Meeting report: 30th International Conference on Antiviral Research, in Atlanta, GA, USA

Vere Hodge, R Anthony

The flavivirus E protein, which exists as a pre-fusion dimer on the surface of virions, attaches to the host cell through interactions with host factors on the plasma membrane. This triggers clathrin-dependent uptake of the virion. Acidification of the endosomal compartment triggers structural changes in E leading to its reorganisation and refolding as a post-fusion trimer (E 3 ). These structural changes in E bring the endosome and viral membranes in close enough proximity to fuse, leading to formation of a fusion pore through which the viral genome can escape into the cytoplasm. In this fusion process, E acts as a catalyst in that it lowers the energy barrier for membrane fusion, but it has no classical active site to which an inhibitor can be rationally targeted. In addition, although each virion has 180 copies of E (90 pre-fusion dimers) that can reorganise as 60 post-fusion trimers, it has been unclear how many of these copies of E must be bound by an inhibitor to prevent fusion. Is it possible to inhibit this process with drugs? Earlier structural studies in which pre-fusion E co-crystallised with a detergent, b-octoglucoside, identified a potential drug-binding pocket located between domains I and II. Does that give a binding location for potential inhibitors?