Inhibition of Membrane Fusion as a Target for Antiviral Therapy

Entry of enveloped viruses into cells is initiated by virus binding to a target cell receptor. Subsequent conformational changes in the viral envelope proteins are triggered either by receptor binding or by the low pH of the endosome, depending on the virus family, and facilitate fusion, or merging of the viral and host cell membranes. This allows transfer of the viral genome into the target cell, initiating a new infectious cycle. Inhibitors of viral entry constitute a novel class of antivirals that target discrete steps of this process. Although long-studied for their antiviral potential, entry inhibitors have only recently been brought to market with the licensing of the first-in-class HIV fusion inhibitor T-20 (enfuvirtide, Fuzeon). Entry inhibitors are currently in development against major human and animal pathogens such as HIV, SARS coronavirus, and members of the paramyxovirus family including, amongst others, measles, respiratory syncytial virus (RSV), and Nipah virus. This antiviral class includes antibodies, peptides, and non-peptidic small molecules that act on different steps of the entry process. This review will concentrate on peptidic and non-peptidic inhibitors of viral entry, and describe their mechanisms of action and current development status. Particular emphasis will be given to the development of peptidic and small molecule inhibitors of membrane fusion.