New Starting Point For Flu Drug Design

Influenza viruses enter cells by using spiky proteins called hemagglutinins to bind with cell-surface receptors that are tipped with sialic acid. Blocking this interaction is an obvious strategy for flu therapies, and many drug discovery efforts start with a sialic acid scaffold to block the hemagglutinin binding pocket. The problem: Sialic acid is a lousy binder.

What’s needed is a different starting point. New structures of human antibody fragments bound to H2N2 flu virus, a type of Asian flu, could point the way to new scaffolds. (The H and N stand for hemagglutinin and neuraminidase, respectively, and the numbers determine the virus subtype.)

“In the circle of influenza aficionados, the H2N2 subtype is considered to be a dormant giant,” says Wayne A. Marasco, an influenza researcher and professor of medicine at Dana-Farber Cancer Institute and Harvard Medical School, who was not involved with the current structure study. The Asian flu virus, which caused a 1957 pandemic, stopped circulating in humans in the late 1960s but continues to reside in birds and pigs. Scientists worry that it could jump from animals back to humans, sparking another pandemic.

Structural biologist Ian A. Wilson of Scripps Research Institute, immunologist James E. Crowe Jr. of Vanderbilt University, and coworkers have now solved crystal structures of H2 hemagglutinin complexed with the antigen-binding fragment of three human antibodies that neutralize the 1957 Asian flu virus (Nat. Struct. Mol. Biol., DOI: 10.1038/nsmb.2500).

“Even though the antibodies approach from different directions and have completely different sequences, they’re actually finding commonality in the way they interact with the receptor-binding site,” Wilson says.

In each case, the antibody inserts an aromatic ring into a hydrophobic pocket in the receptor-binding site. The aromatic ring interacts with a tryptophan residue in the site via π-π stacking. The researchers also showed that hemagglutinin mutations that enable the virus to evade the antibodies greatly reduce the protein’s ability to bind sialic acid.

The work shows that the hemagglutinin receptor-binding site is “an important mold for drug engineers in their search for new scaffolds for small-molecule drug design,” Marasco says. In terms of vaccines, the structures expand the map of binding sequences that neutralize hemagglutinin and “can serve as a blueprint for novel antigens and as a measure to characterize and judge antibody responses to future H2N2 vaccines.”