1 Viral entry inhibitors targeted to the membrane site of action

Fusion of enveloped viruses with the host cell is driven by specialized fusion proteins to initiate infection. The “class I ” fusion proteins harbor two regions, typically two heptad repeat (HR) domains, which are central to the complex conformational changes leading to fusion: the first heptad repeat (HRN) is adjacent to the fusion peptide, while the second (HRC) immediately precedes the transmembrane domain. Peptides derived from the HR regions can inhibit fusion, and one HR peptide, T20 (enfuvirtide), is in clinical use for HIV-1. For paramyxoviruses, the activity of two membrane proteins, the receptor-binding protein (hemagglutinin-neuraminidase; HN, or G) and the fusion protein (F), initiates viral entry. Binding of HN or G to its receptor on a target cell triggers activation of F, which then inserts into the target cell and mediates the membrane fusion that initiates infection. We have shown for paramyxoviruses, that the inhibitory efficacy of HR peptides is inversely proportional to the rate of F activation. For HIV-1, the antiviral potency of an HRC-derived peptide can b