Tag Archives: membrane fusion

Locking Viruses into Endosomes – An Advancement in Influenza Therapeutics

Contributed by Guest Blogger: E. Cesanek ’13

Enveloped viruses have developed a clever technique to enter host cells and release viral genome into the cell for replication. In order to enter the cell, a virus particle takes advantage of the endosomal transport system, in which large particles bud into the cell after being enclosed by a section of the cell’s lipid membrane. Then, the acidic environment of the endosome provides the cellular energy needed to fuse the viral membrane. This process requires energy because it involves changing the conformation of the viral membrane to bend it towards the lipid membrane enclosing it. Clearly, membrane fusion is an essential part of the viral life cycle as it is the only way viral genome can be released into the host cell.
As a result, lots of recent research has been directed at identifying molecules that effectively inhibit membrane fusion. A crystallography study has helped to elucidate the mechanism by which tert-butyl hydroquinone (TBHQ), a small molecular compound that binds to influenza HA envelope protein, inhibits membrane fusion and reduces viral infectivity. Unfortunately, TBHQ only works on influenza group 2 subtypes (e.g., H3 or H14), which have a special hydrophobic binding pocket for the molecule. Once there, TBHQ works as a kind of “molecular glue,” stabilizing the structural conformation of the HA envelope protein. As a result, the amount of energy required for membrane fusion is increased to the point that HA is unresponsive to the acidic environment of the endosome.
The findings of this study may provide a framework for structural design of effective membrane fusion inhibitors for use as therapeutics against enveloped viruses. Molecular compounds that are structurally similar to TBHQ are both easier to synthesize and have more drug-like chemical properties than other types of membrane fusion inhibitors (e.g., enfurvirtide, an HIV-1 membrane fusion inhibitor).
However, it is important to remember that the TBHQ binding site is only one possibility for such conformation-locking molecules. Further research should explore alternative sites, and also explore the problem of viral resistance developing against TBHQ inhibition of membrane fusion.