We synthesized and characterized a unique modified cyclodextrin that simultaneously mimics heparan sulfate and sialic acid. This novel compound demonstrated broad-spectrum antiviral activity against important human pathogens: parainfluenza virus 3, respiratory syncytial virus, influenza virus H1N1, SARS-CoV-2. Additionally, the compound is active against different avian strains of influenza virus, revealing its importance for pandemic preparedness. The compound retains broad- spectrum activity in ex vivo models of respiratory tissues and in vivo experiments against RSV and Influenza virus, using both prophylactic and therapeutic strategies. These findings represent a significant step forward in the development of future treatments and preventive measures for respiratory viral infections. Significance StatementFollowing the SARS-CoV-2 pandemic, Influenza A H5N1 has become widespread in poultry and has already begun to spill over into mammals, posing a potential risk for the next pandemic. Indeed, respiratory viruses represent a major threat for future global health crises. Unfortunately, there is a significant lack of broad-spectrum antivirals available for such scenarios. To address this gap, our study developed a single molecule with the capacity to inhibit a wide range of clinically relevant human respiratory viruses including avian strains of influenza virus. This antiviral demonstrated verified efficacy not only in cellular systems but also in human-derived respiratory tissues and animal models.

microbiology↗

bioRxiv2024

Enterovirus A71 adaptation to heparan sulfate comes with capsid stability tradeoff

Because of high mutation rates, viruses constantly adapt to new environments. When propagated in cell lines, certain viruses acquire positively charged amino acids on their surface proteins, enabling them to utilize negatively charged heparan sulfate (HS) as an attachment receptor. In this study, we used enterovirus A71 (EV-A71) as model and demonstrated that unlike the parental MP4 variant, the cell-adapted strong HS-binder MP4-97R/167G does not require acidification for uncoating and releases its genome in the neutral or weakly acidic environment of early endosomes. We experimentally confirmed that this pH-independent entry is not associated with the use of HS as an attachment receptor but rather with compromised capsid stability. We then extended these findings to another HS-dependent strain, suggesting that adaptation to HS generally modifies capsid stability and alters entry mechanism. Our data show EV-A71 pH-independent entry for the first time and, more importantly, highlight the intricate interplay between HS-binding, capsid stability, and viral fitness, wherein enhanced multiplication in cell lines leads to attenuation in hostile in vivo environments such as the gastrointestinal tract.

microbiology↗

bioRxiv2022

Geneticin shows selective antiviral activity against SARS-CoV-2 by targeting programmed -1 ribosomal frameshifting

SARS-CoV-2 is currently causing an unprecedented pandemic. While vaccines are massively deployed, we still lack effective large-scale antiviral therapies. In the quest for antivirals targeting conserved structures, we focused on molecules able to bind viral RNA secondary structures. Aminoglycosides are a class of antibiotics known to interact with the ribosomal RNA of both prokaryotes and eukaryotes and have previously been shown to exert antiviral activities by interacting with viral RNA. Here we show that the aminoglycoside geneticin is endowed with antiviral activity against all tested variants of SARS-CoV-2, in different cell lines and in a respiratory tissue model at non-toxic concentrations. The mechanism of action is an early inhibition of RNA replication and protein expression related to a decrease in the efficiency of the -1 programmed ribosomal frameshift (PRF) signal of SARS-CoV-2. Using in silico modelling, we have identified a potential binding site of geneticin in the pseudoknot of frameshift RNA motif. Moreover, we have selected, through virtual screening, additional RNA binding compounds, interacting with the same site with increased potency.

microbiology↗