SKELETON KEY MAY DEFUSE FLU STRUCTURAL BIOLOGY: Antibodies
bind a flu protein nook common to many viral strains
A
FAMILY OF ANTIBODIES neutralizes multiple
types of flu by targeting a weak spot in the virus, according to a pair of studies. The discovery could point the way to treatments that shield people from both seasonal and pandemic flu. Every new year brings a new flu season and a new flu vaccine to go with it. Flu vaccines are developed by predicting which types of flu will dominate the coming season, structural biologist Ian A. Wilson of the Scripps Research Institute says. “If anything different comes along, the vaccine won’t be as effective,” he says. Most vaccines elicit antibodies to hemagglutinin, a protein on the virus’s surface. But the region of hemagglutinin that the antibodies target mutates rapidly, allowing viruses to elude human immune systems. Now, independent teams led by Wilson and Wayne A. Marasco of the Dana-Farber Cancer Institute, in Boston, have found antibodies targeting a portion of hemagglutinin that is less variable and is consistent in many types of flu. Each team started with a library containing large numbers of antibodies compiled from human volunteers. Marasco’s library was built in-house, whereas Wilson collaborated with Dutch biotechnology company Crucell. They fished out antibodies of interest by using avian flu hemagglutinin as their lure. With Ruben O. Donis of the Centers for Disease Control & Prevention, Marasco found that his handful of hits suppressed disparate types of flu in mice, a finding replicated by Wilson’s team.
The antibodies are versatile because they don’t interact with hemagglutinin’s variable region. Two other groups found similar antibodies last year, but they didn’t unambiguously describe their mechanism of action. Now, to get at the mechanism, Marasco and Dana-Farber colleague Jianhua Sui teamed with Robert C. Liddington and William C. Hwang of the Burnham Institute for Medical Research, in La Jolla, Calif., to obtain a crystal structure of an antibody bound to avian flu hemagglutinin (Nat. Struct. Mol. Biol., DOI: 10.1038/nsmb.1566). Independently, Wilson and Damian C. Ekiert obtained that structure, as well as one of an antibody bound to hemagglutinin from the 1918 epidemic flu (Science, DOI: 10.1126/science.1171491). In every structure, the antibody targets the same pocket, which is in the stem of hemagglutinin rather than its variable head. The stem pocket is conserved because it is involved in a conformational change that’s crucial for viral infection, Wilson says. With an antibody bound in this pocket, hemagglutinin can no longer change its shape, a step required before the virus can fuse with a cell and send in its genetic material. Physicians might someday be able to inject this type of antibody into people infected with the flu, or the stem pocket could be used to make a new vaccine that doesn’t need retooling every year, Marasco says. “Hopefully, these works will provide a starting point for rational vaccine design and ultimately improve the therapeutic treatment of influenza,” says Zihe Rao, an expert in crystallography of flu proteins at Tsinghua University, in Beijing.— MORE ONLINE CARMEN DRAHL
WILLIA M HWA NG
NEWS O F TH E W E E K
In this X-ray structure, an antibody (red) binds to a conserved pocket in each of three copies (blue, yellow, and green) of avian flu hemagglutinin.
ACQUISITIONS Pursuer becomes the pursued in fertilizer takeover drama CF Industries’ plan to acquire U.S. fertilizer industry rival Terra Industries has run into a snag. Last week, Agrium, a Canadian fertilizer company, announced that it wants to acquire CF. The competing bids highlight an urge to merge in fertilizers, one of the only segments of the chemical industry that has been doing well lately. Whereas big chemical makers posted earnings declines or even losses in the fourth quarter of 2008, CF and Terra both reported big gains (C&EN, Feb. 23, page 35). The fertilizer saga started in January, when CF disclosed an unsolicited
offer to acquire Terra for $2.1 billion. It said the combination would create the world’s largest producer of nitrogenbased fertilizers (C&EN, Jan. 26, page 8). Terra soon rejected the bid, calling it inadequate. On Monday, Feb. 23, CF announced that it was formally launching the offer and taking steps to replace Terra directors at the company’s upcoming annual meeting. Two days later, Agrium revealed its bid for CF. Agrium offered to pay $72.00 per share, or $3.6 billion, a 30% premium over CF’s closing stock price on the previous day.
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According to a letter that Agrium CEO Michael M. Wilson sent to CF shareholders, the offer is contingent on CF terminating its bid for Terra. CF later put out a press release saying it would evaluate the deal in light of its own plans, including its planned acquisition of Terra. In a conference call hosted by Agrium after its announcement, a stock analyst asked Wilson whether he’d try to acquire the enlarged CF if the bid for Terra goes through. Wilson declined to contemplate that turn of events. “We are interested in CF, so it’s hard to respond to a hypothetical case,” he said.—MICHAEL MCCOY
