Abstract
We previously described fusion-inhibitory peptides that are targeted to the cell membrane by cholesterol conjugation and potently inhibit enveloped viruses that fuse at the cell surface, including HIV, parainfluenza, and henipaviruses. However, for viruses that fuse inside of intracellular compartments, fusion-inhibitory peptides have exhibited very low antiviral activity. We propose that for these viruses, too, membrane targeting via cholesterol conjugation may yield potent compounds. Here we compare the activity of fusion-inhibitory peptides derived from the influenza hemagglutinin (HA) and show that although the unconjugated peptides are inactive, the cholesterol-conjugated compounds are effective inhibitors of infectivity and membrane fusion. We hypothesize that the cholesterol moiety, by localizing the peptides to the target cell membrane, allows the peptides to follow the virus to the intracellular site of fusion. The cholesterol-conjugated peptides trap HA in a transient intermediate state after fusion is triggered but before completion of the refolding steps that drive the merging of the viral and cellular membranes. These results provide proof of concept for an antiviral strategy that is applicable to intracellularly fusing viruses, including known and emerging viral pathogens.
Highlights
Growing resistance to influenza antivirals calls for novel therapeutics
We have suggested previously that cholesterol conjugation of antiviral peptides could be useful for viruses that fuse in the endosomal compartment, including influenza virus, by endowing the inhibitory peptides with the ability to be trafficked, along with virus, to the intracellular sites of membrane fusion [8]
Viruses such as influenza that fuse in intracellular compartments have been considered a difficult target for fusion inhibitors because the peptide needs to be internalized into host cells to have access to transient intermediate conformations of the viral fusion proteins, which become populated only following cell entry [21, 40]
Summary
Growing resistance to influenza antivirals calls for novel therapeutics. Results: Cholesterol conjugates of HA-derived peptides inhibit influenza infection. The cholesterol-conjugated peptides trap HA in a transient intermediate state after fusion is triggered but before completion of the refolding steps that drive the merging of the viral and cellular membranes These results provide proof of concept for an antiviral strategy that is applicable to intracellularly fusing viruses, including known and emerging viral pathogens. We showed that cholesterol-conjugated, membrane-targeted peptides derived from the fusion protein of enveloped viruses are potent inhibitors of infection and gain improved pharmacokinetic properties. We demonstrate that a cholesterol-conjugated peptide derived from the influenza virus HA, the receptor binding/fusion protein, inhibits influenza infection This targeted peptide traps HA in a transient intermediate state, preventing the progression of fusion
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