Design of Flavonoid‐Based Lipid Domains as Fusion Inhibitors to Efficiently Block Coronavirus and Other Enveloped Virus Infection

Abstract Developing a broad‐spectrum antiviral is imperative in light of the recent emergence of recurring viral infections. The critical role of host‐virus attachment and membrane fusion during enveloped virus entry is a suitable target for developing broad‐spectrum antivirals. A new class of flavonoid‐based fusion inhibitors are designed to alter the membrane's physical properties. These flavonoid‐based molecules (MFDA; myristoyl flavonoid di‐aspartic acid) are self‐assembled in the membrane, creating distinct nanodomains and effectively inhibiting membrane fusion by modulating the membrane's interfacial properties. The broad‐spectrum antiviral efficacy of these compounds are established in effectively blocking the entry of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS‐CoV‐2), Type A Influenza, Human coronavirus OC43 (HCoV‐OC43), and Vesicular stomatitis virus (VSV). A slightly more effectivity of MFDA in coronavirus infection than other enveloped viruses may be attributed to its secondary interaction with the receptor binding domain (RBD) of the SARS‐CoV‐2 spike protein. A membrane nanodomain formation strategy is highlighted with natural‐product‐based fusion inhibitors, effectively thwarting the infection of several enveloped viruses, entailing their broad‐spectrum antiviral functionality.