Novel attachment inhibitor with pan-respiratory virus activity

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. Previous research has shown that β-cyclodextrin can inhibit influenza viruses when modified to mimic sialic acid or inhibit respiratory syncytial virus (RSV) and Severe Acute Respiratory Syndrome – Coronavirus 2 (SARS-CoV-2) when mimicking heparan sulfates. Here, we report the identification of a pan-respiratory antiviral strategy based on mimicking both glycans. Starting with human parainfluenza virus 3, an important respiratory pathogen that uses both classes of 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 human parainfluenza virus 3, respiratory syncytial virus, influenza viruses, and SARS-CoV-2. In ex vivo models of human respiratory tissue, the compound retained its broad-spectrum activity against these four respiratory viruses by significantly reducing virion release at the apical surface. The antiviral activity was maintained in <i>in vivo</i> experiments, using both prophylactic and therapeutic strategies, against RSV. These findings represent a significant step forward in the development of future treatments and preventive measures for respiratory viral infections.