De Novo Design of Lipopeptide-Based β-Sheet-Like Self-Assemblies: A Strategy to Develop Fusion Inhibitors as...

The recent surge in emerging viral infections warrants the design of broad-spectrum antivirals. We aim to develop a lead molecule that targets a common biochemical feature of many enveloped viruses, membrane fusion. To achieve the broad-spectrum ability, instead of targeting the fusion machinery, we plan to modulate the physicochemical properties of the host and viral membranes to block fusion. The approach is based on the Coronin-1 protein of Mycobacterium, which presumably inhibits the phagosome-lysosome fusion, and a unique Trp-Asp (WD) sequence is placed at the distorted β-meander motif. We designed a WD-based branched lipopeptide (Myr-D(WD)₂) that supported the intermolecular interactions to create a β-sheet-like supramolecular assembly at the membrane surface. TEM and confocal fluorescence experiments also suggest that the lipopeptide self-assembled at the bilayer interface and modulated the interfacial order and the water penetration. We demonstrated that the supramolecular organization of Myr-D(WD)₂ could block artificial membrane fusion completely and restrict pH-dependent influenza virus (H1N1, H9N2), and pH-independent mouse hepatitis virus, human coronavirus (HCoV-OC43) infections. The present study provided an evidence-based broad-spectrum antiviral potential of a designed self-assembled lipopeptide.