The rapid rise in the number of emerging and re-emerging infectious diseases due to viral pathogens underscores the need for therapeutic approaches that target large classes of viruses using single drugs. To be effective, such “one for many” broad-spectrum antivirals must either interfere with the shared steps of biophysical or biochemical processes of viral entry (i.e., fusion inhibiting mechanisms)2,3 or disable disparate virions by targeting their common structural components (i.e., virocidal mechanisms). To this end, one obvious target is the lipid bilayer component of the viral envelope. Although derived from the host cell, the viral membrane differs from cellular membranes in many physical-chemical properties including chemical composition, curvature, and lateral fluidity as well as the absence of biogenic reparative capacity. These attributes are shared across a variety of different viruses rendering the viral membrane a discrete and susceptible target for developing broad-spectrum antivirals. Specifically, antiviral drug candidates can be designed that selectively alter the nanometer-scale viral envelope – without harming the larger host cell membrane –destabilizing its structural integrity and/or disrupting the ability of the virus to enter the host cell. This talk presents broad-spectrum antiviral potential of two distinctly different classes of membrane-active antiviral drug candidates. First, using model membranes we show how a peptide derived from the hepatitis C virus nonstructural protein NS5A, acquires a broad-spectrum virocidal activity by disrupting model viral membranes in a size- and composition-dependent manner. Second, we demonstrate the ability of a a class of synthetic membrane-active amphiphiles in stabilizing positive curvatures, which inhibit viral entry.

Mechanisms of broad-spectrum antiviral activities of membrane-active molecules targeting enveloped viruses

255th National Meeting (2018)

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