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NAT. STRUCT. MOL. BIOL.
which has also been implicated in Alzheimer’s. Previously reported Aβ-40 fibrils are U-shaped with parallel β-sheets connected by a flexible loop. In contrast, this particular Aβ-42 fibril contains three connected β-sheets that adopt an S-shaped configuration. Different interactions stabilize the Aβ-40 and Aβ-42 structures. The shorter peptide is held together by a salt bridge between lysine 28 and aspartic acid 23. Instead of that interaction, Aβ-42 forms a salt bridge between lysine 28 and alanine 42, a residue that doesn’t exist on the shorter peptide. Previous structural studies by Robert Tycko at the National Institutes of Health and others have shown that amyloid-β fibrils having a given sequence can adopt multiple structures with subtle differences in configuration. The new work is important, Tycko says, “because it demonstrates that conformational variations in amyloid-β fibrils can be dramatic.” In addition, the study suggests an explanation for why fibrils formed by Aβ-40 and Aβ-42 don’t “cross-seed,” or trigger one another to form fibrils, he says. “It remains to be seen whether the fibril structure described in this paper exists in human brain tissue,” he notes. If the structure is found in the brain, drugs that have already been designed to optimally obstruct an arched β-motif in Aβ-40 may not work as well against Alzheimer’s, which might be caused by the more toxic Aβ-42 fibrils, Ishii and coworkers say.—CELIA ARNAUD
WIKIMEDIA COMMONS
AMYLOID FIBRIL’S UNUSUAL STRUCTURE
the launch of Zarxio would undermine the value of its patents. Novartis did not provide Amgen with the information it needs to determine whether Zarxio infringes on its patents, asserts the maker of Neupogen. Amgen is cheering the decision by the U.S. Court of Appeals for the Federal Circuit granting the company’s request for a preliminary injunction that prevents the sale of Zarxio. Novartis, on the other hand, says it hopes for a prompt resolution to the case so that it can begin selling Zarxio in the U.S. soon. As part of the litigation, Novartis previously had agreed to delay the launch of Zarxio sales until May 11. The new ruling pushes back the U.S. debut of the biosimilar until at least June 3, when the court hears oral arguments in the case. The litigation is being closely watched because its outcome will likely shape the future of the biosimilars market in the U.S. In March, Zarxio became the first biosimilar to successfully navigate the Food & Drug Administration’s new abbreviated approval process for biosimilars. FDA is reviewing at least four more applications for other biosimilar drugs. Biosimilars have the potential to increase patients’ access to drugs that are prescribed less often because of their high prices, according to Louis M. Weiner, director of the Lombardi Comprehensive Cancer Center at Georgetown University. “The approval of Zarxio may reduce costs to the health care system,” he said when FDA approved the drug in March.—BRITT ERICKSON
STRUCTURAL BIOLOGY: Alzheimer’s-
related fibril has S-shaped configuration, study finds
Amyloid β-42’s unusual tripleβ-motif is held together by a salt bridge between lysine 28 and alanine 42.
ANY SCIENTISTS BELIEVE that plaques made of amyloid peptide contribute to brain degeneration in people with Alzheimer’s disease. Moreover, fibrils of a 42-amino-acid fragment of this peptide are increasingly thought to be the main culprits in triggering plaque formation. But structural information about these fibrils has been hard to come by because they are heterogeneous. Yoshitaka Ishii of the University of Illinois, Chicago, and coworkers now report generating a homogeneous Aβ-42 fibril in vitro and obtaining a model of its structure with solid-state nuclear magnetic resonance spectroscopy (Nat. Struct. Mol. Biol. 2015, DOI: 10.1038/ nsmb.2991). The structure differs significantly from that of Aβ-40, Aβ-42’s shorter and more abundant sibling,
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BIOSIMILAR SALES DELAYED PHARMACEUTICALS: Litigation
between two drugmakers delays U.S. launch of Zarxio
S Amgen is suing to keep Novartis’s biosimilar version of Neupogen off the U.S. market.
ALES OF THE FIRST generic-like version of a
biological drug, or biosimilar, in the U.S. are on hold until a lawsuit between rival companies can be resolved. In a case filed by Amgen, a federal appeals court earlier this month temporarily blocked Novartis’s Sandoz from selling a biosimilar called Zarxio. It is a less expensive alternative to Amgen’s Neupogen (filgrastim), a blockbuster drug prescribed to prevent infections in cancer patients. Amgen is fighting to keep Zarxio off the U.S. market, claiming that sales of the knockoff drug would erode the price of Neupogen and cause other irreparable and immediate harms. In its lawsuit, Amgen argues that CEN.ACS.ORG
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