Synthetic heparan sulfate mimics based on chitosan derivatives show broad-spectrum antiviral activity
Julia Revuelta, Luciana Rusu, Clara Francés‐Gómez, Elena Trapero, Susana Iglesias, Eva Calvo Pinilla, Ana-Belén Blázquez, Alfonso Gutiérrez‐Adán, Acsah Konuparamban, Óscar Moreno, María Gómez Martínez, Alicia Forcada‐Nadal, Maria Lopez-Redondo, Ana Isabel Avilés‐Alía, IBV-Covid19-Pipeline, Nadine Gougeard, Clara Marco‐Marín, Anmol Adhav, Carolina Espinosa, María del Pilar Hernández-Sierra, Francisco del Caño‐Ochoa, Roberto Gozalbo‐Rovira, Santiago Ramón‐Maiques, Jerónimo Bravo, Vicente Rubio, Alberto Marina, J.L. Llacer, Jordi Llop, Miguel A. Martín-Acebes, Ron Geller, Alfonso Fernández‐Mayoralas
Abstract
Enveloped viruses enter cells by binding to receptors present on host cell membranes, which trigger internalization and membrane fusion. For many viruses, this either directly or indirectly involves interaction with membrane-anchored carbohydrates, such as heparan sulfate, providing a potential target for a broad-spectrum antiviral approach. Based on this hypothesis, we screened a library of functionalized chitosan sulfates that mimic heparan sulfate in cellular membranes for inhibition of SARS-CoV-2 and respiratory syncytial virus (RSV) entry. An array of compounds blocking SARS-CoV-2 and RSV were identified, with the lead compound displaying broad-spectrum activity against multiple viral strains and clinical isolates. Mechanism of action studies showed the drug to block viral entry irreversibly, likely via a virucidal mechanism. Importantly, the drug was non-toxic in vivo and showed potent post-exposure therapeutic activity against both SARS-CoV-2 and RSV. Together, these results highlight the potential of functionalized carbohydrates as broad-spectrum antivirals targeting respiratory viruses.