NEWS OF THE WEEK
STRUCTURAL BIOLOGY: Different
flu antibodies interact with viral proteins similarly
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NFLUENZA VIRUSES enter cells by using spiky pro-
teins 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 hu-
man 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 receptorbinding 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. Human antibodies interact with H2 In terms of vaccines, hemagglutinin by inserting an aromatic residue the structures expand (yellow) into the sialic acid-binding pocket. 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.”—CELIA RUI XU/SCRIPPS RESEARCH INSTITUTE
NEW SCAFFOLD FOR FLU DRUGS
ARNAUD
DRUG SAFETY Report calls for a national system to track drugs throughout the supply chain Congress should give the Food & Drug Administration authority and resources to establish a mandatory track-and-trace system that provides information about where a particular drug is at any time and where it has been, a new report from the Institute of Medicine (IOM) concludes. The report comes amid increasing concerns about substandard and fake drugs, including the discovery by FDA of counterfeit batches of the cancer drug Avastin. Securing the supply chain is critical to ensuring the quality of medicine and reducing the global problem of counterfeit drugs, says Lawrence O. Gostin, chair of the IOM committee that studied the
growing threat. “The consequences of these illegitimate drugs are compromised treatment,” he says. “They may have no therapeutic active ingredient or [may have] a lower amount, they can harm patients, and in some cases they can kill.” The committee emphasizes that poorquality medicine is a worldwide problem. It calls on the World Health Organization to develop a global code of practice for drug surveillance, regulation, and law enforcement. In the U.S., the committee found that secondary wholesalers are the weakest link in the drug distribution chain. State licensing and regulation of wholesalers
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vary widely, and there is no national database on drug wholesalers. The committee urges FDA to work with states to develop such a database to prevent wholesalers from simply going to another state after they lose their license or fail to meet a particular state’s requirements. FDA Commissioner Margaret A. Hamburg welcomed the committee’s recommendations. Although previous FDA efforts to track drugs have been unsuccessful, Hamburg is optimistic she can transform FDA from a domestically focused agency into one that ensures product safety and quality in a globalized world.—BRITT ERICKSON
