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.