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

Abstract

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.